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Serotonin-Dopamine Interaction as a Focus of Novel Antidepressant Drugs
Abstract
Central serotonergic and dopaminergic systems play a critical role in the regulation of normal and abnormal behavior. Recent evidence suggests that a dysfunction of dopamine (DA) and serotonin (5-HT) neurotransmitter systems contributes to various pathological conditions. Among the multiple classes of 5-HT receptors described in the central nervous system, much attention has been devoted to the role of 5-HT2 receptor family in the control of central dopaminergic activity, because of the moderate to dense localization of both transcript and protein for 5-HT2A and 5-HT2C receptors in the substantia nigra (SN) and ventral tegmental area (VTA), as well as their terminal regions. Moreover, modulation of 5-HT2 receptor function by various drugs that has been shown to influence DA function in these brain areas is thought to be important in motor activation, motivation, and reward. Indeed, a number of electrophysiological and biochemical data have shown that 5-HT2C receptor agonists decrease, while 5-HT2C receptor antagonists enhance mesocorticolimbic DA function. Recent studies have focused on the functional interaction between the serotonergic and dopaminergic systems to explain the mechanism of the antidepressant action of SSRIs and 5-HT2 antagonists. In this article, the most relevant data regarding the role of these receptors in the control of brain DA function are reviewed, and the importance of this subject in the search of new antidepressant drugs is discussed.
... Indications are present for 5-HT2 receptors to modulate dopaminergic activity. Moreover, 5-HT2A receptors and 5-HT2c receptors exert opposite effects on dopamine release (Esposito, 2006). ...
... Subsequently, blockade of 5-HT1A and 5-HT2A receptors was achieved by administration of pindolol and ketanserin respectively. Evidence exists that 5-HT2 receptors modulate dopaminergic activity (Esposito, 2006). It was expected that blocking the postsynaptic 5-HT2A receptor by ketanserin may decrease dopamine release (Bortolozzi et al., 2005;Lucas & Spampinato, 2000). ...
... This strongly suggests that postsynaptic 5-HT2A receptor blockade plays a modulatory role in vigilance performance. Various animal studies indicate that 5-HT2 receptors modulate dopaminergic activity and that 5-HT2A receptors and 5-HT2C receptors even exert opposite effects on dopamine release (Esposito, 2006). Dopamine release is inhibited by 5-HT2C receptor stimulation (Di Matteo et al., 2001;Lucas & Spampinato, 2000) and dopamine is enhanced by 5-HT2A receptor activation (Bortolozzi et al., 2005;Lucas & Spampinato, 2000). ...
Proefschrift Maastricht. Lit. opg. - Met een samenvatting in het Nederlands.
... 5-HT and DA are released in brain regions involved in cognitive and emotional processes, such as the cerebral cortex, limbic cortex, hippocampus, thalamus, and basal ganglia [9,44]. Both excitatory glutamatergic pyramidal neurons and inhibitory GABAergic interneurons in the PFC receive rich aminergic modulatory input from the dopaminergic ventral tegmental area and serotonergic raphe nuclei [69,70]. Enriched in both aminergic receptors, including 5-HT2AR and dopamine D1R, pyramidal and inhibitory neurons may be able to integrate signals at various cellular locations, such as apical and basal dendrites, cell bodies, and the axon hillock [26,70]. ...
... Both excitatory glutamatergic pyramidal neurons and inhibitory GABAergic interneurons in the PFC receive rich aminergic modulatory input from the dopaminergic ventral tegmental area and serotonergic raphe nuclei [69,70]. Enriched in both aminergic receptors, including 5-HT2AR and dopamine D1R, pyramidal and inhibitory neurons may be able to integrate signals at various cellular locations, such as apical and basal dendrites, cell bodies, and the axon hillock [26,70]. Reciprocally, the PFC also directly influences aminergic neuronal activities in the brainstem. ...
Dopamine and serotonin signalling are associated with major depressive disorder, which is a prevalent life-threatening illness worldwide. Numerous FDA-approved dopamine/serotonin signalling-modifying drugs are available but are associated with concurrent side effects and limited efficacy. Thus, identifying and targeting their signalling pathway is crucial for improving depression treatment. Here, we determined that serotonin receptor 2A (5-HT2AR) abundantly forms a protein complex with dopamine receptor 1 (D1R) in high abundance via its carboxy-terminus in the brains of mice subjected to various chronic stress paradigms. Furthermore, the D1R/5-HT2AR interaction elicited CREB/ERK/AKT modulation during synaptic regulation. An interfering peptide (TAT-5-HT2AR-SV) agitated the D1R/5-HT2AR interaction and attenuated depressive symptoms accompanied by CREB/ERK molecule costimulation. Interestingly, HDAC antagonism but not TrkB antagonism reversed the antidepressant effect of competitive peptides. These findings revealed a novel D1R/5-HT2AR heteroreceptor complex mechanism in the pathophysiology of depression, and their uncoupling ameliorates depressive-like behaviours through HDAC-, and not BDNF-, dependent mechanisms.
... Moreover, after chronic treatment, WAY163909 reduced the hyperactivity associated with olfactory bulbectomy in rats [186,187]. It is possible that the mediated antidepressant effects of these compounds were due to the stimulation of 5-HT2C receptors and the resulting activation of postsynaptic serotonin receptors [188]. Other selective 5-HT2C receptor agonists have also been effective in animal models of depression and obsessive-compulsive disorder [189]. ...
... Moreover, after chronic treatment, WAY163909 reduced the hyperactivity associated with olfactory bulbectomy in rats [186,187]. It is possible that the mediated antidepressant effects of these compounds were due to the stimulation of 5-HT 2C receptors and the resulting activation of postsynaptic serotonin receptors [188]. Other selective 5-HT 2C receptor agonists have also been effective in animal models of depression and obsessive-compulsive disorder [189]. ...
