ArticleLiterature Review

New therapeutic opportunities for 5-HT2C receptor ligands in neuropsychiatric disorders

January 2016
Pharmacology & Therapeutics 157(3):125-162

DOI:10.1016/j.pharmthera.2015.11.009

Authors:

Giuseppe Di Giovanni

Magna Graecia University

Philippe De Deurwaerdère

University of Bordeaux

Lateral Habenula 5-HT2C Receptor Function Is Altered by Acute and Chronic Nicotine Exposures

Article

Full-text available

Apr 2021
INT J MOL SCI

Serotonin (5-HT) is important in some nicotine actions in the CNS. Among all the 5-HT receptors (5-HTRs), the 5-HT2CR has emerged as a promising drug target for smoking cessation. The 5-HT2CRs within the lateral habenula (LHb) may be crucial for nicotine addiction. Here we showed that after acute nicotine tartrate (2 mg/kg, i.p.) exposure, the 5-HT2CR agonist Ro 60-0175 (5–640 µg/kg, i.v.) increased the electrical activity of 42% of the LHb recorded neurons in vivo in rats. Conversely, after chronic nicotine treatment (6 mg/kg/day, i.p., for 14 days), Ro 60-0175 was incapable of affecting the LHb neuronal discharge. Moreover, acute nicotine exposure increased the 5-HT2CR-immunoreactive (IR) area while decreasing the number of 5-HT2CR-IR neurons in the LHb. On the other hand, chronic nicotine increased both the 5-HT2CR-IR area and 5-HT2CR-IR LHb neurons in the LHb. Western blot analysis confirmed these findings and further revealed an increase of 5-HT2CR expression in the medial prefrontal cortex after chronic nicotine exposure not detected by the immunohistochemistry. Altogether, these data show that acute and chronic nicotine exposure differentially affect the central 5-HT2CR function mainly in the LHb and this may be relevant in nicotine addiction and its treatment.

A Subset of Purposeless Oral Movements Triggered by Dopaminergic Agonists Is Modulated by 5-HT2C Receptors in Rats: Implication of the Subthalamic Nucleus

Article

Full-text available

Nov 2020
INT J MOL SCI

Dopaminergic medication for Parkinson's disease is associated with troubling dystonia and dyskinesia and, in rodents, dopaminergic agonists likewise induce a variety of orofacial motor responses, certain of which are mimicked by serotonin2C (5-HT 2C) receptor agonists. However, the neural substrates underlying these communalities and their interrelationship remain unclear. In Sprague-Dawley rats, the dopaminergic agonist, apomorphine (0.03-0.3 mg/kg) and the preferential D2/3 receptor agonist quinpirole (0.2-0.5 mg/kg), induced purposeless oral movements (chewing, jaw tremor, tongue darting). The 5-HT 2C receptor antagonist 5-methyl-1-[[2-[(2-methyl-3-pyridyl)oxyl]-5-pyridyl]carbamoyl]-6-trifluoromethylindone (SB 243213) (1 mg/kg) reduced the oral responses elicited by specific doses of both agonists (0.1 mg/kg apomorphine; 0.5 mg/kg quinpirole). After having confirmed that the oral bouts induced by quinpirole 0.5 mg/kg were blocked by another 5-HT 2C antagonist (6-chloro-5-methyl-1-[6-(2-methylpiridin-3-yloxy)pyridine-3-yl carbamoyl] indoline (SB 242084), 1 mg/kg), we mapped the changes in neuronal activity in numerous sub-territories of the basal ganglia using c-Fos expression. We found a marked increase of c-Fos expression in the subthalamic nucleus (STN) in combining quinpirole (0.5 mg/kg) with either SB 243213 or SB 242084. In a parallel set of electrophysiological experiments, the same combination of SB 243213/quinpirole produced an irregular pattern of discharge and an increase in the firing rate of STN neurons. Finally, it was shown that upon the electrical stimulation of the anterior cingulate cortex, quinpirole (0.5 mg/kg) increased the response of substantia nigra pars reticulata neurons corresponding to activation of the "hyperdirect" (cortico-subthalamonigral) pathway. This effect of quinpirole was abolished by the two 5-HT 2C antagonists. Collectively, these results suggest that induction of orofacial motor responses by D2/3 receptor stimulation involves 5-HT 2C receptor-mediated activation of the STN by recruitment of the hyperdirect (cortico-subthalamonigral) pathway.

A Subset of Purposeless Oral Movements Triggered by Dopaminergic Agonists Is Modulated by 5-HT2C Receptors in Rats: Implication of the Subthalamic Nucleus

Article

Full-text available

Nov 2020
INT J MOL SCI

Dopaminergic medication for Parkinson’s disease is associated with troubling dystonia and dyskinesia and, in rodents, dopaminergic agonists likewise induce a variety of orofacial motor responses, certain of which are mimicked by serotonin2C (5-HT2C) receptor agonists. However, the neural substrates underlying these communalities and their interrelationship remain unclear. In Sprague-Dawley rats, the dopaminergic agonist, apomorphine (0.03–0.3 mg/kg) and the preferential D2/3 receptor agonist quinpirole (0.2–0.5 mg/kg), induced purposeless oral movements (chewing, jaw tremor, tongue darting). The 5-HT2C receptor antagonist 5-methyl-1-[[2-[(2-methyl-3-pyridyl)oxyl]-5-pyridyl]carbamoyl]-6-trifluoromethylindone (SB 243213) (1 mg/kg) reduced the oral responses elicited by specific doses of both agonists (0.1 mg/kg apomorphine; 0.5 mg/kg quinpirole). After having confirmed that the oral bouts induced by quinpirole 0.5 mg/kg were blocked by another 5-HT2C antagonist (6-chloro-5-methyl-1-[6-(2-methylpiridin-3-yloxy)pyridine-3-yl carbamoyl] indoline (SB 242084), 1 mg/kg), we mapped the changes in neuronal activity in numerous sub-territories of the basal ganglia using c-Fos expression. We found a marked increase of c-Fos expression in the subthalamic nucleus (STN) in combining quinpirole (0.5 mg/kg) with either SB 243213 or SB 242084. In a parallel set of electrophysiological experiments, the same combination of SB 243213/quinpirole produced an irregular pattern of discharge and an increase in the firing rate of STN neurons. Finally, it was shown that upon the electrical stimulation of the anterior cingulate cortex, quinpirole (0.5 mg/kg) increased the response of substantia nigra pars reticulata neurons corresponding to activation of the “hyperdirect” (cortico-subthalamonigral) pathway. This effect of quinpirole was abolished by the two 5-HT2C antagonists. Collectively, these results suggest that induction of orofacial motor responses by D2/3 receptor stimulation involves 5-HT2C receptor-mediated activation of the STN by recruitment of the hyperdirect (cortico-subthalamonigral) pathway.

In Silico Study of the 5-Hydroxytryptamine-2C Receptor Antagonist Activity of Anthocyanins as Antidepressant Therapy

Article

Full-text available

May 2023

This study aimed to evaluate the drug-likeness, pharmacokinetic and safety prediction of six types of anthocyanins (ANC) as well as virtual molecular interaction between ANC and 5-hydroxytryptamine-2C (5HT-2C) receptor for antagonist target of antidepressant drug development. The Lipinski rule of five was used to predict the oral drug-likeness of ANC. The pharmacokinetic and safety prediction was analyzed with a free accessible web server. The ligands of ANC were retrieved from PubChem National Centre for Biotechnology Information (NCBI) database. The protein of the 5HT-2C receptor was obtained from Protein Data Bank. Molecular docking was performed by PyRx software and visualized using Discovery Studio Software. The results showed ANC is proposed as an oral drug candidate. The pharmacokinetic prediction of ANC was demonstrated to have high absorption in the intestinal route, solubility in the aqueous phase, capability to evade hepatic first-pass metabolism and high total clearance from the kidney. Virtual toxicity prediction showed a higher threshold of chronic lethal dose than control with no toxicity on the salmonella typhimurium reverses mutation assay (AMES) test, liver, and skin. Molecular prediction found ANC type of delphinidin has the most similar interaction site with the control antagonist ligand on the 5HT-2C receptor which is facilitated with hydrogen bonds and hydrophobic bonds at amino residues of Trp324, Phe328, Ala222 and Val135. We concluded ANC particularly delphinidin is proposed as an oral drug candidate potentially used as a 5HT-2C receptor antagonist and thus, further in vitro and in vivo studies are necessary to confirm the effect on antidepressant activity.

Sonochemical synthesis and biological evaluation of isoquinolin-1(2H)-one/isoindolin-1-one derivatives: Discovery of a positive ago-allosteric modulator (PAAM) of 5HT2CR

Article

Dec 2022
BIOORG CHEM

Efforts have been devoted for the discovery and development of positive allosteric modulators (PAMs) of 5-HT2CR because of their potential advantages over the orthosteric agonist like Lorcaserin that was withdrawn from the market. On the other hand, pursuing a positive ago-allosteric modulator (PAAM) is considered as beneficial particularly when an agonist is not capable of affecting the potency of the endogenous agonist sufficiently. In search of a suitable PAAM of 5-HT2CR we adopted an in silico based approach that indicated the potential of the 3-(1-hydroxycycloalkyl) substituted isoquinolin-1-one derivatives against the 5-HT2CR as majority of these molecules interacted with the site other than that of Lorcaserin with superior docking scores. These compounds along with the regioisomeric 3-methyleneisoindolin-1-one derivatives were prepared via the Cu(OAc)2 catalyzed coupling of 2-iodobenzamide with 1-ethynylcycloalkanol under ultrasound irradiation. According to the in vitro studies, most of these compounds were not only found to be potent and selective agonists but also emerged as PAAM of 5-HT2CR whereas Lorcaserin did not show PAAM activities. According to the SAR study the isoquinolin-1(2H)-ones appeared as better PAAM than isoindolin-1-ones whereas the presence of hydroxyl group appeared to be crucial for the activity. With the potent PAAM activity for 5-HT2CR (EC50 = 1 nM) and 107 and 86-fold selectivity towards 5-HT2C over 5-HT2A and 5-HT2B the compound 4i was identified as a hit molecule. The compound showed good stability in male BALB/c mice brain homogenate (∼85 % remaining after 2 h), moderate stability in the presence of rat liver microsomes (42 % remaining after 1 h) and acceptable PK properties with fast reaching in the brain maintaining ∼ 1:1 brain/plasma concentration ratio. The compound at a dose of 50 mg/kg exhibited decreased trend in the food intake starting from day 3 in S.D. rats, which reached significant by 5th day, and the effect was comparable to Lorcaserin (10 mg/kg) on day 5. Thus, being the first example of PAAM of 5-HT2CR the compound 4i is of further medicinal interest.

Deleting Snord115 genes in mice remodels monoaminergic systems activity in the brain toward cortico-subcortical imbalances

Article

Aug 2022

The neuronal-specific SNORD115 has gathered interest because its deficiency may contribute to the pathophysiology of Prader-Willi syndrome (PWS), possibly by altering post-transcriptional regulation of the gene encoding the serotonin (HTR2C) receptor. Yet, Snord115-KO mice do not resume the main symptoms of PWS and only subtle altered A-to-I RNA editing of Htr2c mRNAs were uncovered. Because HTR2C signaling fine-tunes the activity of monoaminergic neurons, we addressed the hypothesis that lack of Snord115 alters monoaminergic systems. We first showed that Snord115 was expressed in both monoaminergic and non-monoaminergic cells of the ventral tegmental area (VTA) and the dorsal raphe nucleus (DRN) harboring cell bodies of dopaminergic and serotonergic neurons, respectively. Measuring the tissue level of monoamines and metabolites, we found very few differences except that the content of homovanillic acid—a metabolite of dopamine—was decreased in the orbitofrontal and prefrontal cortex of Snord115-KO mice. The latter effects were, however, associated with a few changes of monoamine tissue content connectivity across the 12 sampled brain regions. Using in vivo single cell extracellular recordings, we reported that the firing rate of VTA dopaminergic neurons and DRN serotonergic neurons was significantly increased in Snord115-KO mice. These neural circuit dysfunctions were not, however, associated with apparent defects in binge eating, conditioned place preference to cocaine, cocaine-induced hyperlocomotion or compulsive behavior. Altogether, our multiscale study shows that the absence of Snord115 impacts on central monoaminergic circuits to an extent that does not elicit gross behavioral abnormalities.

Agomelatine for the treatment of generalized anxiety disorder: focus on its distinctive mechanism of action

Article

Full-text available

Jun 2022

Mark J Millan

Generalized anxiety disorder (GAD), the most frequently diagnosed form of anxiety, is usually treated by cognitive-behavioural approaches or medication; in particular, benzodiazepines (acutely) and serotonin or serotonin/noradrenaline reuptake inhibitors (long term). Efficacy, compliance, and acceptability are, however, far from ideal, reinforcing interest in alternative options. Agomelatine, clinically employed in the treatment of major depression, expresses anxiolytic properties in rodents and was effective in the treatment of GAD (including severely ill patients) in several double-blind, short-term (12 weeks) and relapse-prevention (6 months) studies. At active doses, the incidence of adverse effects was no higher than for placebo. Agomelatine possesses a unique binding profile, behaving as a melatonin (MT 1 /MT 2 ) receptor agonist and 5-HT 2C receptor antagonist, yet recognizing neither monoamine transporters nor GABA A receptors. Extensive evidence supports a role for 5-HT 2C receptors in the induction of anxious states, and their blockade likely plays a primary role in mediating the anxiolytic actions of agomelatine, including populations in the amygdala and bed nucleus of stria terminalis, as well as the hippocampus. Recruitment of MT receptors in the suprachiasmatic nucleus, thalamic reticular nucleus, and hippocampus appears to fulfil a complimentary role. Downstream of 5-HT 2C and MT receptors, modulation of stress-sensitive glutamatergic circuits and altered release of the anxiogenic neuropeptides, corticotrophin-releasing factor, and vasopressin, may be implicated in the actions of agomelatine. To summarize, agomelatine exerts its anxiolytic actions by mechanisms clearly distinct from those of other agents currently employed for the management of GAD. Plain Language Summary How agomelatine helps in the treatment of anxiety disorders Introduction • Anxiety disorders have a significant negative impact on quality of life. • The most common type of anxiety disorder, called generalized anxiety disorder (GAD), is associated with nervousness and excessive worry. • These symptoms can lead to additional symptoms like tiredness, sleeplessness, irritability, and poor attention. • GAD is generally treated through either cognitive-behavioural therapy or medication. However, widely used drugs like benzodiazepines and serotonin reuptake inhibitors have adverse effects. • Agomelatine, a well-established antidepressant drug, has shown anxiety-lowering (‘anxiolytic’) properties in rats and has been shown to effectively treat GAD with minimal side effects. • However, exactly how it acts on the brain to manage GAD is not yet clear. • Thus, this review aims to shed light on agomelatine’s mechanism of action in treating GAD. Methods • The authors reviewed studies on how agomelatine treats anxiety in animals. • They also looked at clinical studies on the effects of agomelatine in people with GAD. Results • The study showed that agomelatine ‘blocks’ a receptor in nerve cells, which plays a role in causing anxiety, called the 5-HT 2C receptor. • Blocking this receptor, especially in specific brain regions such as nerve cells of the amygdala, bed nucleus of stria terminalis, and hippocampus, produced the anxiety reduction seen during agomelatine treatment. • Agomelatine also activates the melatonin (MT) receptor, which is known to keep anxiety in check, promote sleep, and maintain the sleep cycle. • Agomelatine should thus tackle sleep disturbances commonly seen in patients with GAD. • Beyond 5-HT 2C and MT receptors, signalling molecules in nerve cells that are known to be involved in anxiety disorders (called ‘neurotransmitters’ and ‘neuropeptides’) are also affected by agomelatine. Conclusion • Agomelatine’s anxiolytic effects are caused by mechanisms that are distinct from those of other medications currently used to treat GAD. • This explains its therapeutic success and minimal adverse side effects.

Effect of 5-HT2A receptor antagonism on levels of D2/3 receptor occupancy and adverse behavioral side-effects induced by haloperidol: a SPECT imaging study in the rat

Article

Full-text available

Jan 2021

Several studies suggested that 5-HT 2A receptor (5-HT 2A R) blockade may provide a more favorable efficacy and side-effect profile to antipsychotic treatment. We hypothesized that a combined haloperidol (a D 2/3 receptor (D 2/3 R) antagonist) and MDL-100,907 (a 5-HT 2A R antagonist) treatment would reverse the side effects and the neurochemical alterations induced by haloperidol alone and would potentialize its efficacy. We thus chronically treated male Mdr1a knock-out rats with several doses of haloperidol alone or in combination with a saturating dose of a MDL-100,907. Receptor occupancy at clinically relevant levels was validated with a dual-radiotracer in-vivo SPECT imaging of D 2/3 R and 5-HT 2A R occupancy. Experimental tests of efficacy (dizocilpine-disrupted prepulse inhibition (PPI) of the startle reflex) and side effects (catalepsy, vacuous chewing movements) were performed. Finally, a second dual-radiotracer in-vivo SPECT scan assessed the neurochemical changes induced by the chronic treatments. Chronic haloperidol failed to reverse PPI disruption induced by dizocilpine, whilst administration of MDL-100,907 along with haloperidol was associated with a reversal of the effect of dizocilpine. Haloperidol at 0.5 mg/kg/day and at 1 mg/kg/day induced catalepsy that was significantly alleviated (by ~50%) by co-treatment with MDL-100,907 but only at 0.5 mg/kg/day dose of haloperidol. Chronic haloperidol treatment, event at doses as low as 0.1 mg/kg/day induced a significant upregulation of the D 2/3 R in the striatum (by over 40% in the nucleus accumbens and over 20% in the caudate-putamen nuclei), that was not reversed by MDL-100,907. Finally, an upregulation of 5-HT 2A R after chronic haloperidol treatment at a moderate dose only (0.25 mg/kg/day) was demonstrated in frontal cortical regions and the ventral tegmental area. Overall, a partial contribution of a 5-HT 2A R antagonism to the efficacy and side-effect profile of antipsychotic agents is suggested.