Serotonin modulates several physiological and cognitive pathways throughout the human body that affect emotions, memory, sleep, and thermal regulation. The complex nature of the serotonergic system and interactions with other neurochemical systems indicate that the development of depression may be mediated by various pathomechanisms, the common denominator of which is undoubtedly the disturbed transmission in central 5-HT synapses. Therefore, the deliberate pharmacological modulation of serotonergic transmission in the brain seems to be one of the most appropriate strategies for the search for new antidepressants. As discussed in this review, the serotonergic system offers great potential for the development of new antidepressant therapies based on the combination of SERT inhibition with different pharmacological activity towards the 5-HT system. The aim of this article is to summarize the search for new antidepressants in recent years, focusing primarily on the possibility of benefiting from interactions with various 5-HT receptors in the pharmacotherapy of depression.
... Likewise, serotonin (5-HT) also plays an integral and pivotal role in controlling emotions, food intake, anxiety behaviors and endocrine functions (Berger et al., 2009;Charney et al., 1990;Ren-Patterson et al., 2006;Shah et al., 2003). The disturbance of this delicate balance between DA and 5-HT leads to many pathological conditions translating itself in the form of multiple neuropsychiatric disorders (Esposito, 2006;Wood and Wren, 2008). 5-HT per se is an important neurotransmitter and any disturbance of 5-HT may cause series of neurologic and psychiatric illnesses, like hallucination, anxiety, depression and migraine (Hou et al., 2006). ...
... In this respect, it has been reported that the ratios of metabolites to neurotransmitters are more sensitive measure as compared to steady state levels of neurotransmitters (Baldessarini et al., 1992). Agents that increase DA and its metabolites concentration have abuse potential like opiates, cocaine, and compounds that lower DA induce cognitive, behavioral and motor coordination defects (Berridge and Robinson, 1998;Esposito, 2006). ...
Bacopa monnieri (BM) is a perennial herb, with a historic nootropic image and utility in ayurvedic system of medicine, for the management of various central nervous system disorders like epilepsy, depression and memory deficit amongst others. We investigated the effects of acute and sub chronic (one week) treatment of BM methanolic extract (Mt-ext BM) on dopamine (DA) and serotonin (5-HT) turn over in mice whole brain. Mt-ext BM was screened on high performance liquid chromatography (HPLC) with ultraviolet (UV) detection for the quantification of BM major bioactive compound, Bacoside A, mainly comprising of Bacopasaponin C, Bacoside A3, and Bacopaside ll. For acute study, mice groups were administered single dose of 10, 20 or 30 mg/kg of Mt-ext BM orally, while in sub chronic study separate groups received single daily dose of 10, 20 or 30 mg/kg of Mt-ext BM orally for one week. Animals were killed 1 h after the dose by decapitation, and whole brains were excised and analyzed on HPLC coupled with electrochemical detector for changes in DA, 5-HT, dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5 hydroxyindolacetic acid (5HIAA). Our results show that both acute and sub chronic oral administration of Mt-ext BM have no significant effect on DA and 5-HT turn over. The neurotransmitters data reflects safety of the BM in acute and sub chronic uses from DA and 5-HT modulation and subsequent pre disposition to neuropsychiatric problems. Although more studies are warranted to explore BM role in DA and 5-HT interplay in specified brain regions. Key words: Bacoside A, Bacopa monnieri, high performance liquid chromatography (HPLC), dopamine (DA), serotonin (5-HT).
... Esto sugiere que la mejora de la disfunción endotelial observada en estos animales podría ser consecuencia, al menos parcialmente, de un aumento de la disponibilidad de NO al disminuir su degradación por aniones superóxido (69). Diversos estudios en diferentes modelos experimentales han demostrado que el bloqueo del SRA tiene efectos importantes para el proceso oxidativo asociado al desarrollo aterosclerótico (70,71,72,73); es así como en ratones ateroscleróticos por deficiencia en apolipoproteína E, se observó una reducción del estrés oxidativo acompañado de una reducción de LDL oxidada en la lesión aterosclerótica, tras el tratamiento con un ARAII (74). Otra evidencia del efecto antioxidante de los ARAII es la disminución de la peroxidación lipídica de LDL, observada en primates ateroscleróticos, en ratones con deficiencia en apolipoproteína E (49). ...
... Los neurotransmisores monoaminérgicos (dopamina, noradrenalina y serotonina) cumplen con funciones importantes en el cerebro y están relacionados con enfermedades neuropsiquiátricas como la enfermedad de Parkinson y la depresión; se ha demostrado que el desequilibrio en la síntesis y liberación de ellos es la base fisiopatológica para este tipo de enfermedades (71)(72)(73). La liberación de estos neurotransmisores se encuentra influenciada por múltiples factores biológicos, dependiendo del tejido cerebral donde se encuentren. El ON es un importante regulador de la liberación de estas monoaminas y es así como Hanbauer y colaboradores (74) reportaron que la aplicación de NO exógeno producía liberación de dopamina en cultivos neuronales. ...
This is the case of a 54-year-old woman who had a pathological fracture of the left femoral neck, in the area of a brown tumor. A diagnosis of primary hyperparathyroidism (PHPT) was made based on the findings of: hypercalcemia, high serum levels of parathohormone, and the presence of a parathyroid adenoma of the lower right parathyroid in the gammagraphic image. The patient also has a brown bone tumor in the left femoral neck, a pathologic fracture of the right clavicle, chronic renal insufficiency and arterial hypertension. A lower right parathyroidec- tomy was made. After this procedure the patient developed hungry bone syndrome. During the surgical procedure a thyroid nodule was found in the contralateral side from the parathyroid
... MLK_MOD-43, on the other hand, displayed a dual mechanism by maintaining a high affinity for both DRD2 and 5-HT1A, making it an attractive multi-target candidate for neuropsychiatric disorders. The dual activity of MLK_MOD-43 aligns with emerging research advocating for compounds that balance dopamine and serotonin neurotransmission to achieve enhanced therapeutic efficacy [22]. In addition to MLK_MOD-42 and MLK_MOD-43, other derivatives also demonstrated promising properties. ...
Background/Objectives: Montelukast (MLK), a leukotriene receptor antagonist, has been associated with neuropsychiatric side effects. This study aimed to rationally modify MLK’s structure to reduce these risks by optimizing its interactions with dopamine D2 (DRD2) and serotonin 5-HT1A receptors using computational molecular simulation techniques. Methods: A library of MLK derivatives was designed and screened using structural similarity analysis, molecular docking, molecular dynamics (MD) simulations, MM/PBSA binding free energy calculations, and ADME-Tox predictions. Structural similarity analysis, based on Tanimoto coefficient fingerprinting, compared MLK derivatives to known neuropsychiatric drugs. Docking was performed to assess initial receptor binding, followed by 100 ns MD simulations to evaluate binding stability. MM/PBSA calculations quantified binding affinities, while ADME-Tox profiling predicted pharmacokinetic and toxicity risks. Results: Several MLK derivatives showed enhanced DRD2 and 5-HT1A binding. MLK_MOD-42 and MLK_MOD-43 emerged as the most promising candidates, exhibiting MM/PBSA binding free energies of −31.92 ± 2.54 kcal/mol and −27.37 ± 2.22 kcal/mol for DRD2 and −30.22 ± 2.29 kcal/mol and −28.19 ± 2.14 kcal/mol for 5-HT1A, respectively. Structural similarity analysis confirmed that these derivatives share key pharmacophoric features with atypical antipsychotics and anxiolytics. However, off-target interactions were not assessed, which may influence their overall safety profile. ADME-Tox analysis predicted improved oral bioavailability and lower neurotoxicity risks. Conclusions: MLK_MOD-42 and MLK_MOD-43 exhibit optimized receptor interactions and enhanced pharmacokinetics, suggesting potential neuropsychiatric applications. However, their safety and efficacy remain to be validated through in vitro and in vivo studies. Until such validation is performed, these derivatives should be considered as promising candidates with optimized receptor binding rather than confirmed safer alternatives.
... MLK_MOD-43, on the other hand, displayed a dual mechanism by maintaining a high affinity for both DRD2 and 5-HT1A, making it an attractive multi-target candidate for neuropsychiatric disorders. The dual activity of MLK_MOD-43 aligns with emerging research advocating for compounds that balance dopamine and serotonin neurotransmission to achieve enhanced therapeutic efficacy [22]. In addition to MLK_MOD-42 and MLK_MOD-43, other derivatives also demonstrated promising properties. ...
Background/Objectives: Montelukast (MLK), a leukotriene receptor antagonist, has been associated with neuropsychiatric side effects, raising concerns about its safety. This study aimed to rationally modify MLK’s structure to reduce these risks by optimizing its interactions with dopamine D2 (DRD2) and serotonin 5-HT1A receptors using computational molecular simulation techniques. Methods: A library of MLK derivatives was designed and screened using structural similarity analysis, molecular docking, molecular dynamics (MD) simulations, MM/PBSA binding free energy calculations, and ADME-Tox predictions. Structural similarity analysis, based on Tanimoto coefficient fingerprinting, compared MLK derivatives to known neuropsychiatric drugs. Docking was performed to assess initial receptor binding, followed by 100 ns MD simulations to evaluate binding stability. MM/PBSA calculations quantified binding affinities, while ADME-Tox profiling predicted pharmacokinetic and toxicity risks. Results: Several MLK derivatives showed enhanced DRD2 and 5-HT1A binding. MLK_MOD-42 and MLK_MOD-43 emerged as the most promising candidates, exhibiting MM/PBSA binding free energies of −31.92 ± 2.54 kcal/mol and −27.37 ± 2.22 kcal/mol for DRD2 and −30.22 ± 2.29 kcal/mol and −28.19 ± 2.14 kcal/mol for 5-HT1A, respectively. Structural similarity analysis confirmed that these derivatives share key pharmacophoric features with atypical antipsychotics and anxiolytics. ADME-Tox analysis predicted improved oral bioavailability and lower neurotoxicity risks. Conclusions: MLK_MOD-42 and MLK_MOD-43 exhibit optimized receptor interactions, enhanced pharmacokinetics, and lower toxicity risks, making them promising candidates for reducing neuropsychiatric side effects and potential drug repurposing for neuropsychiatric disorders. Further in vitro and in vivo validation is warranted to confirm their therapeutic potential.
... Drug addiction is reinforcing and elicit behavioural sensitisation (Koob and Volkow 2016), which in turn lead to craving and relapse to drug use after abstinence (Self 1998), as a public health, social and economic problem (Yang et al. 2015). The mesocortico-limbic dopamine (DA) system is strongly implicated in drug dependence that provides the anatomical substrate for emotions, motivation, the stress and reward-related events, locomotor sensitisation and high concentrations of dopamine produce a rewarding effect, reinforced behaviour and behavioural sensitisation (Fonseca and Navarro 1998;Esposito 2006). On the other hand, it was shown that DA reward system receive a prominent innervation from serotonin (5-hydroxytryptamine, 5-HT) and the dysfunction of DA and 5-HT system are involved in the mechanism of morphine reinforcement (Di Giovanni et al. 2010). ...