Editorial: Contemporary Perspective on 5-HT2C Receptor Function and Its Pharmacological Targeting

Article

Full-text available

Nov 2020

This compilation of research and review articles presents contemporary perspectives dedicated to serotonin (5-HT) 5-HT2C receptor (5-HT2CR) and its pharmacological targeting. The volume also covers the impact of disease conditions or treatments on 5-HT2CR expression and function in preclinical models of human pathologies. The 5-HT2CR is indeed an intriguing and fascinating G protein-coupled receptor (GPCR) with amazing regulatory features devised by biology, including its pre-transcriptional regulation, alternative splice variants and post-transcriptional RNA editing. RNA editing is an important molecular process from a pharmacological perspective because of the generation of multiple 5-HT2CR isoforms with distinct pharmacological properties. Most recently, the 5-HT2CR has been shown to exist in oligomeric formations and the 5-HT2CR is thought to signal as homodimer and could function as a heterodimer in complex with other GPCRs with the consequence of changing the molecular and cellular impact of the receptor signaling. The allure of uncovering the scientific secrets of the 5-HT2CR system lies in the prospects 5-HT2CR ligands as potential therapeutics given its value as a pharmacological target in a number of neuropsychiatric diseases including eating disorders, drug addiction, schizophrenia, mood disorders, impulse control disorders, obsessive compulsive disorder, and epilepsy (Howell and Cunningham, 2015; Chagraoui et al., 2016; Di Giovanni and De Deurwaerdère, 2016). Some medications employed in the clinic bind to the 5-HT2CR including some atypical antipsychotics, the antidepressants agomelatine, mianserin and mirtazapine, and lorcaserin which achieved the most advanced drug targeting 5-HT2CR to reach the clinic. However, lorcaserin was voluntarily removed from the market in 2020 due to an FDA safety communication. At this time, there are no FDA-approved 5-HT2CR-selective agonists, however, lorcaserin was marketed to promote weight loss in patients with a body mass index of greater than 30 or with a BMI of greater than 27 comorbid with type-2 diabetes, hypertension, or dyslipidemia. Lorcaserin is emblematic for at least four reasons in neuropharmacology and in the field of 5-HT2CR research. First, it achieved status as an anti-obesity product issued from years of intensive research aimed at deciphering the mechanism of action underlying the anorexigenic effect of d-fenfluramine, thereby identifying the 5-HT2CR as one of the main actors. Second, upon its accession to the clinic, lorcaserin became emblematic of clinical and preclinical orientations to repurpose drugs away from their initial purpose; in the case of lorcaserin, preclinical studies predict the efficacy of a 5-HT2CR-selective agonist for treatment of drug addiction and impulse control disorders (Higgins et al., 2020). Some of the preclinical arguments are presented herein in the article by Soto et al. who report that lorcaserin or the investigatory 5-HT2CR agonist WAY-163,909 reduces the ability of trained rats to discriminate cocaine from saline (Soto et al., 2019). Third, even though a drug like lorcaserin could be selected to fulfill a hypothesized mechanism of action in the treatment of drug abuse, e.g., to oppose dopaminergic transmission in the reward system, its mechanism of action has some shadowy aspects. For instance, Di Giovanni et al. recall that lorcaserin has mitigated effects on dopamine extracellular levels. However, they report that lorcaserin changes the profile and the number of correlations of postmortem monoamines tissue markers across 30 brain areas toward a decrease for dopamine, and an increase for serotonin and noradrenaline (Di Giovanni et al., 2020). Thus beyond the dopaminergic system, 5-HT2CR agonists modulate the other monoaminergic systems which could permit to develop multi-drug design to boost the efficacy of 5-HT2CR agonists. Fourth, at a time where lorcaserin was under study in clinical protocols for diseases other than those afferent to obesity, lorcaserin was withdrawn from the market due to suspected cases of cancer. Thus, lorcaserin studies have confirmed that 5-HT2CR targeting was valuable in neuropsychiatric diseases where there is no clear treatment, opening the path to develop new pharmacological strategies. The real purpose of the article of Soto et al. is to emphasize one of these strategies from the peptide design to the behavioral studies in the context of cocaine addiction. Briefly, they show that disruption of the 5-HT2CR interaction with the protein phosphatase and tensin homolog (PTEN) via peptidomimetics enhances 5-HT2CR-mediating signaling in vitro and potentiates selective 5-HT2CR agonists in behavioral rodent models. The search continues particularly in the field of individual responses to drug of abuse. In their review article, Tanaka and Watanabe elaborate on the editing of the 5-HT2CR mRNA and alcohol consumption. They recall the molecular origins of the 5-HT2CR mRNA editing with the involvement of the deaminated to inosine by adenosine deaminase enzymes comprising three subtypes isolated so far. They summarize the data showing that the distribution of the various 5-HT2CR edited products varies across brain regions, mammal species and strain, and pathophysiological conditions. The authors focus herein on alcohol preference in different mouse strains and a possible abnormal editing of the 5-HT2CR mRNA in the nucleus accumbens. That the activity of 5-HT2CR mRNA editing could impact behavioral traits and accompany pathophysiological states is highlighted by the transgenic mouse model used by Paizanis et al. in which only the full edited 5-HT2CR product VGV is expressed (Paizanis et al., 2020). These transgenic mice exhibit anxiety and abnormal fear conditioning and contextualized learning, modeling some features of the post-traumatic stress disorder. In contrast to the expectations of the authors, VGV mice do not exhibit enhanced voluntary alcohol and cocaine consumption. Rather, alcohol and cocaine exhibited some potential therapeutic effects in VGV mice, normalizing the expression of brain-derived neurotrophic factor mRNA expression in the hippocampus compared to wildtype mice. The link between 5-HT2CR mechanisms and anxiety and mood disorders has been acknowledged for several years but requires additional neurobiological exploration to align the proper pharmacological modification of 5-HT2CR required for therapeutic improvement (Chagraoui et al., 2016; Di Giovanni and De Deurwaerdère, 2016). This complexity is possibly related to the distinct sites of 5-HT2CR expression in the brain which participate in the regulation of mood and cognition. Baptista-de-Souza et al. focused on 5-HT transmission within the amygdala and the periaqueductal gray matter (PAG) of mice in the context of fear-induced anti-nociception. In these studies, treatment with the selective serotonin reuptake inhibitor (SSRI) fluoxetine impaired the ability of the 5-HT2CR or 5-HT1AR within the amygdala and PAG to intensify nociceptive responses to aversive stimuli. Papp et al. studied the alterations of the gamma power of the electroencephalogram (EEG) in rats as a suggested biomarker of depression. Correspondingly, quantitative EEG analysis revealed that acute treatment with the selective 5-HT2CR antagonist SB-242,084 mimicked chronic treatment with the SSRI escitalopram in increasing gamma power (30–60 Hz) in light and deep slow-wave sleep. This profile prompted the authors to conclude that SB-242,084 may potentially be a useful antidepressant. Some single nucleotide polymorphisms (SNPs) in the X-linked HTR2C gene have been correlated with aggressive behavior, antipsychotic drug-induced hyperprolactinemia and tardive dyskinesia as recalled by (Ochi et al., 2019). It is believed that these SNPs could either accompany pathological states and/or the efficacy of treatments. However, Ochi et al. report that, in a human cohort treated for major depressive disorder, no associations between the efficacy of antidepressant drugs (SSRI or tricyclic antidepressants) and several 5-HT receptor genes, including those concerning the HT2CR SNPs. The authors do not exclude the possibility that differential responses to antidepressants in males vs. females may relate to specific 5-HT receptor SNPs as the sample size was limited, impairing sub-analysis of the data. In conclusion of this collection of articles, 5-HT2CR remains an attractive target for the treatment of several chronic health disorders. Future studies that interrogate this unique receptor from its transcription to integrative neurobiology are required to target therapeutics for normalization of 5-HT2CR function in disease states. Importantly, the classical means of conceiving treatments with agonists, antagonists, and biased agonists has already been implemented in 5-HT2CR research by allosteric modulators (Wold et al., 2019) acting on specific site of the receptor (Wold et al., 2020). It could be further implemented by treatments specifically targeting transcription, translation, and intracellular signaling. The clinical data are important to elaborate on the participation of 5-HT2CR in a given pathology and/or in response to treatments. For instance, the 5-HT2CR-selective agonist vabicaserin was shown to suppress activated central dopaminergic transmission, which served as the basis for the clinical trial in schizophrenia (Shen et al., 2014). The reported findings supported the safety, tolerability, and efficacy of vabicaserin in acute schizophrenia, but future studies are required to firmly establish the role of central dopaminergic systems in this outcome in humans. Another dimension which is not treated in this collection is that a multi-target approach combining 5-HT2CR ligands and compounds targeting other sites (for instance the combination 5-HT2CR agonist and 5-HT2AR antagonist in cocaine addiction (Howell and Cunningham, 2015) could offer broader and safer spectrums of clinical efficacy. Thus, additional studies are needed for establishing 5-HT2CR biological roles alone or in interaction with other systems in the regulation of the activity of neurobiological networks of the whole central nervous system. Clearly, there are rich opportunities for several other collections on this intriguing topic in the future.

Molecular Sciences Review Serotonin in Animal Cognition and Behavior

Article

Full-text available

Jan 2020

SLC6A3, HTR2C and HTR6 Gene Polymorphisms and the Risk of Haloperidol-Induced Parkinsonism

Article

Full-text available

Dec 2022

Antipsychotic-induced parkinsonism (AIP) is the most common type of extrapyramidal side effect (EPS), caused by the blockage of dopamine receptors. Since dopamine availability might influence the AIP risk, the dopamine transporter (DAT) and serotonin receptors (5-HTRs), which modulate the dopamine release, may be also involved in the AIP development. As some of the individual differences in the susceptibility to AIP might be due to the genetic background, this study aimed to examine the associations of SLC6A3, HTR2C and HTR6 gene polymorphisms with AIP in haloperidol-treated schizophrenia patients. The Extrapyramidal Symptom Rating Scale (ESRS) was used to evaluate AIP as a separate entity. Genotyping was performed using a PCR, following the extraction of blood DNA. The results revealed significant associations between HTR6 rs1805054 polymorphism and haloperidol-induced tremor and rigidity. Additionally, the findings indicated a combined effect of HTR6 T and SLC6A3 9R alleles on AIP, with their combination associated with significantly lower scores of ESRS subscale II for parkinsonism, ESRS-based tremor or hyperkinesia and ESRS subscales VI and VIII. These genetic predictors of AIP could be helpful in better understanding its pathophysiology, recognizing the individuals at risk of developing AIP and offering personalized therapeutic strategies for the patients suffering from this EPS.

Influence of the neutral sphingomyelinase on central monoaminergic signaling in a model of voluntary alcohol consumption

Thesis

Jan 2022

Esther Weigand

Introduction Alcohol use disorder is a serious psychiatric disorder that poses major challenges to the health care system. The development of the disease is often multifactorial, and a minority of patients can be successfully treated with medication. Several neurotransmitter systems, particularly the serotonergic and dopaminergic reward pathways, are affected by alcohol exposure and contribute to the development of alcohol dependence. Here, the sphingolipids and their metabolism are considered mediators in the development of addictive disorders including alcohol use disorder. Indeed, increased activity of the acid sphingomyelinase (ASM), which has been identified as a key enzyme of sphingolipid metabolism, not only affects monoamine homeostasis in the brain by reducing tissue levels of serotonin (5-HT) and dopamine (DA) in the ventral striatum, but also increases alcohol intake. However, remarkably high levels of another sphingomyelinase are found in the brain: neutral sphingomyelinase 2 (NSM). Interestingly in early abstinent patients with alcohol dependence, not only an increase in NSM activity was measured. In a cell model, decreased activity of NSM causes a decrease in 5-HT uptake, DA uptake, and DA release. However, besides the reported impairment of brain monoamines, further results indicate an association between single nucleotide polymorphisms in the NSM-encoding gene Sphingomyelin phosphodiesterase (SMPD) 3 and alcohol intake. This work aimed to investigate the influence of NSM hypoexpression in mice on central monoaminergic signaling in a model of voluntary alcohol consumption. Methods 24 male and 24 female C57 black6/J mice, half of which carried a heterozygous fragilitas ossium (fro) mutation, were used for the study. In the fro mice, one allele of the gene encoding NSM was knocked out. In a two-bottle paradigm, all animals received ethanol at increasing concentrations (2-16% by volume). The control group was exposed to tap water. Alcohol consumption, alcohol preference, water intake, and total intake of all groups were determined. After 36 days of the experiment and sufficient establishment of alcohol drinking behaviour, the animals were killed, and the removed brains were examined for mRNA expression of dopamine and serotonin receptors/transporters in the ventral striatum. Results NSM hypoactivity partially increases voluntary alcohol consumption in male mice at 2% alcohol solution with no effect on the total intake. Moreover, NSM regulates monoaminergic signalling in male mice: Alcohol-induced alteration of serotonin-1a-receptor, serotonin-2c-receptor, serotonin- transporter and dopamine-transporter was prevented. This effect appears to be strongly sex dependent. With respect to female littermates, our results do not indicate a significant change in voluntary alcohol consumption or total intake. However, alcohol naive female fro mice show significantly reduced D2 expression. Alcohol consumption further reveals an effect of NSM hypoexpression on monoaminergic signalling in females: On the one hand, alcohol-induced neuroplasticity was prevented as in serotonin-3a-receptor, and on the other hand, new adaptations of other receptors such as serotonin-1a-receptor occurred. Conclusion Our results reveal the crucial influence of the fro mutation on the adaptation of monoaminergic signalling to alcohol exposure. Interestingly, the effect of NSM on the monoaminergic system turns out to be strongly sex dependent. This results in lower susceptibility to alcohol-induced neuroplasticity due to NSM hypoexpression in males. Furthermore, we report an influence of NSM hypoexpression on alcohol consumption in men, namely partially reduced alcohol intake, but not in women. These results indicate the involvement of the NSM and possible downstream mechanisms in the development of alcohol dependence and may provide a possible basis for explaining the sex difference in alcohol use disorders. Furthermore, the dopaminergic and serotoninergic reward systems are essential for the reinforcing effects of alcohol and the transition to addiction. The fact that NSM exerts an influence on the monoaminergic response to alcohol exposure supports the idea that NSM may be a promising pharmacological target for the treatment of alcohol dependence.

Agomelatine rescues lipopolysaccharide-induced neural injury and depression-like behaviors via suppression of the Gαi-2-PKA-ASK1 signaling pathway

Article

Full-text available

May 2022
J NEUROINFLAMM

Background Agomelatine has been shown to be effective in the treatment of depression, but the molecular mechanisms underlying its antidepressant effects have yet to be elucidated. Identification of these molecular mechanisms would not only offer new insights into the basis for depression but also provide the foundation for the development of novel treatments for this disorder. Methods Intraperitoneal injection of LPS was used to induce depression-like behaviors in rats. The interactions of the 5-HT2C reporter and Gαi-2 were verified by immunoprecipitation or immunofluorescence assay. Inflammatory related proteins, autophagy related proteins and apoptosis markers were verified by immunoblotting or immunofluorescence assay. Finally, electron microscopy analysis was used to observe the synapse and ultrastructural pathology. Results Here, we found that the capacity for agomelatine to ameliorate depression and anxiety in a lipopolysaccharide (LPS)-induced rat model of depression was associated with an alleviation of neuroinflammation, abnormal autophagy and neuronal apoptosis as well as the promotion of neurogenesis in the hippocampal dentate gyrus (DG) region of these rats. We also found that the 5-HT2C receptor is coupled with G alphai (2) (Gαi-2) protein within hippocampal neurons and, agomelatine, acting as a 5-HT2C receptor antagonist, can up-regulate activity of the Gαi-2-cAMP-PKA pathway. Such events then suppress activation of the apoptosis signal-regulating kinase 1 (ASK1) pathway, a member of the mitogen-activated protein kinase (MAPK) family involved in pathological processes of many diseases. Conclusion Taken together, these results suggest that agomelatine plays a neuroprotective role in regulating neuroinflammation, autophagy disorder and apoptosis in this LPS-induced rat model of depression, effects which are associated with the display of antidepressant behaviors. These findings provide evidence for some of the potential mechanisms for the antidepressant effects of agomelatine. Graphical Abstract

Multiple facets of serotonergic modulation

Book

Jan 2021

The serotonergic system of the central nervous system (CNS) has been implicated in a broad range of physiological functions and behaviors, such as cognition, mood, social interaction, sexual behavior, feeding behavior, sleep-wake cycle and thermoregulation. Serotonin (5-hydroxytryptamine, 5-HT) establishes a plethora of interactions with neurochemical systems in the CNS via its numerous 5-HT receptors and autoreceptors. The facets of this control are multiple if we consider the molecular actors playing a role in the autoregulation of 5-HT neuron activity including the 5-HT1A, 5-HT1B, 5-HT1D, 5-HT2B, 5-HT7 receptors as well as the serotonin transporter. Moreover, extrinsic loops involving other neurotransmitters giving the other 5-HT receptors the possibility to impact 5-HT neuron activity. Grasping the complexity of these interactions is essential for the development of a variety of therapeutic strategies for cognitive defects and mood disorders. Presently we can illustrate the plurality of the mechanisms and only conceive that these 5-HT controls are likely not uniform in terms of regional and neuronal distribution. Our understanding of the specific expression patterns of these receptors on specific circuits and neuronal populations are progressing and will expand our comprehension of the function and interaction of these receptors with other chemical systems. Thus, the development of new approaches profiling the expression of 5-HT receptors and autoreceptors should reveal additional facets of the 5-HT controls of neurochemical systems in the CNS.

Serotonin receptors in epilepsy: Novel treatment targets?