Morphine withdrawal increases locomotor sensitisation, relapse and impair regulation of serotonin system. We evaluated the effectiveness of Raha syrup on the cerebrospinal fluid (CSF) serotonin levels following locomotor sensitisation in morphine-withdrawn rats receiving the opium tincture (OT). Morphine withdrawal rats gavaged daily with OT and Raha syrup (for 30 days) and then challenged with morphine and evaluated for locomotor activity and CSF serotonin levels before morphine challenge and 2 weeks after cessation of treatment. Raha syrup attenuated locomotor activity, increased the CSF serotonin after morphine challenge, and continued 2 weeks after cessation of treatment in rats receiving OT. Whereas, rats receiving OT alone after morphine challenge exhibited a relative decrease in locomotor activity, without changing CSF serotonin. Raha syrup attenuated locomotor sensitisation in morphine-withdrawn rats receiving OT probably by increasing serotonin. Therefore, administration of Raha syrup along with OT may benefit to treatment relapse in addicts receiving OT maintenance treatment.
... The 5-HT 2C receptor cellular co-expression with other 5-HT 2 receptor subtypes tempts the possibility of receptor dimerization (Bonhaus et al., 1995;Pompeiano et al., 1994). The 5-HT 2C receptor is co-expressed with 5-HT 2A receptors in pyramidal neurons and GABAergic interneurons in the prefrontal cortex (Carr, 2002;Nocjar et al., 2015) and dopaminergic neurons in the VTA Esposito, 2006), and with 5-HT 2B receptors in pro-opiomelanocortin (Moutkine et al., 2017). 5-HT 2C appears to exert dominance when in complex with its 5-HT 2 subtypes; this 'signalling masking' of its pair protomers is an interesting aspect that remains to be explored before appreciating any further therapeutic potential. ...
Substance use disorder (SUD) is a chronic condition, with maintained abuse of a substance leading to physiological and psychological alterations and often changes in cognitive and social behaviours. Current therapies include psychotherapy coupled with medication; however, high relapse rates reveal the shortcomings of these therapies. The signalling, expression profile, and neurological function of the serotonin 2C receptor (5‐HT2C receptor) make it a candidate of interest for the treatment of SUD. Recently, psychedelics, which broadly act at 5‐HT2 receptors, have indicated potential for the treatment of SUD, implicating the 5‐HT2C receptor. The modern psychedelic movement has rekindled interest in the 5‐HT2C receptor, resulting in many new studies, especially structural analyses. This review explores the structural, molecular and cellular mechanisms governing 5‐HT2C receptor function in the context of SUD. This provides the basis of the preclinical and clinical evidence for their role in SUD and highlights the potential for future exploration.
... Due to tardive dyskinesia caused by antipsychotic drugs, researchers seek new drugs with less adverse extrapyramidal side effects [43,45]. The roles of 5-hydroxytryptamine (serotonin)-1A and 2A/2C receptors in the regulation of dopaminergic neurotransmission in preclinical studies have been suggested [46,47]. Research is also aimed at finding better therapeutic strategies for schizophrenia and related diseases. ...
Schizophrenia is a mental disorder characterized by episodes of psychosis; major symptoms include hallucinations, delusions, and disorganized thinking. More recent theories focus on particular disorders of interneurons, dysfunctions in the immune system, abnormalities in the formation of myelin, and augmented oxidative stress that lead to alterations in brain structure. Decreased dopaminergic activity and increased phospholipid metabolism in the prefrontal cortex might be involved in schizophrenia. Antipsychotic drugs used to treat schizophrenia have many side effects. Alternative therapy such as curcumin (CUR) can reduce the severity of symptoms without significant side effects. CUR has important therapeutic properties such as antioxidant, anti-mutagenic, anti-inflammatory, and antimicrobial functions and protection of the nervous system. Also, the ability of CUR to pass the blood–brain barrier raises new hopes for neuroprotection. CUR can improve and prevent further probable neurological and behavioral disorders in patients with schizophrenia. It decreases the side effects of neuroleptics and retains lipid homeostasis. CUR increases the level of brain-derived neurotrophic factor and improves hyperkinetic movement disorders. CUR may act as an added counteraction mechanism to retain cell integrity and defense against free radical injury. Thus it appears to have therapeutic potential for improvement of schizophrenia. In this study, we review several properties of CUR and its ability to improve schizophrenia and minimize the side effects of antipsychotic drugs, and we explore the underlying mechanisms by which CUR affects schizophrenia and its symptoms.
... Isolating the effects of a single neurotransmitter is useful, but covariance of neurotransmitter activity also has diagnostic and treatment implications. [9][10][11] Abnormalities in these interactions may be part of the causal process in fundamental cognitive functions. 12 If endorphin suppression is insensitive to dopamine blockade, a relative endorphin excess may create symptoms. ...
... 5-HT 2A , 5-HT 2B and 5-HT 2C receptors are both G q/11coupled receptors, which mediate excitatory neurotransmission [650]. These receptors are co-expressed in GABAergic interneurons and in a subpopulation of pyramidal neurons of the prefrontal cortex (PFC) [651,652] and in dopaminergic neurons of the ventral tegmental area [653,654]. Using Co-IP and BRET techniques, Moutkine and co-workers demonstrated that 5-HT 2A -5-HT 2B and 5-HT 2A -5-HT 2C heterodimers can be formed when co-expressed in heterologous expression systems [655]. In 5-HT 2C -containing heterodimers, ligands bind and activate only the 5-HT 2C protomer. ...
Neurodegenerative diseases affect over 30 million people worldwide with an ascending trend. Most individuals suffering from these irreversible brain damages belong to the elderly population, with onset between 50 and 60 years. Although the pathophysiology of such diseases is partially known, it remains unclear upon which point a disease turns degenerative. Moreover, current therapeutics can treat some of the symptoms but often have severe side effects and become less effective in long-term treatment. For many neurodegenerative diseases the involvement of G protein-coupled receptors (GPCRs), which are key players of neuronal transmission and plasticity, has become clearer and holds great promise in elucidating their biological mechanism. With this review, we introduce and summarize class A and class C GPCRs, known to form heterodimers or oligomers to increase their signalling repertoire. Additionally, the examples discussed here were shown to display relevant alterations in brain signalling and have already been associated with the pathophysiology of certain neurodegenerative diseases. Lastly, we classified the heterodimers into two categories of crosstalk, positive or negative, for which there is known evidence.
... Major excitatory, glutamatergic inputs arise from the laterodorsal and pendunculopontine tegmentum, lateral hypothalamus, bed nucleus of the stria terminalis, and prefrontal cortex (Carr & Sesack, 2000;Omelchenko & Sesack, 2005;Massi et al., 2008;Watabe-Uchida et al., 2012;Kallo et al., 2015). Additionally, serotonergic (5-HT) neurons of the dorsal raphe nucleus transmit mainly excitatory, metabotropic signals to VTA neurons (Herve et al., 1987;Esposito, 2006). Prominent inhibitory, GABAergic innervation of the VTA is provided by the rostromedial tegmental nucleus, ventral pallidum, laterodorsal tegmentum, bed nucleus of the stria terminalis, lateral hypothalamus, lateral habenula, amygdala, and the NAc (Rahman & McBride, 2000;Geisler & Zahm, 2005;Jhou et al., 2009a;Xia et al., 2011;Janak & Tye, 2015;Kallo et al., 2015). ...
Alcohol use is a prominent contributor to global disease burden and a leading cause of preventable mortality. Long-term severe problem drinking is clinically diagnosed as alcohol use disorder (AUD), one of the most prevalent neuropsychiatric diseases worldwide. Despite the persistent public health concern posed by alcohol abuse, treatments targeting specific brain mechanisms impacted by and driving pathological alcohol use are lacking. Behavioral animal models have revealed that the mesolimbic dopamine reward pathway is a critical mediator of alcohol’s reinforcing effects. The ventral tegmental area (VTA) is a central hub of this reward circuitry and subversion of alcohol-induced neuronal activity in the VTA has been linked to increased alcohol consumption. Among its many effects in the brain, alcohol enhances release of the inhibitory neurotransmitter GABA in the VTA. This acute effect of alcohol is exacerbated by prior alcohol, drug, or stress exposure, which are all risk factors for subsequent alcohol abuse. For these reasons, the central hypothesis of this dissertation was that disruptions in alcohol-induced inhibitory GABA signaling in the VTA contribute to escalated alcohol consumption. To delineate the mechanisms of disturbed VTA inhibitory transmission that may lead to increased alcohol consumption, electrophysiological recordings, in vivo pharmacological manipulations, and alcohol self-administration paradigms were performed in rodents. The second and third chapters provide evidence that an acute stressor in adulthood or chronic nicotine exposure in adolescence promote subsequent alcohol self-administration behavior via chloride ion (Cl-) dysregulation in VTA GABA neurons. Normalizing Cl- homeostasis by intra-VTA pharmacological upregulation of the potassium-Cl- cotransporter KCC2 prevented the increased alcohol drinking phenotype observed after stress or nicotine. In the fourth and fifth chapters, rescue of disrupted Cl- homeostasis via serotonin 2A receptor (5-HT2AR) activation is demonstrated ex vivo and correlated with 5-HT2AR agonist-mediated reduction in heavy alcohol consumption. Collectively, this body of work suggests that dysregulation of VTA Cl- transport, dictated largely by KCC2 function, increases risk for alcohol abuse. Targeting this form of inhibitory plasticity represents a novel interventional approach for AUD. Therefore, future work is needed to identify clinically safe and efficacious pharmacotherapies to reverse disturbances in midbrain Cl- homeostasis in alcohol-dependent individuals.
... These receptors have been shown to mediate a modest depolarization leading to increased DA activity and DA release (Pessia et al., 1994). However, 5-HT2A/C receptor activation in substantia nigra GABAergic neurons may indirectly inhibit DA neuron activity (Demireva et al., 2018;Esposito, 2006;Tepper et al., 1995). ...
Serotonin is a critical neuromodulator involved in development and behavior. Its role in reward is however still debated. Here, we first review classical studies involving electrical stimulation protocols and pharmacological approaches. Contradictory results on the serotonergic’ involvement in reward emerge from these studies. These differences might be ascribable to either the diversity of cellular types within the raphe nuclei or/and the specific projection pathways of serotonergic neurons. We continue to review more recent work, using optogenetic approaches to activate serotonergic cells in the Raphe to VTA pathway. From these studies, it appears that activation of this pathway can lead to reinforcement learning mediated through the excitation of dopaminergic neurons by serotonergic neurons co-transmitting glutamate. Finally, given the importance of serotonin during development on adult emotion, the effect of abnormal early-life levels of serotonin on the dopaminergic system will also be discussed. Understanding the interaction between the serotonergic and dopaminergic systems during development and adulthood is critical to gain insight into the specific facets of neuropsychiatric disorders.
... There is strong support for the role of the 5-HT 2A receptor in depression and the mechanism of action of antidepressants (Barnes et al., 2021;Guiard and Di Giovanni, 2015) that may involve DA function modulation (Belujon and Grace, 2017;Esposito, 2006). ...
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.
... However, dopamine may play a substantial role in suicidal behavior due to its stimulatory role on the activation of the HPA axis in response to a severe stressor and involvement in the maintenance of post-stress activation of the HPA axis (Belda and Armario, 2009), which evinces multilevel dysfunction associated with increased suicide risk (Oquendo et al., 2014b). Furthermore, serotonin and dopamine interact with each other (Daw et al., 2002;Di Giovanni et al, 2008Esposito, 2006;Olvera-Cortés et al., 2008) and may be both involved in the individual's ability to cope with suicidal thoughts (Ryding et al., 2008). Serotonin-dopamine interaction may act as a moderator of decision making (Rogers, 2011), commonly observed to be impaired during suicidal crises (Szanto et al., 2015). ...
Background
It remains unclear whether the dopaminergic and noradrenergic systems may be implied in suicide attempt risk. In addition, although the serotonergic system has been extensively studied, no formal meta-analysis has been performed to examine its association with suicide attempt.