Article

Full-text available

Feb 2022

Despite the availability of over 30 antiseizure medications (ASMs), there is no “one size fits it all,” so there is a continuing search for novel ASMs. There are divergent data demonstrating that modulation of distinct serotonin (5‐hydroxytryptamine, 5‐HT) receptors subtypes could be beneficial in the treatment of epilepsy and its comorbidities, whereas only a few ASM, such as fenfluramine (FA), act via 5‐HT. There are 14 different 5‐HT receptor subtypes, and most epilepsy studies focus on one or a few of these subtypes, using different animal models and different ligands. We reviewed the available evidence of each 5‐HT receptor subtype using MEDLINE up to July 2021. Our search included medical subject heading (MeSH) and free terms of each “5‐HT subtype” separately and its relation to “epilepsy or seizures.” Most research underlines the antiseizure activity of 5‐HT1A,1D,2A,2C,3 agonism and 5‐HT6 antagonism. Consistently, FA, which has recently been approved for the treatment of seizures in Dravet syndrome, is an agonist of 5‐HT1D,2A,2C receptors. Even though each study focused on a distinct seizure/epilepsy type and generalization of different findings could lead to false interpretations, we believe that the available preclinical and clinical studies emphasize the role of serotonergic modulation, especially stimulation, as a promising avenue in epilepsy treatment.

Use of Zebrafish Models to Boost Research in Rare Genetic Diseases

Article

Full-text available

Dec 2021
INT J MOL SCI

Rare genetic diseases are a group of pathologies with often unmet clinical needs. Even if rare by a single genetic disease (from 1/2000 to 1/more than 1,000,000), the total number of patients concerned account for approximatively 400 million peoples worldwide. Finding treatments remains challenging due to the complexity of these diseases, the small number of patients and the challenge in conducting clinical trials. Therefore, innovative preclinical research strategies are required. The zebrafish has emerged as a powerful animal model for investigating rare diseases. Zebrafish combines conserved vertebrate characteristics with high rate of breeding, limited housing requirements and low costs. More than 84% of human genes responsible for diseases present an orthologue, suggesting that the majority of genetic diseases could be modelized in zebrafish. In this review, we emphasize the unique advantages of zebrafish models over other in vivo models, particularly underlining the high throughput phenotypic capacity for therapeutic screening. We briefly introduce how the generation of zebrafish transgenic lines by gene-modulating technologies can be used to model rare genetic diseases. Then, we describe how zebrafish could be phenotyped using state-of-the-art technologies. Two prototypic examples of rare diseases illustrate how zebrafish models could play a critical role in deciphering the underlying mechanisms of rare genetic diseases and their use to identify innovative therapeutic solutions.

Exploring the kinetic selectivity of antipsychotics for dopamine D 2 and 5-HT 2A receptors: implications for the prevalence of EPS and receptor occupancy

Preprint

Full-text available

Nov 2021

Certain atypical antipsychotic drugs (APDs) used in the treatment of schizophrenia have been hypothesized to show reduced extrapyramidal side effects (EPS), due to their ability to promote nigrostriatal dopamine release through 5-HT 2A receptor (5-HT 2A R) blockade. The strength of this hypothesis is currently limited to a consideration of the relative receptor affinities of APDs for the 5-HT 2A R and dopamine D 2 receptor (D 2 R). Here we measure the 5-HT 2A R kinetic binding properties of a series of typical and atypical APDs in a novel time-resolved fluorescence resonance energy transfer assay and correlate these properties with their observed EPS at therapeutic doses. For compounds with negligible affinity for 5-HT 2A R, EPS is robustly predicted by a D 2 R specific rebinding model that integrates D 2 R association and dissociation rates to calculate the net rate of reversal of receptor blockade ( k r ). However, we show that for compounds with significant affinity for the 5-HT 2A R, such as sertindole, higher relative 5-HT 2A occupancy over time is an indicator for a reduced propensity to cause EPS. This study suggests that there is room for the development of novel kinetically optimised antipsychotic agents that modulate both serotonergic and dopamine function in a manner beneficial in the treatment of this chronic and debilitating disease.

Multiple facets of serotonergic modulation

Chapter

Mar 2021
Progr Brain Res

5-HT/GABA interaction in epilepsy

Chapter

Jan 2021
Progr Brain Res

Epilepsy is a neurological condition characterized by synchronous neuronal oscillations (seizures) in the electroencephalogram. Seizures are classified in focal or generalized (depending on the brain territory interested during seizures), and in convulsive and/or not convulsive (depending on the presence or not of involuntary movements). The current pharmacological treatments are mainly based on GABA modulation although different neurotransmitters are also involved in epilepsy, including serotonin. However despite much extensive progress in the understanding of epilepsy mechanisms, still, a percentage of people with epilepsy are pharmaco-resistant calling for the need for new therapeutic targets. Here we review preclinical and human evidence showing that serotonin modulates epilepsy that this likely happens via a major modulation/interaction with GABA.

Chronic Lorcaserin Treatment Reverses the Nicotine Withdrawal-Induced Disruptions to Behavior and Maturation in Developing Neurons in the Hippocampus of Rats

Article

Full-text available

Jan 2021
INT J MOL SCI

Preclinical data have shown that treatment with serotonin (5-HT)2C receptor agonists inhibits the behavioral effects of nicotine, including self-administration, reinstatement, and locomotor responses to nicotine. Since the data on the effects of 5-HT2C receptor agonism on nicotine withdrawal signs are limited, we aimed to investigate whether 5-HT2C receptor agonism alleviated the behavioral and neurobiochemical (hippocampal neurogenesis) consequences of nicotine withdrawal in Sprague-Dawley rats. Our data indicate that withdrawal from nicotine self-administration induced locomotor hyperactivity, lengthened immobility time (the forced swim test), induced ‘drug-seeking’ behavior and deficits in cognition-like behavior (the novel object recognition task). A two-week exposure to the 5-HT2C receptor agonist lorcaserin attenuated locomotor hyperactivity and induced recovery from depression-like behavior. Analyses of brain slices from nicotine-withdrawn animals revealed that lorcaserin treatment recovered the reduced number of doublecortin (DCX)-positive cells, but it did not affect the number of Ki-67- or 5-bromo-2’-deoxyuridine (BrdU)-positive cells or the maturation of proliferating neurons in drug-weaned rats. To summarize, we show that lorcaserin alleviated locomotor responses and depression-like state during nicotine withdrawal. We propose that the modulatory effect of lorcaserin on the ‘affective’ aspects of nicotine cessation may be linked to the positive changes caused by the compound in hippocampal neurogenesis during nicotine withdrawal.

Cortical influences of serotonin and glutamate on layer V pyramidal neurons

Chapter

Jan 2021
Progr Brain Res

Layer V pyramidal neurons constitute principle output neurons of the medial prefrontal cortex (mPFC)/neocortex to subcortical regions including the intralaminar/midline thalamic nuclei, amygdala, basal ganglia, brainstem nuclei and the spinal cord. The effects of 5-hydroxytryptamine (5-HT) on layer V pyramidal cells primarily reflect a range of excitatory influences through 5-HT2A receptors and inhibitory influences through non-5-HT2A receptors, including 5-HT1A receptors. While the 5-HT2A receptor is primarily a postsynaptic receptor on throughout the apical dendritic field of 5-HT2A receptors, activation of a minority of 5-HT2A receptors also appears to increase spontaneous excitatory postsynaptic currents/potentials (EPSCs/EPSPs) via a presynaptic effect on thalamocortical terminals arising from the midline and intralaminar thalamic nuclei. Activation of 5-HT2A receptors by the phenethylamine hallucinogen also appears to increase asynchronous release of glutamate upon the layer V pyramidal dendritic field, an effect that is suppressed by 5-HT itself through non-5-HT2A receptors. Serotonergic hallucinogens acting on 5-HT2A receptors also appears to increase gene expression of immediate early genes (iEG) and other receptors appearing to induce an iEG-like response like BDNF. Psychedelic hallucinogens acting on 5-HT2A receptors also induce head twitches in rodents that appear related to induction of glutamate release. These electrophysiological, biochemical and behavioral effects of serotonergic hallucinogens appear to be related to modulating glutamatergic thalamocortical neurotransmission and/or shifting the balance toward 5-HT2A receptor activation and away from non-5-HT2A receptor activation. These 5-HT2A receptor induced responses are modulated by feedback homeostatic mechanisms through mGlu2, mGlu4, and mGlu8 presynaptic receptors on thalamocortical terminals. These 5-HT2A receptor and glutamatergic interactions also appear to play a role on higher cortical functions of the mPFC such as motoric impulsivity and antidepressant-like behavioral responses on the differential-reinforcement-of low rate 72-s (DRL 72-s schedule). These mutually opposing effects between 5-HT2A receptor and mGlu autoreceptor activation (e.g., blocking 5-HT2A receptors and enhancing activity at mGlu2 receptors) may play a clinical role with respect to currently prescribed or novel antidepressant drugs. Thus, there is an important balance between 5-HT2A receptor activation and activation of mGlu autoreceptors on prefrontal cortical layer V pyramidal cells with respect to the electrophysiological, biochemical and behavioral effects serotonergic hallucinogenic drugs.

Molecular, biochemical and behavioural evidence for a novel oxytocin receptor and serotonin 2C receptor heterocomplex

Article

Full-text available

Feb 2021
NEUROPHARMACOLOGY

The complexity of oxytocin-mediated functions is strongly associated with its modulatory effects on other neurotransmission systems, including the serotonin (5-hydroxytryptamine, 5-HT) system. Signalling between oxytocin (OT) and 5-HT has been demonstrated during neurodevelopment and in the regulation of specific emotion-based behaviours. It is suggested that crosstalk between neurotransmitters is driven by interaction between their specific receptors, particularly the oxytocin receptor (OTR) and the 5-hydroxytryptamine 2C receptor (5-HTR2C), but evidence for this and the downstream signalling consequences that follow are lacking. Considering the overlapping central expression profiles and shared involvement of OTR and 5-HTR2C in certain endocrine functions and behaviours, including eating behaviour, social interaction and locomotor activity, we investigated the existence of functionally active OTR/5-HTR2C heterocomplexes. Here, we demonstrate evidence for a potential physical interaction between OTR and 5-HTR2C in vitro in a cellular expression system using flow cytometry-based FRET (fcFRET). We could recapitulate this finding under endogenous expression levels of both receptors via in silico analysis of single cell transcriptomic data and ex vivo proximity ligation assay (PLA). Next, we show that co-expression of the OTR/5-HTR2C pair resulted in a significant depletion of OTR-mediated Gαq-signalling and significant changes in receptor trafficking. Of note, attenuation of OTR-mediated downstream signalling was restored following pharmacological blockade of the 5-HTR2C. Finally, we demonstrated a functional relevance of this novel heterocomplex, in vivo, as 5-HTR2C antagonism increased OT-mediated hypoactivity in mice. Overall, we provide compelling evidence for the formation of functionally active OTR/5-HTR2C heterocomplexes, adding another level of complexity to OTR and 5-HTR2C signalling functionality. This article is part of the special issue on Neuropeptides.

Serotonin research: Crossing scales and boundaries

Article

Dec 2020
NEUROPHARMACOLOGY

Nearly 100 years after the discovery of serotonin, its role remains elusive. Modulation of serotonin transmission is considered in numerous central nervous system (CNS) diseases including depression, anxiety, schizophrenia, obsessive-compulsive disorders, addiction, Parkinson's disease, and Alzheimer's disease. The therapeutic strategies based on serotonin systems have evolved thanks to better identification of the involvement of serotonin in various diseases, the better use of animal models, a better understanding of the molecular environment of serotonin receptors, and ultimately the better understanding of the interaction of serotonin neurotransmission with other biological systems. Some 5-HT receptors are still the object of numerous investigations including 5-HT1A, 5-HT2A, and 5-HT6 receptor subtypes. It is noteworthy that the direction of research is moving towards a simultaneous action at multiple targets either through different 5-HT targets or the consideration of both 5-HT and other targets to achieve better therapeutic responses.

Acute EPA-induced learning and memory impairment in mice is prevented by DHA

Article

Full-text available

Oct 2020

Eicosapentaenoic acid (EPA), an omega-3 fatty acid, has been widely used to prevent cardiovascular disease (CVD) and treat brain diseases alone or in combination with docosahexaenoic acid (DHA). However, the impact of EPA and DHA supplementation on normal cognitive function and the molecular targets of EPA and DHA are still unknown. We show that acute administration of EPA impairs learning and memory and hippocampal LTP in adult and prepubescent mice. Similar deficits are duplicated by endogenously elevating EPA in the hippocampus in the transgenic fat-1 mouse. Furthermore, the damaging effects of EPA are mediated through enhancing GABAergic transmission via the 5-HT 6 R. Interestingly, DHA can prevent EPA-induced impairments at a ratio of EPA to DHA similar to that in marine fish oil via the 5-HT 2C R. We conclude that EPA exhibits an unexpected detrimental impact on cognitive functions, suggesting that caution must be exercised in omega-3 fatty acid supplementation and the combination of EPA and DHA at a natural ratio is critical for learning and memory and synaptic plasticity.

NRG1, PIP4K2A, and HTR2C as Potential Candidate Biomarker Genes for Several Clinical Subphenotypes of Depression and Bipolar Disorder

Article

Full-text available

Aug 2020

GSK3B, BDNF, NGF, NRG1, HTR2C, and PIP4K2A play important roles in molecular mechanisms of psychiatric disorders. GSK3B occupies a central position in these molecular mechanisms and is also modulated by psychotropic drugs. BDNF regulates a number of key aspects in neurodevelopment and synaptic plasticity. NGF exerts a trophic action and is implicated in cerebral alterations associated with psychiatric disorders. NRG1 is active in neural development, synaptic plasticity, and neurotransmission. HTR2C is another important psychopharmacological target. PIP4K2A catalyzes the phosphorylation of PI5P to form PIP2, the latter being implicated in various aspects of neuronal signal transduction. In the present study, the six genes were sequenced in a cohort of 19 patients with bipolar affective disorder, 41 patients with recurrent depressive disorder, and 55 patients with depressive episode. The study revealed a number of genetic variants associated with antidepressant treatment response, time to recurrence of episodes, and depression severity. Namely, alleles of rs35641374 and rs10508649 (NRG1 and PIP4K2A) may be prognostic biomarkers of time to recurrence of depressive and manic/mixed episodes among patients with bipolar affective disorder. Alleles of NC_000008.11:g.32614509_32614510del, rs61731109, and rs10508649 (also NRG1 and PIP4K2A) seem to be predictive biomarkers of response to pharmacological antidepressant treatment on the 28th day assessed by the HDRS-17 or CGI-I scale. In particular, the allele G of rs10508649 (PIP4K2A) may increase resistance to antidepressant treatment and be at the same time protective against recurrent manic/mixed episodes. These results support previous data indicating a biological link between resistance to antidepressant treatment and mania. Bioinformatic functional annotation of associated variants revealed possible impact for transcriptional regulation of PIP4K2A. In addition, the allele A of rs2248440 (HTR2C) may be a prognostic biomarker of depression severity. This allele decreases expression of the neighboring immune system gene IL13RA2 in the putamen according to the GTEx portal. The variant rs2248440 is near rs6318 (previously associated with depression and effects of psychotropic drugs) that is an eQTL for the same gene and tissue. Finally, the study points to several protein interactions relevant in the pathogenesis of mood disorders. Functional studies using cellular or animal models are warranted to support these results.

Diazepine Agonists of the 5-HT 2C Receptor with Unprecedented Selectivity: Discovery of Bexicaserin (LP352)

Article

May 2025
J MED CHEM

Rational Design of the First Dual Agonist at Trace Amine-Associated Receptor 1 and 5-HT 2C Receptors Based on Binding Pocket Similarity for the Treatment of Schizophrenia and Alzheimer’s Disease-Related Psychosis

Article

Mar 2025
J MED CHEM

DRN-SNc serotonergic circuit drives stress-induced motor deficits and Parkinson’s disease vulnerability

Article

Mar 2025
NEUROPSYCHOPHARMACOL

Agomelatine: pharmacological profile, possible application, advantages

Article

Aug 2024

Agomelatine is an antidepressant with a unique pharmacological action that is both a melatonin agonist and a selective serotonin antagonist. The drug's unique pharmacological profile includes the properties of a dual 5-HT2С receptor antagonist as well as the properties of a melatonin MT1 and MT2 receptor agonist. Through its effect on melatonin receptors, agomelatine resynchronizes disturbed circadian rhythms and has a positive effect on sleep architecture. In addition, agomelatine shows a novel and fundamentally different mechanism of anxiolytic action compared to other classes of drugs used to treat anxiety. The article presents studies of agomelatine that demonstrate good treatment results in terms of response rates and remission in major depressive disorder of varying severity and generalized anxiety disorder. Agomelatine in a daily dose of 25–50 mg not only reduces the degree of anhedonia, apathy, anxiety, reduces somatic symptoms of depressive and anxiety disorders, but is also well tolerated, normalizes sexual dysfunctions in patients in psychiatric and general medical networks, it is used in cardiovascular, neurological diseases, and post-COVID-19.

Imaging the 5-HT2C receptor with PET: Evaluation of 5-HT2C and 5-HT2A affinity of pimavanserin in the primate brain

Article

Aug 2024
J CEREBR BLOOD F MET

Two complimentary techniques were used to estimate occupancy of pimavanserin (a selective 5-HT 2A/2C inverse agonist) to 5-HT 2A and 5-HT 2C receptors in non-human primate brains. One employed the 5-HT 2A/2C selective radioligand [ ¹¹ C]CIMBI-36 combined with quantification of binding potentials in brain regions known to be enriched in 5-HT 2A (cortex) or 5-HT 2C (choroid plexus) receptors to estimate occupancy. Pimavanserin was 6–10 fold more potent displacing [ ¹¹ C]CIMBI-36 from cortex (ED 50 = 0.007 mg/kg; EC 50 = 0.6 ng/ml) than from choroid plexus (ED 50 =0.046 mg/kg; EC 50 = 6.0 ng/ml). The assignment of [ ¹¹ C]CIMBI-36 binding to 5-HT 2A and 5-HT 2C receptors by anatomical brain structure was confirmed using the 5-HT 2A selective inverse agonist MDL 100,907 and the 5-HT 2C selective antagonist SB 242584 to displace [ ¹¹ C]CIMBI-36. The second technique employed a novel, 5-HT 2C selective tracer called [ ¹¹ C]AC1332. [ ¹¹ C]AC1332 bound robustly to choroid plexus, moderately to hippocampus, and minimally to cortex. Pimavanserin displaced [ ¹¹ C]AC1332 with similar potency (ED 50 = 0.062 mg/kg; EC 50 = 2.5 ng/ml) as its potency displacing [ ¹¹ C]CIMBI-36 binding from choroid plexus. These results demonstrate the feasibility of simultaneously estimating drug occupancy of 5-HT 2A and 5-HT 2C receptors in vivo, and the utility of a novel 5-HT 2C receptor selective tracer ligand.