Methods
Using PRISMA methodology, we performed a systematic literature review and random-effects meta-analyses of the differences in cerebrospinal fluid (CSF) levels of 5-HIAA, HVA and MHPG between suicide attempters and individuals who never attempted suicide.
Results
We identified 30 studies including 937 suicide attempters and 1128 non-attempters; 29 of them measured CSF levels of 5-HIAA, 22 measured CSF levels of HVA and 14 measured CSF levels of MHPG. CSF levels of 5-HIAA and HVA were significantly lower in suicide attempters than in non-attempters [SMD= -0.43 (95% CI: -0.71 to -0.15; p<0.01) and SMD= -0.45 (95% CI: -0.72 to -0.19; p<0.01), respectively]. We did not find a significant association between CSF MHPG levels and suicide attempt.
Limitations
Our analyses relied on a limited number of studies of good quality and most studies included small sample sizes.
Conclusion
Both serotonin and dopamine systems may play a role in suicide attempt risk. Our findings suggest that a silo approach to biomarkers should be phased out in favor of the study of multiple systems in parallel and in the same populations to progress in the identification of the biological components independently associated with suicide risk, with the goal of identifying new treatment targets and improving suicide risk prediction.
... The VTA is a group of neurons located close to the midline, on the floor of the midbrain. Normal mesolimbic function and affective processes, such as reward-mediated drive, are highly dependent on dopaminergic neurotransmission emanating from the VTA [37,38]. Pain relief is thought to be signaled as a reward via VTA dopaminergic neurons. ...
Chronic pain (pain lasting for >3 months) decreases patient quality of life and even occupational abilities. It can be controlled by treatment, but often persists even after management. To properly control pain, its underlying mechanisms must be determined. This review outlines the role of the mesolimbic dopaminergic system in chronic pain. The mesolimbic system, a neural circuit, delivers dopamine from the ventral tegmental area to neural structures such as the nucleus accumbens, prefrontal cortex, anterior cingulate cortex, and amygdala. It controls executive, affective, and motivational functions. Chronic pain patients suffer from low dopamine production and delivery in this system. The volumes of structures constituting the mesolimbic system are known to be decreased in such patients. Studies on administration of dopaminergic drugs to control chronic pain, with a focus on increasing low dopamine levels in the mesolimbic system, show that it is effective in patients with Parkinson’s disease, restless legs syndrome, fibromyalgia, dry mouth syndrome, lumbar radicular pain, and chronic back pain. However, very few studies have confirmed these effects, and dopaminergic drugs are not commonly used to treat the various diseases causing chronic pain. Thus, further studies are required to determine the effectiveness of such treatment for chronic pain.
... Normal mesolimbic function and affective processes, such as reward-mediated drive, are highly dependent on dopaminergic neurotransmission emanating from the VTA (26)(27)(28). Fibromyalgia patients demonstrate blunted VTA activity during pain anticipation and evoked pain, and trigeminal neuralgia patients have decreased ventral diencephalon volume, which includes the VTA (29,30). Researchers have found that chronic migraine is associated with decreased connectivity between the extended amygdala and the VTA, both of which are areas significantly involved in the management of executive function and emotional responses (31). ...
Chronic pain is a complex neuropsychiatric disorder characterized by sensory, cognitive, and affective symptoms. Over the past 2 decades, researchers have made significant progress toward understanding the impact of meso-limbic dopamine circuitry in acute and chronic pain. These efforts have provided insights into the circuits and intracellular pathways in the brain reward center that are implicated in sensory and affective manifestations of chronic pain. Studies have also identified novel therapeutic targets as well as factors that affect treatment responsiveness. Dysregulation of dopamine function in the brain reward center may further promote comorbid mood disorders and vulnerability to addiction. This review discusses recent clinical and preclinical findings on the neuroanatomical and neurochemical adaptations triggered by prolonged pain states in the brain reward pathway. Furthermore, this discussion highlights evidence of mechanisms underlying comorbidities among pain, depression, and addiction.
... Cocaine is a non-selective DAT inhibitor which also inhibits the re-uptake transporters of serotonin (SERT) and norepinephrine (NET). The excitatory serotonergic and noradrenergic innervation of the VTA (Adell and Artigas 2004;Esposito 2006) notably mediated by 5-HT2C (Pessia et al. 1994; and alpha1-adrenergic receptors (Grenhoff et al. 1995;Steffensen et al. 1998) have been proposed as key processes to limit the inhibitory effect of acutely administered cocaine on VTA DA neuronal activity. Using intracerebral microdialysis in awake freely moving mice, we showed that cocaine elicits a robust increase (800%) in extracellular DA levels in the NAc. ...
RATIONALE:
Pregabalin is a psychoactive drug indicated in the treatment of epilepsy, neuropathic pain, and generalized anxiety disorders. Pregabalin acts on different neurotransmission systems by inactivating the alpha2-delta subunit of voltage-gated calcium channels. In light of this pharmacological property, the hypothesis has been raised that pregabalin may regulate the mesolimbic dopamine pathway and thereby display a potential for misuse or abuse as recently observed in humans. Although some preclinical data support this possibility, the rewarding properties of gabapentinoid are still a matter for debate.
OBJECTIVE:
The aim of this work was to evaluate the rewarding properties of pregabalin and to determine its putative mechanism of action in healthy mice.
RESULTS:
Pregabalin alone (60 mg/kg; s.c.) produced a rewarding effect in the conditioned place preference (CPP) test albeit to a lower extent than cocaine (30 mg/kg; s.c.). Interestingly, when assessing locomotor activity in the CPP, the PGB60 group, similarly to the cocaine group, showed an increased locomotor activity. In vivo single unit extracellular recording showed that pregabalin had mixed effects on dopamine (DA) neuronal activity in the ventral tegmental area since it decreased the activity of 50% of neurons and increased 28.5% of them. In contrast, cocaine decreased 75% of VTA DA neuronal activity whereas none of the neurons were activated. Intracerebal microdialysis was then conducted in awake freely mice to determine to what extent such electrophysiological parameters influence the extracellular DA concentrations ([DA]ext) in the nucleus accumbens. Although pregabalin failed to modify this parameter, cocaine produced a robust increase (800%) in [DA]ext.