Neurotransmitters, Receptors, and Transporters

Chapter

Jul 2024

Editorial: New insights into investigating schizophrenia as a disorder of molecular pathways

Article

Full-text available

Jan 2024

Mohan Naga Kommu

Aporphines: A privileged scaffold in CNS drug discovery

Article

May 2023

Aporphine alkaloids embedded in 4H-dibenzo[de,g]quinoline four-ring structures belong to one of the largest subclasses of isoquinoline alkaloids. Aporphine is a privileged scaffold in the field of organic synthesis and medicinal chemistry for the discovery of new therapeutic agents for central nervous system (CNS) diseases, cancer, metabolic syndrome, and other diseases. In the past few decades, aporphine has attracted continuing interest to be widely used to develop selective or multitarget directed ligands (MTDLs) targeting the CNS (e.g., dopamine D1/2/5, serotonin 5-HT1A/2A/2C and 5-HT7, adrenergic α/β receptors, and cholinesterase enzymes), thereby serving as valuable pharmacological probes for mechanism studies or as potential leads for CNS drug discovery. The aims of the present review are to highlight the diverse CNS activities of aporphines, discuss their SAR, and briefly summarize general synthetic routes, which will pave the way for the design and development of new aporphine derivatives as promising CNS active drugs in the future.

Insights into the Promising Prospect of Medicinal Chemistry studies against Neurodegenerative Disorders: A Potential Study

Article

Feb 2023
CHEM-BIOL INTERACT

Medicinal chemistry is an interdisciplinary field that incorporates organic chemistry, biochemistry, physical chemistry, pharmacology, informatics, molecular biology, structural biology, cell biology, and other disciplines. Additionally, it considers molecular factors such as the mode of action of the drugs, their chemical structure-activity relationship (SAR), and pharmacokinetic aspects like absorption, distribution, metabolism, elimination, and toxicity. Neurodegenerative disorders (NDs), which are defined by the breakdown of neurons over time, are affecting an increasing number of people. Oxidative stress, particularly the increased production of Reactive Oxygen Species (ROS), plays a crucial role in the growth of various disorders, as indicated by the identification of protein, lipid, and Deoxyribonucleic acid (DNA) oxidation products in vivo. Because of their inherent nature, most biological molecules are vulnerable to ROS, even if they play a role in metabolic parameters and cell signaling. Due to their high polyunsaturated fatty acid content, low antioxidant barrier, and high oxygen uptake, neurons are particularly vulnerable to oxidation by nature. As a result, excessive ROS generation in neurons looks especially harmful, and the mechanisms associated with biomolecule oxidative destruction are several and complex. This review focuses on the formation and management of ROS, as well as their chemical characteristics (both thermodynamic and kinetic), interactions, and implications in NDs.

How RNA editing keeps an I on physiology

Article

Full-text available

Aug 2022

Adenosine deaminases acting on RNAs convert adenosines (A) to inosines (I) in structured or double- stranded RNAs. In mammals, this process is widespread. In the human transcriptome more than a million different sites have been identified that undergo an ADAR-mediated A to I exchange (1). Inosines have an altered base pairing potential due to the missing amino group when compared to the original adenosine. Consequently, inosines prefer to base pair with guanosines but can also base pair with uracil or adenine (2). This altered base pairing potential not only affects protein decoding at the ribosome but also influences the folding of RNAs and the proteins that can associate with it. Consequently, an A to I exchange can also affect RNA processing and turnover (3, 4). All of these events will interfere with gene expression and therefore, can also affect cellular and organismic physiology. As double-stranded RNAs are a hallmark of viral pathogens RNA-editing not only affects RNA-processing, coding and gene expression but also controls the antiviral response to double-stranded RNAs. Most interestingly, recent advances in our understanding of ADAR enzymes reveal multiple layers of regulation by which ADARs can control antiviral programs. In this review we focus on the recoding of mRNAs where the altered translation products lead to physiological changes. We also address recent advances in our understanding of the multiple layers of antiviral responses and innate immune modulations mediated by ADAR1.

Semisynthetic Transformations on (+)-Boldine Reveal a 5-HT 2A/2C R Antagonist

Article

Aug 2022

Aporphine alkaloids have shown affinity for serotonin receptors (5-HTRs), and there has been a recent upsurge of interest in aporphines as 5-HT2CR ligands. 1,2,9,10-Tetraoxygenated aporphine alkaloids in particular have demonstrated good affinity for 5-HTRs. In continued efforts to understand the impacts of structural modification of the 1,2,9,10-tetraoxygenated aporphine template on affinity, selectivity, and activity at 5-HT2R subtypes, we used (+)-boldine (8) as a semisynthetic feedstock in the preparation of C-2-alkoxylated (+)-predicentrine analogues. Compound 10n, which contains a benzyloxy group at C-2, has been identified as a novel 5-HT2CR ligand with strong affinity (4 nM) and moderate selectivity versus 5-HT2BR and 5-HT2AR (12-fold and 6-fold, respectively). Compound 10n functions as an antagonist at 5-HT2A and 5-HT2C receptors. Computational experiments indicate that several hydrophobic interactions as well as strong H-bond and salt bridge interactions between the protonated amine moiety in 10n and Asp134 are responsible for the potent 5-HT2CR affinity of this compound. Furthermore, compound 10n displays favorable predicted drug-like characteristics, which is encouraging toward future optimization.

Serotonin modulation of hippocampal functions: From anatomy to neurotherapeutics

Book

Jan 2021

The hippocampal region receives a dense serotoninergic innervation originating from both medial and dorsal raphe nuclei. This innervation regulates hippocampal activity through the activation of distinct receptor families that are expressed in excitatory and inhibitory neurons, terminals of several afferent neurotransmitter systems, and glial cells. Preclinical and clinical studies indicate that hippocampal dysfunctions are involved in learning and memory deficits, dementia, Alzheimer's disease, epilepsy and mood disorders such as anxiety, depression and post-traumatic syndrome disorder, whereas the hippocampus participates also in the therapeutic mechanisms of numerous medicines. Not surprisingly, several drugs acting via 5-HT mechanisms are efficacious to some extent in some diseases and the link between 5-HT and the hippocampus although clear remains difficult to untangle. For this reason, we review reported data concerning the distribution and the functional roles of the 5-HT receptors in the hippocampal region in health and disease. The impact of the 5-HT systems on the hippocampal function is such that the research of new 5-HT mechanisms and drugs is still very active. It concerns notably drugs acting at the 5-HT1A,2A,2C,4,6 receptor subtypes, in addition to the already existing drugs including the selective serotonin reuptake inhibitors.

Structural optimizations and bioevaluation of N-H aporphine analogues as Gq-biased and selective serotonin 5-HT2C receptor agonists

Article

Apr 2022
BIOORG CHEM

The concept of subtype selectivity and functional bias has recently reshaped current GPCR drug discovery for G protein-coupled receptors. A series of new N-H aporphines with A-ring modifications have been synthesized, and their efficacy on 5-HT2 receptor activation was evaluated. SAR analysis led to the discovery of several more potent and selective 5-HT2C receptor agonists (e.g., 11b and 11f) with low nanomolar activity. Molecular docking analysis of this series of aporphines was in accordance with our SAR results. The functional selectivity of specific compounds was tested via both Gq-mediated calcium flux and β-arrestin recruitment assays, which revealed that these compounds exhibited no β-arrestin recruitment activity. Further ADMET study combined with behavioral assessment using a methamphetamine-induced hyperactivity model identified compound 11b and 11f possessing promising drug-like profiles and having antipsychotic potential. These agonists with an exclusive bias toward Gq signaling may serve as valuable pharmacological probes to facilitate the elucidation of therapeutically relevant 5-HT2C signaling pathways and the development of alternative antipsychotic medications.

Signalisation de l'insuline au sein du système sérotoninergique central : nexus de la comorbidité diabète-dépression

Thesis

Dec 2021

Sébastien Bullich

Les études épidémiologiques estiment que le risque de dépression majeure (DM) est plus élevé chez les patients diabétiques comparé à la population générale. Des études plus spécifiques mettent en lumière des corrélations entre la dégradation de certains paramètres métaboliques et les symptômes anxio-dépressifs chez l'humain. C'est notamment le cas pour l'insulino-résistance périphérique qui est positivement corrélée à la sévérité de la DM. En revanche, les conséquences de l'insulino-résistance centrale sur les troubles dépressifs n'ont jamais été étudiés de manière approfondie non seulement en clinique mais également chez l'animal de laboratoire. Compte tenu de la présence du récepteur à l'insuline dans le cerveau, une des hypothèses serait que cette hormone module directement (ou indirectement) l'activité des systèmes monoaminergiques et notamment celle des neurones sérotoninergiques (5-HT) majoritairement regroupé dans le noyau dorsal du raphé (NDR). En effet, si l'influence de l'insuline sur le système dopaminergique et le comportement alimentaire a déjà été montré, très peu d'études se sont intéressées à son impact sur le système 5-HT pourtant clé dans la physiopathologie de la DM. Au cours de ce travail de thèse nous avons pu montrer que le récepteur à l'insuline est présent sur les neurones 5-HT du NDR. Grâce à des techniques d'électrophysiologie ex- et in-vivo et de microdialyse intracérébrale réalisées sur modèle murin, nous avons caractérisé l'effet excitateur de l'insuline sur l'activité électrique des neurones 5-HT. Ces résultats nous ont amené à tester les effets comportementaux de l'insuline et à montrer les effets anxiolytiques de son injection intra-raphé et intra-nasale chez la souris saine. Dans un second temps, afin de se placer dans un contexte pathologique et de mieux comprendre l'impact de la perturbation de la signalisation de l'insuline sur l'humeur, nous avons étudié l'activité du système 5-HT et les comportements de type anxio-dépressifs dans des modèles murins de diabète de type 1 et 2 (DT1/DT2). Dans ces deux modèles, que ce soit dans un contexte d'insulinopénie (DT1) ou d'insulino-résistance (DT2), les souris présentent un phénotype anxieux et certains traits de la DM associés à un diminution de l'activité du système sérotoninergique du NDR. Enfin, nous avons tenté d'identifier l'implication de l'apeline, une adipokine connue pour ses propriétés insulino-sensibilisatrice sur les anomalies comportementales induites par un DT2. Nos résultats montrent que les souris présentant une invalidation génétique de l'apeline, sont plus susceptibles à développer une insulino-résistance en réponse à un régime alimentaire diabétogène et des troubles comportementaux. De manière intéressante le traitement par la metformine, un antidiabétique aux propriétés insulino-sensibilisatrice, ne permet pas l'amélioration des paramètres métaboliques de ces souris mutantes mais améliore leur état anxieux. Ainsi ce travail de thèse a permis de souligner l'existence d'interactions anatomiques et fonctionnelles entre le système insulinergique et sérotoninergique central ainsi que leur importance dans l'anxiété, un trouble psychiatrique souvent annonciateur d'un épisode dépressif. [...]

Lorcaserin for Dravet Syndrome: A Potential Advance Over Fenfluramine?

Article

Jan 2022

Lorcaserin, a selective serotonin 5-HT2C receptor agonist, was developed as an appetite suppressant with the rationale of minimizing the risk of cardiovascular toxicity associated with non-selective serotoninergic agents such as fenfluramine. Eight years after FDA approval, however, it was withdrawn from the market, when a large safety study suggested a potential cancer risk. Following in the fenfluramine footsteps and utilizing the repurposing approach coupled with the regulatory orphan drug designation, lorcaserin is currently in clinical development for the treatment of epilepsy. This potential novel indication builds on the evidence that 5-HT2C receptor stimulation can protect against seizures, and accounts at least in part for fenfluramine’s antiseizure effects in Dravet syndrome models. In animal models, lorcaserin shows a narrower range of antiseizure activity than fenfluramine. In particular, lorcaserin is inactive in classical acute seizure tests such as maximal electroshock and subcutaneous pentylenetetrazole in mice and rats, and the 6-Hz stimulation model in mice. However, it is active in the GAERS absence seizure model, and in mutant zebrafish models of Dravet syndrome. Preliminary uncontrolled studies in patients with Dravet syndrome have yielded promising results, and a phase III, double-blind, placebo-controlled, parallel group trial is currently ongoing to assess its efficacy and safety in children and adults with Dravet syndrome.

Serotonin modulates melatonin synthesis as an autocrine neurotransmitter in the pineal gland

Article

Oct 2021

Significance The pineal gland secretes melatonin at night mainly driven by adrenergic sympathetic inputs. Many other neurotransmitters are found in the pineal gland, suggesting potential fine modulation of melatonin release. Serotonin as a precursor of melatonin synthesis is known to be significantly released by pinealocytes and its receptor also is expressed in pinealocytes. By identifying the release mechanism, cell signaling in the pinealocytes, and its effect on norepinephrine-induced melatonin secretion, our study defines serotonin as an autocrine neurotransmitter in the pineal gland and suggests possible modulatory targets for melatonin secretion.

Amberlyst-15 catalysed synthesis of novel indole derivatives under ultrasound irradiation: Their evaluation as serotonin 5‑HT2C receptor agonists

Article

Oct 2021
BIOORG CHEM

A series of indole based novel Schiff bases was designed as potential agonists of 5‑HT2C receptor that was supported by docking studies in silico. These compounds were synthesized via Amberlyst-15 catalysed condensation of an appropriate pyrazole based primary amine with the corresponding indole-3-aldehyde under ultrasound irradiation at ambient temperature. A number of target Schiff bases were obtained in good yields (77-87%) under mild conditions within 1 h. Notably, the methodology afforded the corresponding pyrazolo[4,3-d]pyrimidin-7(4H)-one derivatives when the primary amine was replaced by a secondary amine. Several Schiff bases showed agonist activity when tested against human 5-HT2C using luciferase assay in HEK293T cells in vitro. The SAR (Structure-Activity-Relationship) studies suggested that the imine moiety was more favorable over its cyclic form i.e. the corresponding pyrazolopyrimidinone ring. The Schiff bases 3b (EC50 1.8 nM) and 3i (EC50 5.7 nM) were identified as the most active compounds and were comparable with Lorcaserin (EC50 8.5 nM). Also like Lorcaserin, none of these compounds were found to be PAM of 5-HT2C. With ∼24 and ∼150 fold selectivity towards 5-HT2C over 5-HT2A and 5-HT2B respectively the compound 3i that reduced locomotor activity in zebrafish (Danio rerio) larvae model emerged as a promising hit molecule for further study.

Serotonin/dopamine interaction: Electrophysiological and neurochemical evidence

Chapter

Mar 2021
Progr Brain Res

The interaction between serotonin (5-HT) and dopamine (DA) in the central nervous system (CNS) plays an important role in the adaptive properties of living animals to their environment. These are two modulatory, divergent systems shaping and regulating in a widespread manner the activity of neurobiological networks and their interaction. The concept of one interaction linking these two systems is rather elusive when looking at the mechanisms triggered by these two systems across the CNS. The great variety of their interacting mechanisms is in part due to the diversity of their neuronal origin, the density of their fibers in a given CNS region, the distinct expression of their numerous receptors in the CNS, the heterogeneity of their intracellular signaling pathway that depend on the cellular type expressing their receptors, and the state of activity of neurobiological networks, conditioning the outcome of their mutual influences. Thus, originally conceptualized as inhibition of 5-HT on DA neuron activity and DA neurotransmission, this interaction is nowadays considered as a multifaceted, mutual influence of these two systems in the regulation of CNS functions. These new ways of understanding this interaction are of utmost importance to envision the consequences of their dysfunctions underlined in several CNS diseases. It is also essential to conceive the mechanism of action of psychotropic drugs directly acting on their function including antipsychotic, antidepressant, antiparkinsonian, and drug of abuse together with the development of therapeutic strategies of Alzheimer's diseases, epilepsy, obsessional compulsive disorders. The 5-HT/DA interaction has a long history from the serendipitous discovery of antidepressants and antipsychotics to the future, rationalized treatments of CNS disorders.

Serotonin modulation of hippocampal functions: From anatomy to neurotherapeutics

Chapter

Mar 2021
Progr Brain Res

Synthesis, docking studies, and pharmacological evaluation of 2-hydroxypropyl-4-arylpiperazine derivatives as serotoninergic ligands

Article

Feb 2021
ARCH PHARM

A new series of norbornene and exo-N-hydroxy-7-oxabicyclo[2.2.1]hept-5-ene-2,3-dicarboximide derivatives was prepared, and their affinities to the 5-HT1A , 5-HT2A , and 5-HT2C receptors were evaluated and compared with a previously synthesized series of derivatives characterized by the same nuclei, to identify selective ligands for the subtype receptors. Arylpiperazines represent one of the most important classes of 5-HT1A R ligands, and the research of new derivatives has been focused on the modification of one or more portions of this pharmacophore. The combination of structural elements (heterocyclic nucleus, hydroxyalkyl chain, and 4-substituted piperazine), known to be critical for the affinity to 5-HT1A receptors, and the proper selection of substituents resulted in compounds with high specificity and affinity toward serotoninergic receptors. The most active compounds were selected for further in vivo assays to determine their functional activity. Finally, to rationalize the obtained results, molecular docking studies were performed. The results of the pharmacological studies showed that 3e, 4j, and 4n were the most active and promising derivatives for the serotonin receptor considered in this study.

Endocannabinoid-serotonin systems interaction in health and disease

Chapter

Jan 2021
Progr Brain Res

Endocannabinoid (eCB) and serotonin (5-HT) neuromodulatory systems work both independently and together to finely orchestrate neuronal activity throughout the brain to strongly sculpt behavioral functions. Surprising parallelism between the behavioral effects of 5-HT and eCB activity has been widely reported, including the regulation of emotional states, stress homeostasis, cognitive functions, food intake and sleep. The distribution pattern of the 5-HT system and the eCB molecular elements in the brain display a strong overlap and several studies report a functional interplay and even a tight interdependence between eCB/5-HT signaling. In this review, we examine the available evidence of the interaction between the eCB and 5-HT systems. We first introduce the eCB system, then we describe the eCB/5-HT crosstalk at the neuronal and synaptic levels. Finally, we explore the potential eCB/5-HT interaction at the behavioral level with the implication for psychiatric and neurological disorders. The precise elucidation of how this neuromodulatory interaction dynamically regulates biological functions may lead to the development of more targeted therapeutic strategies for the treatment of depressive and anxiety disorders, psychosis and epilepsy.

CB1/5-HT/GABA interactions and food intake regulation

Chapter

Jan 2021
Progr Brain Res

Despite historically the serotonergic, GABAergic, and cannabinoid systems have been shown to play a crucial role in the central regulation of eating behavior, interest in the study of the interactions of these neurotransmission systems has only now been investigated. Current evidence suggests that serotonin may influence normal and pathological eating behavior in significantly more complex ways than was initially thought. This knowledge has opened the possibility of exploring the potential clinical utility of new therapeutic strategies more effective and safer than the current approaches to treat pathological eating behavior. Furthermore, the nature and complexity of the interactions between these neurotransmitter systems have provided a better understanding of the pathophysiological mechanisms not only of eating behavior and eating disorders but also of some of the comorbidities associated with modulation of cortical circuits, which are involved in high order cognitive processes. Accordingly, in the present chapter, the clinical and experimental findings of the interactions between serotonin, GABA, and cannabinoids are synthesized, emphasizing the pharmacological, neurophysiological, and neuroanatomical aspects that could potentially improve the current therapeutic approaches against pathological eating behavior.

Serotonergic control of the glutamatergic neurons of the subthalamic nucleus

Chapter

Jan 2021
Progr Brain Res

The subthalamic nucleus (STN) houses a dense cluster of glutamatergic neurons that play a central role in the functional dynamics of the basal ganglia, a group of subcortical structures involved in the control of motor behaviors. Numerous anatomical, electrophysiological, neurochemical and behavioral studies have reported that serotonergic neurons from the midbrain raphe nuclei modulate the activity of STN neurons. Here, we describe this serotonergic innervation and the nature of the regulation exerted by serotonin (5-hydroxytryptamine, 5-HT) on STN neuron activity. This regulation can occur either directly within the STN or at distal sites, including other structures of the basal ganglia or cortex. The effect of 5-HT on STN neuronal activity involves several 5-HT receptor subtypes, including 5-HT1A, 5-HT1B, 5-HT2C and 5-HT4 receptors, which have garnered the highest attention on this topic. The multiple regulatory effects exerted by 5-HT are thought to be modified under pathological conditions, altering the activity of the STN, or due to the benefits and side effects of treatments used for Parkinson's disease, notably the dopamine precursor l-DOPA and high-frequency STN stimulation. Originally understood as a motor center, the STN is also associated with decision making and participates in mood regulation and cognitive performance, two domains of personality that are also regulated by 5-HT. The literature concerning the link between 5-HT and STN is already important, and the functional overlap is evident, but this link is still not entirely understood. The understanding of this link between 5-HT and STN should be increased due to the possible importance of this regulation in the control of fronto-STN loops and inherent motor and non-motor behaviors.

International Union of Basic and Clinical Pharmacology. CX. Classification of Receptors for 5-hydroxytryptamine; Pharmacology and Function

Article

Full-text available

Jan 2021

5-HT receptors expressed throughout the human body are targets for established therapeutics and various drugs in development. Their diversity of structure and function reflects the important role 5-HT receptors play in physiologic and pathophysiological processes. The present review offers a framework for the official receptor nomenclature and a detailed understanding of each of the 14 5-HT receptor subtypes, their roles in the systems of the body, and, where appropriate, the (potential) utility of therapeutics targeting these receptors. SIGNIFICANCE STATEMENT: This review provides a comprehensive account of the classification and function of 5-hydroxytryptamine receptors, including how they are targeted for therapeutic benefit.

A new understanding of GHSR1a——independent of ghrelin activation

Article

Dec 2020
AGEING RES REV

Growth hormone secretagogue receptor 1a (GHSR1a), a member of the G protein-coupled receptor (GPCR) family, is a functional receptor of ghrelin. The expression levels and activities of GHSR1a are affected by various factors. In past years, it has been found that the ghrelin-GHSR1a system can perform biological functions such as anti-inflammation, anti-apoptosis, and anti-oxidative stress. In addition to mediating the effect of ghrelin, GHSR1a also has abnormally high constitutive activity; that is, it can still transmit intracellular signals without activation of the ghrelin ligand. This constitutive activity affects brain functions, growth and development of the body; therefore, it has profound impacts on neurodegenerative diseases and some other age-related diseases. In addition, GHSR1a can also form homodimers or heterodimers with other GPCRs, affecting the release of neurotransmitters, appetite regulation, cell proliferation and insulin release. Therefore, further understanding of the constitutive activities and dimerization of GHSR1a will enable us to better clarify the characteristics of GHSR1a and provide more therapeutic targets for drug development. Here, we focus on the roles of GHSR1a in various biological functions and provide a comprehensive summary of the current research on GHSR1a to provide broader therapeutic prospects for age-related disease treatment.

Serotonergic innervation and serotonin receptor expression of NPY-producing neurons in the rat lateral and basolateral amygdaloid nuclei

Article

Full-text available

Apr 2016

Pharmacobehavioral studies in experimental animals, and imaging studies in humans, indicate that serotonergic transmission in the amygdala plays a key role in emotional processing, especially for anxiety-related stimuli. The lateral and basolateral amygdaloid nuclei receive a dense serotonergic innervation in all species studied to date. We investigated interrelations between serotonergic afferents and neuropeptide Y (NPY)-producing neurons, which are a subpopulation of inhibitory interneurons in the rat lateral and basolateral nuclei with particularly strong anxiolytic properties. Dual light microscopic immunolabeling showed numerous appositions of serotonergic afferents on NPY-immunoreactive somata. Using electron microscopy, direct membrane appositions and synaptic contacts between serotonin-containing axon terminals and NPY-immunoreactive cellular profiles were unequivocally established. Double in situ hybridization documented that more than 50 %, and about 30–40 % of NPY mRNA-producing neurons, co-expressed inhibitory 5-HT1A and excitatory 5-HT2C mRNA receptor subtype mRNA, respectively, in both nuclei with no gender differences. Triple in situ hybridization showed that individual NPY mRNA-producing interneurons co-express both 5-HT1A and 5-HT2C mRNAs. Co-expression of NPY and 5-HT3 mRNA was not observed. The results demonstrate that serotonergic afferents provide substantial innervation of NPY-producing neurons in the rat lateral and basolateral amygdaloid nuclei. Studies of serotonin receptor subtype co-expression indicate a differential impact of the serotonergic innervation on this small, but important, population of anxiolytic interneurons, and provide the basis for future studies of the circuitry underlying serotonergic modulation of emotional stimulus processing in the amygdala.

GPCR modulation of extrasynapitic GABAA receptors

Chapter

Full-text available

Sep 2014

γ-Aminobutyric acid type A (GABAA) receptors (GABAARs), the main inhibitory neurotransmitter-gated ion channels in the central nervous system, are finely tuned by other neurotransmitters and endogenous ligands. The regulation of synaptic GABAARs (sGABAARs) by G protein-coupled receptors (GPCRs) has been well characterized and is known to occur either through the conventional activation of second-messenger signalling cascades by G proteins or directly by protein–protein coupling. In contrast, research on the modulation of extrasynaptic GABAAR (eGABAARs) is still in its infancy and it remains to be determined whether both of the above mechanisms are capable of controlling eGABAAR function. In this chapter, we summarize the available literature on eGABAAR modulation by GPCRs, including GABAB, serotonin (5-HT), dopamine (DA), noradrenaline (NA) and metabotropic glutamate (mGlu) receptors. Although at present these GPCRs-eGABAARs cross-talks have been investigated in a limited number of brain areas (i.e., thalamus, cerebellum, hippocampus, striatum), it is already evident that eGABAARs show a nucleus- and neuronal type-selective regulation by GPCRs that differs from that of sGABAARs. This distinct regulation of eGABAARs versus sGABAARs by GPCRs provides mechanisms for receptor adaptation in response to a variety of physiological stimuli and under different pathophysiological conditions. Further research will advance our understanding of eGABAAR and GPCR signalling and offer novel targets for the treatment of many neurological and neuropsychiatric disorders where abnormalities in eGABAAR have been suggested to exist.

The role of serotonin 5-HT2A receptors in memory and cognition

Article

Full-text available

Oct 2015

Serotonin 5-HT2A receptors (5-HT2ARs) are widely distributed in the central nervous system, especially in brain region essential for learning and cognition. In addition to endogenous 5-HT, several hallucinogens, antipsychotics, and antidepressants function by targeting 5-HT2ARs. Preclinical studies show that 5-HT2AR antagonists have antipsychotic and antidepressant properties, whereas agonist ligands possess cognition-enhancing and hallucinogenic properties. Abnormal 5-HT2AR activity is associated with a number of psychiatric disorders and conditions, including depression, schizophrenia, and drug addiction. In addition to its traditional activity as a G protein-coupled receptor (GPCR), recent studies have defined novel operations of 5-HT2ARs. Here we review progress in the (1) receptor anatomy and biology: distribution, signaling, polymerization and allosteric modulation; and (2) receptor functions: learning and memory, hallucination and spatial cognition, and mental disorders. Based on the recent progress in basic research on the 5-HT2AR, it appears that post-training 5-HT2AR activation enhances non-spatial memory consolidation, while pre-training 5-HT2AR activation facilitates fear extinction. Further, the potential influence that 5-HT2AR-elicited visual hallucinations may have on visual cue (i.e., landmark) guided spatial cognition is discussed. We conclude that the development of selective 5-HT2AR modulators to target distinct signaling pathways and neural circuits represents a new possibility for treating emotional, neuropsychiatric, and neurodegenerative disorders.

Pathophysiology of L-dopa-induced motor and non-motor complications in Parkinson's disease

Article

Full-text available

Jul 2015

Serotonin, but not dopamine, controls stress response and anxiety-like behavior in crayfish, Procambarus clarkii

Article

Full-text available

Jul 2015
J EXP BIOL

In the animal kingdom, biogenic amines are widespread modulators of nervous system that frequently interact in the control of mood. Our previous investigations in crayfish (Procambarus clarkii) have established that stress induces changes in brain serotonin (5-HT) concentrations that are responsible for the appearance of anxiety-like behavior (ALB). The following study further analyzes the roles of 5-HT and of another biogenic amine, dopamine (DA), on crayfish response to stress. Results showed that the intensity of crayfish ALB depended on the intensity of stressful stimulation and was associated with increased concentrations of 5-HT in the brain. These 5-HT levels were significantly correlated, before, as well as after stress, with those of DA, which were approximately 3-5 times less abundant. However, whereas ALB intensity was clearly correlated with brain 5-HT concentrations, it was not significantly correlated with those of DA. Moreover, contrary to 5-HT, DA injections were not able to elicit stress response and ALB. Incidentally, 5-HT and DA levels were not modified by treatment with the anxiolytic chlordiazepoxide, confirming that ALB suppression by this ligand of GABA-A receptors acted downstream and independently from changes in crayfish bioamine levels. Our study also provided evidence that the anxiogenic effect of 5-HT injections can be prevented by a preliminary injection of 5-HT antagonists. Altogether, our results emphasize that the rises in the brain concentrations of 5-HT, but not of DA, play a role in controlling the induction and the intensity of crayfish ALB. © 2015. Published by The Company of Biologists Ltd.

Mice Lacking the Serotonin Htr2B Receptor Gene Present an Antipsychotic-Sensitive Schizophrenic-Like Phenotype

Article

Full-text available

May 2015
NEUROPSYCHOPHARMACOL

Impulsivity and hyperactivity share common ground with numerous mental disorders, including schizophrenia. Recently, a population-specific serotonin 2B (5-HT2B) receptor stop-codon (i.e. HTR2B Q20*) was reported to segregate with severely impulsive individuals, while 5-HT2B mutant (Htr2B(-/-)) mice also showed high impulsivity. Interestingly, in the same cohort, early-onset schizophrenia was more prevalent in HTR2B Q*20 carriers. However, the putative role of 5-HT2B receptor in the neurobiology of schizophrenia has never been investigated. We assessed the effects of the genetic and the pharmacological ablation of 5-HT2B receptors in mice subjected to a comprehensive series of behavioral tests screening for schizophrenic-like symptoms and investigated relevant dopaminergic and glutamatergic neurochemical alterations in the cortex and the striatum. Domains related to the positive, negative and cognitive symptom-clusters of schizophrenia were affected in Htr2B(-/-) mice, as shown by deficits in sensorimotor gating, in selective attention, in social interactions and in learning and memory processes. In addition, Htr2B(-/-) mice presented with enhanced locomotor response to the psychostimulants dizocilpine and amphetamine, and with robust alterations in sleep architecture. Moreover, ablation of 5-HT2B receptors induced a region-selective decrease of dopamine and glutamate concentrations in the dorsal striatum. Importantly, selected schizophrenic-like phenotypes and endophenotypes were rescued by chronic haloperidol treatment. We report herein that 5-HT2B receptor deficiency confers a wide spectrum of antipsychotic-sensitive schizophrenic-like behavioral and psychopharmacological phenotypes in mice and provide first evidence for a role of 5-HT2B in the neurobiology of psychotic disorders.Neuropsychopharmacology accepted article preview online, 04 May 2015. doi:10.1038/npp.2015.126.

Central serotonin-2A (5-HT2A) receptor dysfunction in depression and epilepsy: the missing link?

Article

Full-text available

Mar 2015

5-Hydroxytryptamine 2A receptors (5-HT2A-Rs) are G-protein coupled receptors. In agreement with their location in the brain, they have been implicated not only in various central physiological functions including memory, sleep, nociception, eating and reward behaviors, but also in many neuropsychiatric disorders. Interestingly, a bidirectional link between depression and epilepsy is suspected since patients with depression and especially suicide attempters have an increased seizure risk, while a significant percentage of epileptic patients suffer from depression. Such epidemiological data led us to hypothesize that both pathologies may share common anatomical and neurobiological alteration of the 5-HT2A signaling. After a brief presentation of the pharmacological properties of the 5-HT2A-Rs, this review illustrates how these receptors may directly or indirectly control neuronal excitability in most networks involved in depression and epilepsy through interactions with the monoaminergic, GABAergic and glutamatergic neurotransmissions. It also synthetizes the preclinical and clinical evidence demonstrating the role of these receptors in antidepressant and antiepileptic responses.

Dose equivalents of antidepressants: Evidence-based recommendations from randomized controlled trials

Article

Full-text available

Mar 2015

Dose equivalence of antidepressants is critically important for clinical practice and for research. There are several methods to define and calculate dose equivalence but for antidepressants, only daily defined dose and consensus methods have been applied to date. The purpose of the present study is to examine dose equivalence of antidepressants by a less arbitrary and more systematic method. We used data from all randomized, double-blind, flexible-dose trials comparing fluoxetine or paroxetine as standard drugs with any other active antidepressants as monotherapy in the acute phase treatment of unipolar depression. We calculated the ratio of the mean doses for each study and weighted it by the total sample size to find the weighted mean ratio for each drug, which was then used to define the drug׳s dosage equivalent to fluoxetine 40mg/d. We included 83 studies (14 131 participants). In the primary analysis, fluoxetine 40mg/day was equivalent to paroxetine dosage of 34.0mg/day, agomelatine 53.2mg/day, amitriptyline, 122.3mg/day, bupropion 348.5mg/day, clomipramine 116.1mg/day, desipramine 196.3mg/day, dothiepin 154.8mg/day, doxepin 140.1mg/day, escitalopram 18.0mg/day, fluvoxamine 143.3mg/day, imipramine 137.2mg/day, lofepramine 250.2mg/day, maprotiline 118.0mg/day, mianserin, 101.1mg/day, mirtazapine 50.9mg/day, moclobemide 575.2mg/day, nefazodone 535.2mg/day, nortriptyline 100.9mg/day, reboxetine 11.5mg/day, sertraline 98.5mg/day, trazodone 401.4mg/day, and venlafaxine 149.4mg/day. Sensitivity analyses corroborated the results except for doxepin. The number of studies for some drugs was small. The current method assumes dose response relationship of antidepressants. Our findings can be useful for clinicians when they switch antidepressants and for researchers when they compare various antidepressants in their research. Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.