CONCLUSIONS:
Collectively, these electrophysiological and neurochemical experiments suggest that the rewarding properties of pregabalin result from a different mode of action than that observed with cocaine. Further experiments are warranted to determine whether such undesirable effects can be potentiated under pathological conditions such as neuropathic pain, mood disorders, or addiction and to identify the key neurotransmitter system involved.
KEYWORDS:
Dopamine; Nucleus accumbens; Pregabalin; Rewarding properties; VTA
... Indeed, it can have multifactorial causes, including the augmentation of ADH action in the renal medulla, the re-setting of the osmostat that lowers the threshold for ADH secretion and the interaction with other drugs by inhibition of cytochrome P450 2D6 [35][36][37]. From a mechanistic perspective, some animal studies have shown that increased levels of serotonin can increase ADH secretion, through the hyper-activation of 5-HT 2 receptors [39,40]. The mechanistic explanation of this finding is that an excessive increase in serotonin levels can cause a rebound drop in dopamine levels, via 5-HT 2 receptors [41,42] and insufficient dopamine levels may lead to SIADH [43,44]. ...
Background
Hyponatraemia induced by antidepressant drugs is a rare but potentially life-threatening adverse reaction. Whether it is associated with all or only some antidepressant drugs is still unclear. This needs to be clarified to guide antidepressant therapies, especially in patients with electrolytic imbalances.
Objectives
The primary objective of this study was to quantify the strength of association between the use of different antidepressant drugs and hyponatraemia by using information reported to the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS). The secondary objective was to investigate the putative relationship between different antidepressant pharmacological targets and the risks of hyponatraemia induced by antidepressant drugs using the ‘pharmacovigilance–pharmacodynamic’ method.
Methods
We used the FAERS database to conduct a case/non-case analysis on spontaneous reports, focusing on events of hyponatraemia/syndrome of inappropriate antidiuretic hormone secretion (SIADH) reported in connection with the use of antidepressant drugs. Risk was expressed as a measure of disproportionality using the reporting odds ratio while adjusting for sex, age and concomitant medications associated with hyponatraemia/SIADH. We assessed to what extent the receptor-binding properties of antidepressant drugs could associate with the reporting odds ratios of hyponatraemia/SIADH of antidepressant drugs, building a linear regression model that included as independent variables the binding affinities (pKi) to the serotonin transporter, dopamine transporter, norepinephrine transporter, and serotonin 5-HT2C, 5-HT2A and 5-HT1A, and α1- and α2-adrenergic receptors.
Results
There were 2233 reports identified. The adjusted reporting odds ratio for the association between antidepressant drug use and hyponatraemia was 1.91 (95% confidence interval 1.83–2.00). The association was strongest for mirtazapine, followed by selective serotonin reuptake inhibitors, and lowest with serotonin-modulating antidepressant drugs. A significant linear correlation was found between the adjusted reporting odds ratios for hyponatraemia and pKi for the adrenergic receptors α1 and α2.
Conclusions
Hyponatraemia is reported at a disproportionately higher level with classes of antidepressant drugs (noradrenergic and specific serotonergic antidepressant [mirtazapine] and serotonin modulators [vortioxetine]) that are in general considered to have a better profile of tolerability in terms of hyponatraemia. With regard to the presented results, the risk of hyponatraemia with mirtazapine appears to be greater than what was reported in the literature; however, confounding by indication cannot be ruled out. Our pharmacovigilance–pharmacodynamic analysis also indicates that inhibition of the serotonin transporter may not be involved in the hyponatraemia linked to the use of antidepressant drugs.
... Cocaine is a non-selective DAT inhibitor which also inhibits the re-uptake transporters of serotonin (SERT) and norepinephrine (NET). The excitatory serotonergic and noradrenergic innervation of the VTA (Adell and Artigas 2004;Esposito 2006) notably mediated by 5-HT2C (Pessia et al. 1994; and alpha1-adrenergic receptors (Grenhoff et al. 1995;Steffensen et al. 1998) have been proposed as key processes to limit the inhibitory effect of acutely administered cocaine on VTA DA neuronal activity. Using intracerebral microdialysis in awake freely moving mice, we showed that cocaine elicits a robust increase (800%) in extracellular DA levels in the NAc. ...
Rationale
Pregabalin is a psychoactive drug indicated in the treatment of epilepsy, neuropathic pain, and generalized anxiety disorders. Pregabalin acts on different neurotransmission systems by inactivating the alpha2-delta subunit of voltage-gated calcium channels. In light of this pharmacological property, the hypothesis has been raised that pregabalin may regulate the mesolimbic dopamine pathway and thereby display a potential for misuse or abuse as recently observed in humans. Although some preclinical data support this possibility, the rewarding properties of gabapentinoid are still a matter for debate.
Objective
The aim of this work was to evaluate the rewarding properties of pregabalin and to determine its putative mechanism of action in healthy mice.
Results
Pregabalin alone (60 mg/kg; s.c.) produced a rewarding effect in the conditioned place preference (CPP) test albeit to a lower extent than cocaine (30 mg/kg; s.c.). Interestingly, when assessing locomotor activity in the CPP, the PGB60 group, similarly to the cocaine group, showed an increased locomotor activity. In vivo single unit extracellular recording showed that pregabalin had mixed effects on dopamine (DA) neuronal activity in the ventral tegmental area since it decreased the activity of 50% of neurons and increased 28.5% of them. In contrast, cocaine decreased 75% of VTA DA neuronal activity whereas none of the neurons were activated. Intracerebal microdialysis was then conducted in awake freely mice to determine to what extent such electrophysiological parameters influence the extracellular DA concentrations ([DA]ext) in the nucleus accumbens. Although pregabalin failed to modify this parameter, cocaine produced a robust increase (800%) in [DA]ext.