Regulation of Oligomeric Organization of the Serotonin 5-HT2C Receptor Observed by Spatial Intensity Distribution Analysis

Article

Full-text available

Mar 2015
J BIOL CHEM

The questions of whether G proteincoupled receptors exist as monomers, dimers and/or oligomers and if these species interconvert in a ligand-dependent manner are amongst the most contentious current issues in biology. When employing Spatial Intensity Distribution Analysis to laser scanning confocal microscope images of cells stably expressing either a plasma membraneassociated form of monomeric eGFP or of a tandem of this fluorophore, the eGFP-tandem was identified as a dimer. Similar studies on cells stably expressing an eGFP-tagged form of the Epidermal Growth Factor receptor demonstrated that although largely a monomer in the basal state this receptor rapidly became predominantly dimeric upon addition of its ligand Epidermal Growth Factor. In cells induced to express an eGFPtagged form of the serotonin 5-HT2C receptor global analysis of construct quantal brightness was consistent with the predominant form of the receptor being dimeric. However, detailed Spatial Intensity Distribution Analysis demonstrated the presence of multiple forms ranging from monomers to higher-order oligomers. Furthermore, treatment with chemically distinct 5-HT2C receptor antagonists resulted in a time-dependent change in the quaternary organization to one in which there was a preponderance of receptor monomers. This antagonist-mediated effect was reversible, as washout of the ligand resulted in the regeneration of many of the oligomeric forms of the receptor. Copyright © 2015, The American Society for Biochemistry and Molecular Biology.

5-HT2C Receptor Desensitization Moderates Anxiety in 5-HTT Deficient Mice: From Behavioral to Cellular Evidence

Article

Full-text available

Oct 2014

Desensitization and blockade of 5-HT2C receptors (5-HT2CR) have long been thought to be central in the therapeutic action of antidepressant drugs. However, besides behavioral pharmacology studies, there is little in vivo data documenting antidepressant-induced 5-HT2CR desensitization in specific brain areas. Mice lacking the 5-HT reuptake carrier (5-HTT(-/-)) were used to model the consequences of chronic 5-HT reuptake inhibition with antidepressant drugs. The effect of this mutation on 5-HT2CR was evaluated at the behavioral (social interaction, novelty-suppressed feeding and 5-HT2CR-induced hypolocomotion tests), the neurochemical and the cellular (RT-qPCR, mRNA editing and c-fos-induced expression) levels. Although 5-HTT(-/-) mice had an anxiogenic profile in the novelty-suppressed feeding test, they displayed less 5-HT2CR-mediated anxiety in response to the agonist m-chlorophenylpiperazine in the social interaction test. In addition, 5-HT2CR-mediated inhibition of stress-induced increase in 5-HT turnover, measured in various brain areas, was markedly reduced in 5-HTT(-/-) mutants. These indices of tolerance to 5-HT2CR stimulation were associated neither with altered levels of 5-HT2CR protein and mRNA nor with changes in pre-mRNA editing in the frontal cortex. However, basal c-fos mRNA production in cells expressing 5-HT2CR was higher in 5-HTT(-/-) mutants, suggesting an altered basal activity of these cells following sustained 5-HT reuptake carrier inactivation. Furthermore, the increased c-fos mRNA expression in 5-HT2CR-like immune-positive cortical cells observed in wild-type mice treated acutely with the 5-HT2CR agonist RO-60,0175, was absent in 5-HTT(-/-) mutants. Such blunted responsiveness of the 5-HT2CR system, observed at the cell signaling level, probably contributes to moderate the anxiety phenotype of 5-HTT(-/-) mice. © The Author 2014. Published by Oxford University Press on behalf of CINP.

Optimization of 2-Phenylcyclopropylmethylamines as Selective Serotonin 2C Receptor Agonists and Their Evaluation as Potential Antipsychotic Agents

Article

Full-text available

Jan 2015

The discovery of a new series of compounds that are potent, selective 5-HT2C receptor agonists is described herein, as we continue our efforts to optimize the 2-phenylcyclopropylmethylamine scaffold. Modifications focused on the alkoxyl substituent present on the aromatic ring led to the identification of improved ligands with better potency at the 5-HT2C receptor and excellent selectivity against the 5-HT2A and 5-HT2B receptors. ADMET studies coupled with a behavioral test using the amphetamine-induced hyperactivity model identified four compounds possessing drug-like profiles and having antipsychotic properties. Compound (+)-16b, which displayed an EC50 of 4.2 nM at 5-HT2C, no activity at 5-HT2B, and an 89-fold selectivity against 5-HT2A, is one of the most potent and selective 5-HT2C agonists reported to date. The likely binding mode of this series of compounds to the 5-HT2C receptor was also investigated in a modeling study, using optimized models incorporating the structures of β2-adrenergic receptor and 5-HT2B receptor.

Agomelatine beyond Borders: Current Evidences of Its Efficacy in Disorders Other than Major Depression

Article

Full-text available

Jan 2015
INT J MOL SCI

Agomelatine, a melatonergic antidepressant with a rapid onset of action, is one of the most recent drugs in the antidepressant category. Agomelatine’s antidepressant actions are attributed to its sleep-promoting and chronobiotic actions mediated by MT1 and MT2 receptors present in the suprachiasmatic nucleus, as well as to its effects on the blockade of 5-HT2c receptors. Blockade of 5-HT2c receptors causes release of both noradrenaline and dopamine at the fronto-cortical dopaminergic and noradrenergic pathways. The combined actions of agomelatine on MT1/MT2 and 5-HT2c receptors facilitate the resynchronization of altered circadian rhythms and abnormal sleep patterns. Agomelatine appeared to be effective in treating major depression. Moreover, evidence exists that points out a possible efficacy of such drug in the treatment of bipolar depression, anxiety disorders, alcohol dependence, migraines etc. Thus, the aim of this narrative review was to elucidate current evidences on the role of agomelatine in disorders other than major depression.

Glial Dysfunction in the Mouse Habenula Causes Depressive-Like Behaviors and Sleep Disturbance

Article

Full-text available

Dec 2014

The lateral habenula (LHb) regulates the activity of monoaminergic neurons in the brainstem. This area has recently attracted a surge of interest in psychiatry because studies have reported the pathological activation of the habenula in patients with major depression and in animal models. The LHb plays a significant role in the pathophysiology of depression; however, how habenular neurons are activated to cause various depression symptoms, such as reduced motivation and sleep disturbance, remain unclear. We hypothesized that dysfunctional astrocytes may cause LHb hyperactivity due to the defective uptake activity of extracellular glutamate, which induces depressive-like behaviors. We examined the activity of neurons in habenular pathways and performed behavioral and sleep analyses in mice with pharmacological and genetic inhibition of the activity of the glial glutamate transporter GLT-1 in the LHb. The habenula-specific inhibition of GLT-1 increased the neuronal firing rate and the level of c-Fos expression in the LHb. Mice with reduced GLT-1 activity in the habenula exhibited a depressive-like phenotype in the tail suspension and novelty-suppressed feeding tests. These animals also displayed increased susceptibility to chronic stress, displaying more frequent avoidant behavior without affecting locomotor activity in the open-field test. Intriguingly, the mice showed disinhibition of rapid eye movement sleep, which is a characteristic sleep pattern in patients with depression. These results provide evidence that disrupting glutamate clearance in habenular astrocytes increases neuronal excitability and depressive-like phenotypes in behaviors and sleep. Copyright © 2014 the authors 0270-6474/14/3416273-13$15.00/0.

Reward processing by the lateral habenula in normal and depressive behaviors

Article

Full-text available

Aug 2014

The brain reward circuit has a central role in reinforcing behaviors that are rewarding and preventing behaviors that lead to punishment. Recent work has shown that the lateral habenula is an important part of the reward circuit by providing 'negative value' signals to the dopaminergic and serotonergic systems. Studies have also suggested that dysfunction of the lateral habenula is associated with psychiatric disorders, including major depression. Here, we discuss insights gained from neuronal recordings in monkeys regarding how the lateral habenula processes reward-related information. We then highlight recent optogenetic experiments in rodents addressing normal and abnormal functions of the habenula. Finally, we discuss how deregulation of the lateral habenula may be involved in depressive behaviors.

Serotonin–Dopamine Interaction: Experimental Evidence and Therapeutic Relevance

Book

Full-text available

Jan 2008

“Progress in Brain Research,” Volume 172, presents various aspects of the serotonin–dopamine interactions in both physiological and pathological phenomena. As new evidence has recently emerged due to the development of new techniques in molecular biology, genetics, single cell and membrane physiology, clinical neurology, neuropsychiatry and brain imaging in vivo, this book provides a systematic overview of these recent developments according to the understanding of the chemical neuroanatomy of the interaction of serotonin and dopamine from a functional perspective. The selection starts, after an overview of the topic, by reviewing the interactions between these two monoamines from an electrophysiological and neurochemical point of view, in different brain areas. Thereafter, the polymorphisms in monoamine neurotransmitter pathway genes and the involvement in the physiopathology of schizophrenia, depression, drug abuse, attention-deficit hyperactivity disorder, Parkinson's disease, Tourette's syndrome, and in cognition processes are examined from different perspectives. Both pharmacologists looking for new systems for developing drugs, and neuroscientists, whether researchers or advanced students, are expected to find this book useful. First and foremost, we give our heartfelt thanks to Giuseppe, who conceived the original idea for this book and whose passion and tireless hard work lead to its realization. Moreover, he has always been supportive throughout the highs and lows of editing. The choice of text has been made assuming that the reader has maintained an interest in serotonin and dopamine, a field complicated, vast, and at present, probably one of the richest in scientific literature, and is now keen to embark on a more in-depth study of their interaction. With this in mind, we have sought to offer as varied a picture as possible, by including different points of view, together with different aspects of the serotonin–dopamine interactions in both physiological and pathological phenomena. New evidence has recently emerged thanks to the development of new techniques in molecular biology, genetics, single cell and membrane physiology, clinical neurology, neuropsychiatry and brain imaging in vivo. In this volume, we seek to provide a systematic overview of these recent developments in our understanding of the chemical neuroanatomy of the interaction of serotonin and dopamine from a functional perspective. The selection starts, after an overview of the topic, by reviewing the interactions between these two monoamines from an electrophysiological and neurochemical point of view, in different brain areas. Thereafter, the polymorphisms in monoamine neurotransmitter pathway genes and the involvement in the physiopathology of schizophrenia, depression, drug abuse, attention-deficit hyperactivity disorder, Parkinson's disease, Tourette's syndrome and in cognition processes are examined from different perspectives. We will feel that our labour has been worthwhile if any reader is stimulated to further study of this rich literature or is inspired to research this important and fascinating scientific field. Moreover, both pharmacologists looking for new systems for developing drugs, and neuroscientists, whether researchers or advanced students, will find this important work useful. While covering the latest research, for obvious reasons this book cannot be exhaustive and we are sorry indeed that it has been impossible to include a number of authors of obvious merit. The selection is intended, indeed, to be merely a very varied foretaste of contemporary research on the subject. Therefore, we would like to see this book as an ongoing project, in which future editions will follow the developments in the field. We consider however, that the varied selection has a certain unity as physiologic, pathologic and psychological themes run through the book and supply the logical connections between the various authors. The editors wish to thank all the authors who have responded so willingly to contribute their time and expertise in preparing their individual chapters to a consistently high standard. Our warmest thanks go to Hilary Rowe, Elsevier publishing editor, who believed in the potential of this book and the importance of the messages it conveys and Maureen Twaig who has helped to drive the book's development and eventual publication.

Striatal Serotonin 2C receptors decrease nigrostriatal dopamine release by increasing GABA-A receptor tone in the substantia nigra

Article

Full-text available

Jul 2014
J NEUROCHEM

Drugs acting at the serotonin-2C (5-HT2C) receptor subtype have shown promise as therapeutics in multiple syndromes including obesity, depression, and Parkinson's disease. While it is established that 5-HT2C receptor stimulation inhibits DA release, the neural circuits and the localization of the relevant 5-HT2C receptors remain unknown. The present study used dual-probe in vivo microdialysis to investigate the relative contributions of 5-HT2C receptors localized in the rat substantia nigra (SN) and caudate-putamen (CP) in the control of nigrostriatal DA release. Systemic administration (3.0 mg/kg) of the 5-HT2C receptor selective agonist Ro 60-0175 [(αS)-6-Chloro-5-fluoro-α-methyl-1H-indole-1-ethanamine fumarate] decreased, whereas intrastriatal infusions of the selective 5-HT2C antagonist SB 242084 [6-Chloro-2,3-dihydro-5-methyl-N-[6-[(2-methyl-3-pyridinyl)oxy]-3-pyridinyl]-1H-indole-1-carboxyamide; 1.0 μM] increased, basal DA in the CP. Depending on the site within the SN pars reticulata (SNpr), infusions of SB 242084 had more modest but significant effects. Moreover, infusions of the GABA-A receptor agonist muscimol (10 μM) into the SNpr completely reversed the increases in striatal DA release produced by intrastriatal infusions of SB 242084. These findings suggest a role for 5-HT2C receptors regulating striatal DA release that is highly localized. 5-HT2C receptors localized in the striatum may represent a primary site of action that is mediated by actions on GABAergic activity in the SN.This article is protected by copyright. All rights reserved.

Comparative behavior. Anxiety-like behavior in crayfish is controlled by serotonin

Article

Full-text available

Jun 2014

The crayfish that was afraid of the dark We tend to assume that complex emotions, such as anxiety, only occur in mammals or other cognitively complex vertebrates. But a heightened sense of awareness and the avoidance of novel or dangerous environments could be helpful for any animal species. Fossat et al. show that crayfish exposed to a stressful electric field refuse to enter dark arms in a light/dark maze, even after the electric field has been removed. The animals calmed down when they were injected with an anxiolytic drug used to treat anxiety in humans, and they entered the dark as normal. The stressed animals had increased levels of the neurotransmitter serotonin in the brain, and injections of serotonin induced anxiety-like behavior in control animals. Thus, these invertebrates display a primitive form of anxiety that shares a mechanism with the more complex emotions displayed by vertebrates. Science , this issue p. 1293

Widespread Monoaminergic Dysregulation of Both Motor and Non-Motor Circuits in Parkinsonism and Dyskinesia

Article

Full-text available

Apr 2014
CEREB CORTEX

Beyond dopamine (DA) loss, Parkinson's disease is associated with many other monoamine alterations. While some monoaminergic systems benefit from l-3,4-dihydroxyphenylalanine (l-Dopa) treatment, others seem to be further altered, contributing to dyskinesia and nonmotor symptoms. Surprisingly, the different contributions of parkinsonism and l-Dopa treatment on monoaminergic changes remain largely unknown. Here, both the consequences of vehicle or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) exposure and the subsequent effects of acute or chronic l-Dopa treatment were evaluated in macaques. Monoamine levels were measured in the putamen, the motor and prefrontal cortices, the hippocampus, and the amygdala using postmortem high-pressure liquid chromatography. In normal monkeys, l-Dopa treatment increased DA in the prefrontal cortex and hippocampus, but decreased serotonin levels in motor domains. Chronic l-Dopa treatment elevated monoamine levels in the prefrontal cortex, hippocampus, and amygdala in both normal and MPTP-treated monkeys. A substantial increase in DA levels in these regions, paralleled by a decrease in serotonin concentrations were related with dyskinesia severity, demonstrating that major changes in monoamine release also occur in nonmotor regions. Such monoaminergic dysregulation in limbic domains may also directly contribute to the expression of motor complications, such as dyskinesia, by impairing integrative processes upstream from motor execution.

Somatodendritic localization of 5‐HT1A and preterminal axonal localization of 5‐HT1B serotonin receptors in adult rat brain

Article

Feb 2000
J COMP NEUROL

The 5‐HT1A and 5‐HT1B receptors of serotonin play important roles as auto‐ and heteroreceptors controlling the release of serotonin itself and of other neurotransmitters/modulators in the central nervous system (CNS). To determine the precise localization of these receptors, we examined their respective cellular and subcellular distributions in the nucleus raphe dorsalis and hippocampal formation (5‐HT1A) and in the globus pallidus and substantia nigra (5‐HT1B), using light and electron microscopic immunocytochemistry with specific antibodies. Both immunogold and immunoperoxidase preembedding labelings were achieved. In the nucleus raphe dorsalis, 5‐HT1A immunoreactivity was found exclusively on neuronal cell bodies and dendrites, and mostly along extrasynaptic portions of their plasma membrane. After immunogold labeling, the density of membrane‐associated 5‐HT1A receptors could be estimated to be at least 30–40 times that in the cytoplasm. In the hippocampal formation, the somata as well as dendrites of pyramidal and granule cells displayed 5‐HT1A immunoreactivity, which was also prominent on the dendritic spines of pyramidal cells. In both substantia nigra and globus pallidus, 5‐HT1B receptors were preferentially associated with the membrane of fine, unmyelinated, preterminal axons, and were not found on axon terminals. A selective localization to the cytoplasm of endothelial cells of microvessels was also observed. Because the 5‐HT1A receptors are somatodendritic, they are ideally situated to mediate serotonin effects on neuronal firing, both as auto‐ and as heteroreceptors. The localization of 5‐HT1B receptors to the membrane of preterminal axons suggests that they control transmitter release from nonserotonin as well as serotonin neurons by mediating serotonin effects on axonal conduction. The fact that these two receptor subtypes predominate at extrasynaptic and nonsynaptic sites provides further evidence for diffuse serotonin transmission in the CNS. J. Comp. Neurol. 417:181–194, 2000. ©2000 Wiley‐Liss, Inc.

Catecholamine/Serotonin interactions: systems thinking for brain function and disease.

Article

Jan 2013

Antipsychotic-Induced Weight Gain in First-Episode Psychosis Patients: A Meta-Analysis of Differential Effects of Antipsychotic Medications

Article

Jul 2016

Aim:The first-episode psychosis (FEP) represents a critical period to prevent cardiovascular and metabolic morbidity decades later. Antipsychotic (AP)-induced weight gain is one modifiable factor in this period. The purpose of this study is to conduct a meta-analysis of AP-induced weight and body mass index (BMI) change in FEP.Methods:A comprehensive literature search identified 28 articles that reported data on AP-specific weight or BMI change in FEP. We conducted a meta-analysis of short- and long-term mean weight and BMI differences between placebo and AP medications. We also performed subgroup and meta-regression analysis to examine weight, BMI outcomes and their relationship with location (Asian vs. Western), sponsorship and baseline weight and BMIs.Results:Compared to placebo, AP-caused mean weight gain was 3.22 kg and 1.4 points BMI in the short-term, and 5.30 kg and 1.86 points BMI in the long term. Clinically significant weight gain risk increased about twofold with AP use. Weight gain was associ...

Modeling tardive dyskinesia: Predictive 5-HT2C receptor antagonist treatment

Conference Paper

Jan 2007

Tardive dyskinesia (TD), a movement disorder produced by long-term treatment with a classical antipsychotic drug, is generally considered to be a disorder of dopamine (DA) systems, since classical antipsychotics are potent DA D-2 receptor blockers. Also, acute DA D-1 agonist treatment of rats is known to produce vacuous chewing movements (VCMs), a behavioral feature resembling the oral dyskinesia that is so prominent in most instances of TD. In this paper we outline a series of studies in a new animal model of TD in which DA D, receptor supersensitivity was produced by neonatal 6-hydroxydopamine (6-OHDA) -induced destruction of nigrostriatal DA fibers. In rats so-lesioned 5-HT receptor supersensitivity is additionally produced, and in fact 5-HT receptor antagonists attenuate enhanced DA D, induction of VCMs. Moreover, in 6-OHDA-lesioned rats treated with haloperidol for one year, there is a 2-fold increase in numbers of VCMs (versus intact rats treated with haloperidol); and this high frequency of VCMs persists for more than 6 months after discontinuing haloperidol treatment. During this stage, 5-HT2 receptor antagonists, but not DA D-1 receptor antagonists, attenuate the incidence of VCMs. This series of findings implicates the 5-HT neuronal phenotype in TD, and promotes 5-HT2 receptor antagonists, more specifically 5-HT2C receptor antagonists, as a rational treatment approach for TD in humans.

Differential Regulation of the Mesoaccumbens Circuit by Serotonin 5-Hydroxytryptamine (5-HT) 2A and 5-HT 2C Receptors

Article

Oct 2001

Serotonin [5-hydroxytryptamine (5-HT)] 5-HT(2A) and 5-HT(2C) receptors (5-HT(2A)Rs and 5-HT(2C)Rs), which innervate the dopamine mesoaccumbens pathway, may play an important role in the behavioral effects of cocaine. To test this hypothesis, the present study measured cocaine-evoked locomotor activity after bilateral microinjection of selective 5-HT(2A)R and 5-HT(2C)R antagonists into the ventral tegmental area (VTA) or the nucleus accumbens (NAc) shell. Locomotor activity was measured after intracranial microinjection of saline (0.2 mul/side), the selective 5-HT(2A)R antagonist R-(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-flucrophenylethyl)]-4-piperidine methanol (M100907) (0.1 or 0.3 mug.0.2 mul(-1).side(-1)), or the selective 5-HT(2C)R antagonist 8-[5-(2,4-dimethoxy-5-(4-trifluoromethylphenylsulfon-amido)phenyl-5-oxopentyl)]- 1,3,8-triazaspiro[4.5]decane-2,4-dione hydrochloride (RS 102221) (0.05-0.5 mug.0.2 mul(-1).side(-1)) followed by an injection of saline (1 ml/kg, i.p.) or cocaine (10 mg/kg, i.p.).Microinjection Of M100907 (0.1-0.3 mug/side) into the VTA or RS 102221 (0.15-0.5 mug/side) into the NAc shell attenuated cocaine-induced hyperactivity in a dose-related manner. However, hyperactivity evoked by cocaine was not altered by microinjection of RS 102221 into the VTA or M100907 into the NAc shell. No changes in basal activity were observed after microinjection of M100907 or RS 102221 into either brain region. These findings are the first to demonstrate that the behavioral effects of cocaine are generated in part by activation of 5-HT(2A)Rs in the VTA and by activation of 5-HT(2C)Rs in the NAc shell. The selective regulation of the mesoaccumbens circuit by 5-HT(2A)Rs and 5-HT(2C)Rs implicates these 5-HT receptors as important in the behavioral outcomes of systemic cocaine administration.

The neurobiology of anxious states

Article

Jan 2003
PROG NEUROBIOL

M.J. Millan

5-HT2A and 5-HT2C/2B receptor subtypes modulate dopamine release induced in vivo by amphetamine and morphine in both the rat nucleus accumbens and striatum

Article

Jan 1999

Parkinson's disease

Article

Jan 2011

Genetic absence epilipsy in rats from Strasbourg — A review

Article

Jan 1992

Differential Control by 5-HT and 5-HT1A, 2A, 2C Receptors of Phasic and Tonic GABAA Inhibition in the Visual Thalamus

Article

Nov 2015
CNS NEUROSCI THER

Functional magnetic resonance imaging and c-Fos mapping in rats following an anorectic dose of m-chlorophenylpiperazine

Article

Jan 2006
NEUROIMAGE

We have used blood-oxygenation-level-dependent (BOLD) contrast functional magnetic resonance imaging (fMRI) to characterise brain regions responsive to a regulator of appetite. An anorectic dose of the 5-HT(1B/2C) receptor agonist m-chlorophenylpiperazine (mCPP; 3 mg/kg s.c.) was used to compare BOLD contrast fMRI with expression of the c-Fos protein. mCPP was administered to rats, which were then anaesthetised and perfused with fixative 90 min later to allow immunohistochemistry. In a separate experiment, rats were imaged using a T(2)*-weighted gradient echo in a 7 T magnet for 70 min under alpha-chloralose anaesthesia. Both methods detected positive activation in areas of the limbic system: cingulate and orbitofrontal cortices, nucleus accumbens, paraventricular and dorsomedial regions of the hypothalamus. fMRI detected increased signal in the pontine nuclei, the hippocampal formation and olfactory cortex, areas that did not display c-Fos. In addition, BOLD signal was diminished in the ventral tegmental area, preoptic area and the cerebellum-presumably due to decreased neuronal signalling and, therefore, unlikely to display c-Fos. Activity in the limbic system may reflect the appetitive agonist activity of mCPP at the 5-HT(2C) receptor. We conclude that c-Fos provides excellent spatial information but is less useful for detecting inhibited regions, whereas fMRI provides greater temporal resolution. Thus, the two methodologies provide complementary details of brain activity following pharmacological challenge.

A review of the pharmacological and clinical profile of mirtazapine

Article

Sep 2001
CNS DRUG REV

The novel antidepressant mirtazapine has a dual mode of action. It is a noradrenergic and specific serotonergic antidepressant (NaSSA) that acts by antagonizing the adrenergic α2-autoreceptors and α2-heteroreceptors as well as by blocking 5-HT2 and 5-HT3 receptors. It enhances, therefore, the release of norepinephrine and 5-HT1A-mediated serotonergic transmission. This dual mode of action may conceivably be responsible for mirtazapine's rapid onset of action. Mirtazapine is extensively metabolized in the liver. The cytochrome (CYP) P450 isoenzymes CYP1A2, CYP2D6, and CYP3A4 are mainly responsible for its metabolism. Using once daily dosing, steady-state concentrations are reached after 4 days in adults and 6 days in the elderly. In vitro studies suggest that mirtazapine is unlikely to cause clinically significant drug-drug interactions. Dry mouth, sedation, and increases in appetite and body weight are the most common adverse effects. In contrast to selective serotonin reuptake inhibitors (SSRIs), mirtazapine has no sexual side effects. The antidepressant efficacy of mirtazapine was established in several placebo-controlled trials. In major depression, its efficacy is comparable to that of amitriptyline, clomipramine, doxepin, fluoxetine, paroxetine, citalopram, or venlafaxine. Mirtazapine also appears to be useful in patients suffering from depression comorbid with anxiety symptoms and sleep disturbance. It seems to be safe and effective during long-term use.

Acute Nicotine Induces Anxiety and Disrupts Temporal Pattern Organization of Rat Exploratory Behavior in Hole-Board: A Potential Role for the Lateral Habenula

Article

Jun 2015

Abstract Nicotine is one of the most addictive drugs of abuse. Tobacco smoking is a major cause of many health problems, and is the first preventable cause of death worldwide. Several findings show that nicotine exerts significant aversive as well as the well-known rewarding motivational effects. Less certain is the anatomical substrate that mediates or enables nicotine aversion. Here, we show that acute nicotine induces anxiogenic effects in rats at the doses investigated (0.1, 0.5, and 1.0 mg/kg, i.p.), as measured by the hole-board apparatus and manifested in behaviors such as decreased rearing and head-dipping and increased grooming. No changes in locomotor behavior were observed at any of the nicotine doses given. T-pattern analysis of the behavioral outcomes revealed a drastic reduction and disruption of complex behavioral patterns induced by all three nicotine doses, with the maximum effect for 1 mg/kg. Lesion of the lateral habenula (LHb) induced hyperlocomotion and, strikingly, reversed the nicotine-induced anxiety obtained at 1 mg/kg to an anxiolytic-like effect, as shown by T-pattern analysis. We suggest that the LHb is critically involved in emotional behavior states and in nicotine-induced anxiety, most likely through modulation of monoaminergic nuclei.

Antipsychotic-induced weight gain in first-episode psychosis patients: a meta-analysis of differential effects of antipsychotic medications: Weight gain in FEP patients

Article

May 2015
EARLY INTERV PSYCHIA

The first-episode psychosis (FEP) represents a critical period to prevent cardiovascular and metabolic morbidity decades later. Antipsychotic (AP)-induced weight gain is one modifiable factor in this period. The purpose of this study is to conduct a meta-analysis of AP-induced weight and body mass index (BMI) change in FEP. A comprehensive literature search identified 28 articles that reported data on AP-specific weight or BMI change in FEP. We conducted a meta-analysis of short- and long-term mean weight and BMI differences between placebo and AP medications. We also performed subgroup and meta-regression analysis to examine weight, BMI outcomes and their relationship with location (Asian vs. Western), sponsorship and baseline weight and BMIs. Compared to placebo, AP-caused mean weight gain was 3.22 kg and 1.4 points BMI in the short-term, and 5.30 kg and 1.86 points BMI in the long term. Clinically significant weight gain risk increased about twofold with AP use. Weight gain was associated with duration of AP use. AP medications were associated with more weight gain in Western samples as opposed to Asian samples. Most AP medications were associated with significant body weight gain and BMI increase in FEP patients, except for ziprasidone. Olanzapine and clozapine caused the highest weight gain compared to placebo. Except for ziprasidone, most AP medications were associated with body weight gain and BMI increase in FEP patients. Early and continuing effects of various AP medications on weight gain and BMI increase should be taken into consideration by clinicians. © 2015 Wiley Publishing Asia Pty Ltd.

Therapeutic Potential of 5-HT 2C Receptor Agonists for Addictive Disorders

Article

Apr 2015

The neurotransmitter 5-hydroxytryptamine (5-HT; serotonin) has long been associated with the control of a variety of motivated behaviors, including feeding. Much of the evidence linking 5-HT and feeding behavior was obtained from studies of the effects of the 5-HT releaser (dex)fenfluramine in laboratory animals and humans. Recently, the selective 5-HT2C receptor agonist lorcaserin received FDA approval for the treatment of obesity. This review examines evidence to support the use of selective 5-HT2C receptor agonists as treatments for conditions beyond obesity, including substance abuse (particularly nicotine, psychostimulant, and alcohol dependence), obsessive compulsive, and excessive gambling disorder. Following a brief survey of the early literature supporting a role for 5-HT in modulating food and drug reinforcement, we propose that intrinsic differences between SSRI and serotonin releasers may have underestimated the value of serotonin-based pharmacotherapeutics to treat clinical forms of addictive behavior beyond obesity. We then highlight the critical involvement of the 5-HT2C receptor in mediating the effect of (dex)fenfluramine on feeding and body weight gain and the evidence that 5-HT2C receptor agonists reduce measures of drug reward and impulsivity. A recent report of lorcaserin efficacy in a smoking cessation trial further strengthens the idea that 5-HT2C receptor agonists may have potential as a treatment for addiction. This review was prepared as a contribution to the proceedings of the 11th International Society for Serotonin Research Meeting held in Hermanus, South Africa, July 9-12, 2014.

Prediction of Working Memory Performance in Schizophrenia by Plasma Ratio of Clozapine to N -Desmethylclozapine

Article

Apr 2015
AM J PSYCHIAT

Clozapine's potent antagonism of muscarinic M1 receptors is thought to worsen working memory deficits associated with schizophrenia. In contrast, its major metabolite, N-desmethylclozapine (NDMC), is thought to enhance working memory via its M1 receptor agonist activity. The authors hypothesized that the ratio of serum clozapine and NDMC concentrations would be inversely associated with working memory performance in schizophrenia. Thirty patients with schizophrenia or schizoaffective disorder who were receiving clozapine monotherapy at bedtime completed the MATRICS Consensus Cognitive Battery (MCCB) on the day their blood was collected to assess concentrations of clozapine and NDMC as well as serum anticholinergic activity. The clozapine/NDMC ratio was significantly and negatively associated with working memory performance after controlling for age, gender, education, and symptom severity. No significant associations were found between individual clozapine and NDMC concentrations and working memory performance. Serum anticholinergic activity was significantly associated with clozapine concentration, but not with working memory performance or NDMC concentration. No significant associations were found between any pharmacological measure and performance on other MCCB cognitive domains. This hypothesis-driven study confirms that clozapine/NDMC ratio is a strong predictor of working memory performance in patients with schizophrenia. This finding suggests that manipulating the clozapine/NDMC ratio could enhance cognition in patients with schizophrenia treated with clozapine. It also supports the study of procholinergic agents, such as M1 receptor-positive allosteric modulators, to enhance cognition in schizophrenia.

Ghrelin’s Orexigenic Effect Is Modulated via a Serotonin 2C Receptor Interaction

Article

Mar 2015

Understanding the intricate pathways modulating appetite and subsequent food intake is of particular importance considering the rise in obesity incidence across the globe. The serotonergic system, specifically the 5-HT2C receptor, has shown to be of critical importance in the regulation of appetite and satiety. The GHS-R1a receptor is another key receptor well-known for its role in the homeostatic control of food intake and energy balance. We recently showed compelling evidence for an interaction between the GHS-R1a receptor and the 5-HT2C receptor in an in vitro cell line system heterologously expressing both receptors. Here, we investigated this interaction further. First, we show that the GHS-R1a/5-HT2C dimer-induced attenuation of calcium signalling is not due to coupling to GαS, as no increase in cAMP signalling is observed. Next, flowcytometry fluorescence resonance energy transfer (fcFRET) is used to further demonstrate the direct interaction between the GHS-R1a receptor and 5-HT2C receptor. In addition, we demonstrate co-localized expression of the 5-HT2C and GHS-R1a receptor in cultured primary hypothalamic- and hippocampal rat neurons, supporting the biological relevance of a physiological interaction. Furthermore, we demonstrate that when 5-HT2C receptor signalling is blocked, ghrelin's orexigenic effect is potentiated in vivo. In contrast, the specific 5-HT2C receptor agonist lorcaserin, recently approved for the treatment of obesity, attenuates ghrelin-induced food intake. This underscores the biological significance of our in vitro findings of 5-HT2C receptor-mediated attenuation of GHS-R1a receptor activity. Together, this study demonstrates, for the first time, that the GHS-R1a/5-HT2C receptor interaction translates into biological significant modulation of ghrelin's orexigenic effect. This data highlights the potential development of a combined GHS-R1a and 5-HT2C receptor treatment strategy in weight management.

Serotonergic Function in Obsessive-Compulsive Disorder

Article

Jan 1992
ARCH GEN PSYCHIAT

Eric Hollander

• To evaluate serotonergic (5-hydroxytryptamine) function in obsessive-compulsive disorder, behavioral and neuroendocrine responses to m-chlorophenylpiperazine (m-CPP; 0.5 mg/kg orally) and fenfluramine hydrochloride (60 mg orally) were examined in 20 patients and 10 healthy controls under double-blind, placebo-controlled conditions. Following m-CPP, but not fenfluramine or placebo, 55% (11/20) of the patients with obsessive-compulsive disorder experienced a transient exacerbation of obsessivecompulsive disorder. Prolactin response was blunted in patients following m-CPP but not following fenfluramine. Patients with greater behavioral response to m-CPP had smaller prolactin responses. Cortisol response to m-CPP and fenfluramine did not significantly differ between the groups. Behavioral and neuroendocrine responses appeared divergent. This does not suggest simply upregulation or downregulation of 5-hydroxytryptamine receptors, but rather complex mechanisms involving multiple neurotransmitter and neuromodulator systems.

Activation of serotonin2C receptors in the lateral habenular nucleus increases the expression of depression-related behaviors in the hemiparkinsonian rat

Article

Feb 2015

The roles of lateral habenular nucleus (LHb) glutamate neurons and serotonin2C (5-HT2C) receptors in depression are poorly understood, particularly in Parkinson's disease-associated depression. Here we assessed the importance of LHb glutamate neurons and 5-HT2C receptors for depressive-like behaviors in sham-operated rats and rats with unilateral 6-hydroxydopamine lesions of the substantia nigra. The lesion induced depressive-like responses compared to sham-operated rats. Intra-LHb injection of potent, selective 5-HT2C receptor agonist Ro60-0175 decreased sucrose consumption and increased immobility time in sham-operated rats, indicating the induction of depressive-like responses, and intra-LHb injection of Ro60-0175 further increased the expression of depressive-like behaviors in the lesioned rats. Activation of LHb 5-HT2C receptors by the local administration of Ro60-0175 increased the firing rate of EAAC1 (a neuronal glutamate transporter)-positive neurons and percentage of the neurons with burst-firing pattern in the two groups of rats. Compared to sham-operated rats, the duration of Ro60-0175 action on the firing rate of EAAC1-positive neurons was markedly prolonged in the lesioned rats. Intra-LHb injection of Ro60-0175 decreased dopamine, 5-HT and noradrenaline levels in the medial prefrontal cortex, habenula, hippocampus and amygdala in sham-operated and the lesioned rats. The lesion did not change the percentage of EAAC1/5-HT2C receptor co-expressing neurons in the LHb. These findings indicate that activation of 5-HT2C receptors in the LHb increases firing activity of LHb glutamate neurons and then decreases monoamine levels in several brain regions, which increase the expression of depressive-like behaviors. Further, our results also suggest that the lesion leads to hyperfunctionality of 5-HT2C receptors on glutamate neurons of the LHb. Copyright © 2015. Published by Elsevier Ltd.

Context-controlled nicotine-induced changes in the labeling of serotonin (5-HT)2A and 5-HT2C receptors in the rat brain

Article

Jun 2015

We have previously demonstrated that serotonin (5-HT)2A and 5-HT2C receptor ligands modulate the sensitizing effects of nicotine. In the present study we used male rats to verify the hypothesis that the binding pattern of 5-HT2A and 5-HT2C receptors in the brain is altered by chronic nicotine treatment in different environments. Rats were given repeatedly vehicle or nicotine in different sensitizing regimens (home or experimental cages). On day 10, animals were challenged with nicotine (expression of nicotine sensitization) or vehicle in either home or experimental cages, and were sacrificed immediately after the experiment. Repeated treatment with nicotine in home cages evoked significant increases in [(3)H]ketanserin binding to 5-HT2A receptors in the prefrontal cortex, striatal subregions and ventral tegmental area as well as reductions in [(3)H]mesulergine binding to 5-HT2C receptors in subregions of the prefrontal cortex. In contrast, nicotine paired with environmental context produced robust increases in 5-HT2A receptor labeling in the infralimbic cortex and decreased [(3)H]ketanserin binding in striatal subregions and ventral tegmental area; 5-HT2C receptor labeling in the prefrontal cortex fell. The present data indicate that chronic nicotine administration in home cages induces bi-directional neuroplastic changes within 5-HT2A and 5-HT2C receptors in the prefrontal cortex. Pairing the nicotine with environmental context potentiates the neuroplastic response in the latter region and evokes opposite changes in 5-HT2A receptor binding in striatal and tegmental regions compared with nicotine administered in the absence of the context, indicating a modulatory role of environmental context in the expression of nicotine-induced sensitization. Copyright © 2014 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

Native Serotonin 5-HT2C Receptors Are Expressed as Homodimers on the Apical Surface of Choroid Plexus Epithelial Cells

Article

Jan 2015
MOL PHARMACOL

G protein-coupled receptors (GPCR) are a prominent class of plasma membrane proteins that regulate physiological responses to a wide variety of stimuli and therapeutic agents. While GPCR oligomerization has been studied extensively in recombinant cells, it remains uncertain whether native receptors expressed in their natural cellular environment are monomers, dimers or oligomers. The goal of this study was to determine the monomer/oligomer status of a native GPCR endogenously expressed in its natural cellular environment. Native 5-HT2C receptors in choroid plexus epithelial cells were evaluated using fluorescence correlation spectroscopy (FCS) with photon counting histogram (PCH). An anti-5HT2C fragment antigen binding protein was used to label native 5-HT2C receptors. A known monomeric receptor (CD-86) served as a control for decoding the oligomer status of native 5-HT2C receptors by molecular brightness analysis. FCS with PCH revealed molecular brightness values for native 5-HT2C receptors equivalent to the molecular brightness of a homodimer. 5-HT2C receptors displayed a diffusion coefficient of 5 x 10(-9) cm(2)/s and were expressed at 32 receptors/um(2) on the apical surface of choroid plexus epithelial cells. The functional significance and signaling capabilities of the homodimer were investigated in HEK293 cells using agonists that bind in a wash-resistant manner to one or both protomers of the homodimer. While agonist binding to one protomer resulted in G-protein activation, maximal stimulation required occupancy of both protomers. This study demonstrates, for the first time, the homodimeric structure of 5-HT2C receptors endogenously expressed in their native cellular environment and identifies the homodimer as a functional signaling unit. The American Society for Pharmacology and Experimental Therapeutics.

Abnormal Noradrenergic Function in Posttraumatic Stress Disorder

Article

Aug 1997
ARCH GEN PSYCHIAT

Steven M. Southwick

Background: Yohimbine hydrochloride produces marked behavioral and cardiovascular effects in combat veterans with posttraumatic stress disorder (PTSD). In the present study, yohimbine was used as a probe of noradrenergic activity, and meta-chlorophenylpiperazine (m-CPP) as a probe of serotonergic activity. To our knowledge, this is the first study to describe the behavioral and cardiovascular effects of meta-CPP in patients with PTSD, and to compare these effects with those of yohimbine. Method: Twenty-six patients with PTSD and 14 healthy subjects each received an intravenous infusion of yohimbine hydrochloride (0.4 mg/kg), m-CPP (1.0 mg/kg), or saline solution on 3 separate test days in a randomized balanced order and in double-blind fashion. Behavioral and cardiovascular measurements were determined at multiple times. Results: Eleven (42%) of the patients with PTSD experienced yohimbine-induced panic attacks and had significantly greater increases compared with controls in anxiety, panic, and PTSD symptoms, but not in cardiovascular measurements. Eight patients (31%) with PTSD experienced m-CPP-induced panic attacks and had significantly greater increases compared with controls in anxiety, panic, and PTSD symptoms, and in standing diastolic blood pressure. Yohimbine-induced panic attacks tended to occur in different patients from m-CPPinduced panic attacks. Conclusion: These data suggest the presence of 2 neurobiological subgroups of patients with PTSD, one with a sensitized noradrenergic system, and the other with a sensitized serotonergic system.

Serotonin-2C antagonism augments the effect of citalopram on serotonin and dopamine levels in the ventral tegmental area and nucleus accumbens

Article

Dec 2014

Serotonin 5-HT2 Receptor Interactions with Dopamine Function: Implications for Therapeutics in Cocaine Use Disorder

Article

Jan 2015
PHARMACOL REV

Cocaine exhibits prominent abuse liability, and chronic abuse can result in cocaine use disorder with significant morbidity. Major advances have been made in delineating neurobiological mechanisms of cocaine abuse; however, effective medications to treat cocaine use disorder remain to be discovered. The present review will focus on the role of serotonin (5-HT; 5-hydroxytryptamine) neurotransmission in the neuropharmacology of cocaine and related abused stimulants. Extensive research suggests that the primary contribution of 5-HT to cocaine addiction is a consequence of interactions with dopamine (DA) neurotransmission. The literature on the neurobiological and behavioral effects of cocaine is well developed, so the focus of the review will be on cocaine with inferences made about other monoamine uptake inhibitors and releasers based on mechanistic considerations. 5-HT receptors are widely expressed throughout the brain, and several different 5-HT receptor subtypes have been implicated in mediating the effects of endogenous 5-HT on DA. However, the 5-HT2A and 5-HT2C receptors in particular have been implicated as likely candidates for mediating the influence of 5-HT in cocaine abuse as well as to traits (e.g., impulsivity) that contribute to the development of cocaine use disorder and relapse in humans. Lastly, new approaches are proposed to guide targeted development of serotonergic ligands for the treatment of cocaine use disorder. Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.

Serotonin(2C) receptor stimulation inhibits cocaine-induced Fos expression and DARPP-32 phosphorylation in the rat striatum independently of dopamine outflow

Article

Nov 2014

The serotonin2C receptor (5-HT2CR) is known to control dopamine (DA) neuron function by modulating DA neuronal firing and DA exocytosis at terminals. Recent studies assessing the influence of 5-HT2CRs on cocaine-induced neurochemical and behavioral responses have shown that 5-HT2CRs can also modulate mesoaccumbens DA pathway activity at post-synaptic level, by controlling DA transmission in the nucleus accumbens (NAc), independently of DA release itself. A similar mechanism has been proposed to occur at the level of the nigrostriatal DA system. Here, using in vivo microdialysis in freely moving rats and molecular approaches, we assessed this hypothesis by studying the influence of the 5-HT2CR agonist Ro 60-0175 on cocaine-induced responses in the striatum. The intraperitoneal (i.p.) administration of 1 mg/kg Ro 60-0175 had no effect on the increase in striatal DA outflow induced by cocaine (15 mg/kg, i.p.). Conversely, Ro 60-0175 inhibited cocaine-induced Fos immunoreactivity and phosphorylation of the DA and c-AMP regulated phosphoprotein of Mr 32 kDa (DARPP-32) at threonine 75 residue in the striatum. Finally, the suppressant effect of Ro 60-0175 on cocaine-induced DARPP-32 phosphorylation was reversed by the selective 5-HT2CR antagonist SB 242084 (0.5 mg/kg, i.p.). In keeping with the key role of DARPP-32 in DA neurotransmission, our results demonstrate that 5-HT2CRs are capable of modulating nigrostriatal DA pathway activity at post-synaptic level, by specifically controlling DA signaling in the striatum. Copyright © 2014 Elsevier Ltd. All rights reserved.

Serotonin controlling feeding and satiety

Article

Sep 2014
BEHAV BRAIN RES

Serotonin has been implicated in the control of satiety for almost four decades. Historically, the insight that the appetite suppressant effect of fenfluramine is linked to serotonin has stimulated interest in and research into the role of this neurotransmitter in satiety. Various rodent models, including transgenic models, have been developed to identify the involved 5-HT receptor subtypes. This approach also required the availability of receptor ligands of different selectivity, and behavioural techniques had to be developed simultaneously which allow differentiating between unspecific pharmacological effects of these ligands and 'true' satiation and satiety. Currently, 5-HT1B, 5-HT2C and 5-HT6 receptors have been identified to mediate serotonergic satiety in different ways. The recently approved anti-obesity drug lorcaserin is a 5-HT2C receptor agonist. In brain, both hypothalamic (arcuate nucleus, paraventricular nucleus) and extrahypothalamic sites (parabrachial nucleus, nucleus of the solitary tract) have been identified to mediate the serotonergic control of satiety. Serotonin interacts within the hypothalamus with endogenous orexigenic (Neuropeptide Y/Agouti related protein) and anorectic (α-melanocyte stimulating hormone) peptides. In the nucleus of the solitary tract serotonin integrates peripheral satiety signals. Here, the 5-HT3, but possibly also the 5-HT2C receptor play a role. It has been found that 5-HT acts in concert with such peripheral signals as cholecystokinin and leptin. Despite the recent advances of our knowledge, many of the complex interactions between 5-HT and other satiety factors are not fully understood yet. Further progress in research will also advance the development of new serotonergic anti-obesity drugs.

Activation of serotonin 5-HT2A receptors inhibits high compulsive drinking on schedule-induced polydipsia

Article

Aug 2014

Rationale: Schedule-induced polydipsia (SIP) is an established model for studying compulsive behaviour in rats. Serotoninergic drugs effectively reduce compulsive drinking on SIP, and high compulsive drinker rats selected by SIP have shown differences in serotoninergic brain activity. However, the specific serotoninergic receptors that modulate compulsive SIP remain unclear. Objective: We investigated the functional role of serotonin 5-hydroxytryptamine 2A or C (5-HT2A/C) receptors in compulsive SIP behaviour. Methods: Rats were selected for low (LD) versus high drinking (HD) behaviour on SIP. The effects of the systemic administration of the selective serotonin reuptake inhibitor citalopram, selective norepinephrine reuptake inhibitor atomoxetine, serotonin 5-HT2A/C receptor agonist DOI hydrochloride ((±)-2,5-dimethoxy-4-iodoamphetamine), serotonin 5-HT2C receptor antagonist SB242084, serotonin 5-HT2A receptor antagonist ketanserin and M100907 were assessed on SIP. Subsequently, the effects of DOI were tested after the pre-administration of SB242084, ketanserin and M100907 on SIP. Results: Citalopram and DOI reduced compulsive drinking in HD compared with LD rats on SIP. In contrast, SB242084 increased compulsive drinking in HD compared with LD rats on SIP. Atomoxetine, ketanserin and M100907 had no effect on SIP. The reduction in water intake produced by DOI was blocked by ketanserin and M100907, but not by SB242084 administration, in HD rats. Conclusions: These findings highlight the contribution of serotoninergic 5-HT2A/C receptors compared with noradrenergic mechanisms on SIP and reveal the "therapeutic" activation of serotonin 5-HT2A in the inhibition of the compulsive drinking behaviour in HD rats. Thus, it may represent a potentially new marker of vulnerability and provides additional insight for potential treatments on compulsive behaviours in neuropsychiatric populations.

Assessment of Seizure Liability of Org 306039, a 5-HT2c Agonist, Using Hippocampal Brain Slice and Rodent EEG Telemetry.

Article

Aug 2014
J Pharmacol Toxicol Meth

Introduction: Evaluation of the seizure potential for a CNS-targeted pharmaceutical compound before it is administered to humans is an important part of development. The current in vitro and in vivo studies were undertaken to characterize the seizure potential of the potent and selective 5-HT2c agonist Org 306039. Methods: Rat hippocampal slices (n=5) were prepared and Org 306039 was applied over a concentration range of 0-1000μM. Male Sprague-Dawley rats, implanted with telemetry EEG recording electrodes received either vehicle (n=4) or 100mg/kg Org 306039 (n=4) by oral gavage daily for 10days. EEG was recorded continuously for 22±1h post-dose each day. Post-dose behavior observations were conducted daily for 2h. Body temperature was measured at 1 and 2h post-dose. On Day 7, blood samples were drawn for pharmacokinetic analysis of Org 306039. Results: In hippocampal slice, Org 306039 elicited a concentration-dependent increase in population spike area and number recorded from CA1 area, indicating seizure-genic potential. In telemetered rats, Org 306039 was associated with a decrease in body weight, a decrease in body temperature and the appearance of seizure-related behaviors and pre-seizure waveforms on EEG. One rat exhibited an overt seizure. Plasma concentrations of Org 306039 were similar among the 4 rats in the Org-treated group. Small group size made it difficult to determine a PK-PD relationship. Discussion: These results indicate that the in vitro and in vivo models complement each other in the characterization of the seizure potential of CNS-targeted compounds such as the 5-HT2c agonist Org 306039.

5-HT7 receptor activation: Procognitive and antiamnesic effects

Article

Jul 2014

Rationale: The serotonin (5-hydroxytryptamine (5-HT)) 5-HT7 receptor is localized in brain areas mediating memory; however, the role of this receptor on memory remains little explored. Objective: First, demonstrating the associative nature of Pavlovian/instrumental autoshaping (P/I-A) task, rats were exposed (three sessions) to CS-US (Pavlovian autoshaping), truly random control, free operant, and presentations of US or CS, and they were compared with rats trained-tested for one session to the P/I-A procedure. Also, effects of the 5-HT7 receptor agonist LP-211 administered intraperitoneally after training was determined on short- (1.5 h) and long-term memory 24 and 48 h) and on scopolamine-induced memory impairment and cAMP production. Methods: Autoshaping and its behavioral controls were studied. Other animals were subjected to an autoshaping training session and immediately afterwards were given (intraperitoneal) vehicle or LP-211 (0.1-10 mg/kg) and/or scopolamine (0.2 mg/kg) and tested for short-term memory (STM) and long-term memory (LTM); their brains were extracted for the cAMP ELISA immunoassay. Results: P/I-A group produced the higher %CR. LP-211 did not affect STM; nonetheless, at 0.5 and 1.0 mg/kg, it improved LTM. The 5-HT7 receptor antagonist SB-269970 (SB; 10.0 mg/kg) alone had no effect; nevertheless, the LP-211 (1.0 mg/kg) LTM facilitation was reversed by SB. The scopolamine (0.2 mg/kg) induced-decrement in CR was accompanied by significant increased cAMP production. The scopolamine-induced decrement in CR and increments in cAMP were significantly attenuated by LP-211. Conclusions: Autoshaping is a reliable associative learning task whose consolidation is facilitated by the 5-HT7 receptor agonist LP-211.

Anticonvulsant compounds and 5-hydroxytryptamine in rat brain

Article

Jun 1957
BRIT J PHARMACOL

In rats, a series of anticonvulsant compounds have been shown to cause a significant elevation of brain 5-hydroxytryptamine (5-HT) levels in comparison with control values. This increase in 5-HT only occurred in brain tissue and was not observed in spleen, upper small intestine or blood. Elevation of brain levels of 5-HT by iproniazid (Marsilid) or 5-hydroxytryptophan failed to give protection against the convulsant or lethal action of lept zol (75 mg./kg.).

Tremulous jaw movements in rats:a model of parkinsonian tremor

Article

Jan 1998
PROG NEUROBIOL

Role(s) of the 5-HT2C Receptor in the Development of Maximal Dentate Activation in the Hippocampus of Anesthetized Rats

Article

Jul 2014
CNS NEUROSCI THER

Aims: Substantial evidence indicates that 5-HT2C receptors are involved in the control of neuronal network excitability and in seizure pathophysiology. Here, we have addressed the relatively unexplored relationship between temporal lobe epilepsy (TLE), the most frequent type of intractable epilepsy, and 5-HT2CRs. Methods: In this study, we investigated this issue using a model of partial complex (limbic) seizures in urethane-anesthetized rat, based on the phenomenon of maximal dentate activation (MDA) using 5-HT2C compounds, electrophysiology, immunohistochemistry, and western blotting techniques. Results: The 5-HT2C agonists mCPP (1 mg/kg, i.p) and lorcaserin (3 mg/kg, i.p), but not RO60-0175 (1-3 mg/kg i.p.), were antiepileptogenic reducing the MDA response duration. The selective 5-HT2C antagonist SB242084 (2 mg/kg, i.p) unveiled antiepileptogenic effects of RO60-0175 (3 mg/kg, i.p) but did not alter those induced by mCPP and lorcaserin. Compared with control rats, electrically stimulated rats showed an increase in glutamic acid decarboxylase levels and a heterogeneous decrease in 5-HT2CR immunoreactivity in different hippocampal areas. Conclusions: In our animal model of TLE, mCPP and lorcaserin were anticonvulsant; likely acting on receptor subtypes other than 5-HT2C. Epileptogenesis induced early adaptive changes and reorganization in the 5-HT2CR and GABA systems.

New therapeutic opportunities for 5-HT2C receptor ligands in neuropsychiatric disorders

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