Conclusions
Collectively, these electrophysiological and neurochemical experiments suggest that the rewarding properties of pregabalin result from a different mode of action than that observed with cocaine. Further experiments are warranted to determine whether such undesirable effects can be potentiated under pathological conditions such as neuropathic pain, mood disorders, or addiction and to identify the key neurotransmitter system involved.
... Regulation of the monoaminergic functions in the brain has been shown to be an effective approach to treat depression (Delgado and Moreno 1999;Nutt 2007). Therefore, the serotonergic, noradrenergic, or dopaminergic systems are proper targets in the investigation of available antidepressants, which may lead to innovative drug therapies (Lambert et al. 2000;Esposito 2006). Despite the essential role of the certain selective antidepressants (e.g., fluoxetine and reboxetine) in clinical therapy and experimental assessment of depression, Bmulti-target^medications may prove to be better adapted to improve treatment of those who suffer from this debilitating disease (Millan 2006;Stahl 2013). ...
Acute doses of topiramate (TPM) have been shown to reduce immobility time in the mice forced swimming test (FST) through inhibition of the nitric oxide (NO) pathway. Adenosine triphosphate–sensitive potassium (KATP) channels are known to have an active role in depression. This study investigates the potential participation of KATP channels in the antidepressant-like effect of TPM through the stimulatory effects of NO. FST and tail suspension tests (TST) were applied to adult male mice for assessment of the antidepressant-like activity of TPM. Different doses of glibenclamide and cromakalim were also applied in order to investigate the involvement of KATP channels. Fluoxetine was used as a positive control for evaluation of antidepressant-like effects. In addition, each animal’s locomotor activity was evaluated by the open-field test (OFT). TPM (30 mg/kg intraperitoneal (i.p.)) had a significant reductive effect on the immobility behavior similar to fluoxetine (20 mg/kg). Co-administration of sub-effective doses of glibenclamide (1 mg/kg i.p.) and TPM (10 mg/kg i.p.) led to significant synergistic effects in FST and TST. Additionally, the results showed that administration of the sub-effective dose of cromakalim (0.1 and 0.3 mg/kg i.p.) blocked the antidepressant-like effects of TPM (30 mg/kg i.p.) in both tests. These interventions had no impact on the locomotor movement of mice in OFT. This study shows that the antidepressant-like activity of TPM may potentially be mediated by the blocking of the KATP channels.
... In addition, the flavones available in leaves and flowers can have a suppressing effect on monoamine oxidase, which in turn, can cause antidepressant effects (40,43). It is commonly believed that improving brain monoaminergic functions is beneficial in treating depression, and the serotonergic, noradrenergic, or dopaminergic systems have become targets for the development of antidepressants (45). ...
Background: Matricaria chamomilla and Melissa officinalis have been used as antidepressants in traditional Iranian medicine. Objectives: The aim of this study was to determine the effectiveness of Matricaria chamomilla and Melissa officinalis extracts compared to the classic antidepressant drug, imipramine, in adult non-reserpinized and reserpinized mice through the forced swim test. Methods: In the current experimental study, 80 mice were divided into 10 groups. The first group received normal saline and the second and third groups received 25 and 50 mg/kg of Matricaria chamomilla extract, respectively. The fourth and the fifth groups received 25 and 50 mg/kg of Melissa officinalis extract. The sixth group received imipramine at a dose of 15 mg/kg. The seventh group received 5 mg/kg of reserpine and normal saline. The eighth and ninth groups received 25 and 50 mg/kg of Melissa officinalis and Matricaria chamomilla extracts, respectively. The tenth group was given imipramine through intraperitoneal (I.P) injection. Statistical analyses were performed using one-way analysis of variance (ANOVA) followed by Tukey’s post hoc test in SPSS. Results: Matricaria chamomilla (50 mg/kg), Melissa officinalis (25 mg/kg), and imipramine (15 mg/kg) in non-reserpinized mice significantly decreased the duration of immobility in the forced swim test compared to the control group (P < 0.01). There was a reduction in the duration of immobility in the reserpinized mice administered Matricaria chamomilla at a dose of 50 mg/kg compared to the positive control group (P < 0.01). Conclusions: Matricaria chamomilla and Melissa officinalis have antidepressant effects and may be taken into consideration in treating patients suffering from depression. Copyright © 2018, Jundishapur Journal of Natural Pharmaceutical Products.
... Moreover, WAY163909 also reduced the hyperactivity associated with olfactory bulbectomy in rats after chronic treatment [135,136]. It is possible that the antidepressant-like effect mediated by these compounds was a result of 5-HT2C receptor stimulation and consequent activation of postsynaptic serotonin receptors (reviewed in [137]). Similarly, other selective 5-HT2C receptor agonists were effective in animal models of depression and obsessive-compulsive disorder [138,139]. ...
Serotonin regulates many physiological processes including sleep, appetite, and mood. Thus, serotonergic system is an important target in the treatment of psychiatric disorders, such as major depression and anxiety. This natural neurotransmitter interacts with 7 families of its receptors (5-HT1-7), which cause a variety of pharmacological effects. Using genetically modified animals and selective or preferential agonists and antagonist, numerous studies demonstrated the involvement of almost all serotonin receptor subtypes in antidepressant- or anxiolytic-like effects. In this review, based on animal studies, we discuss the possible involvement of serotonin receptor subtypes in depression and anxiety.
... It has been suggested that indirect activation of the 5-HT2C receptor by increased synaptic availability induced by SSRIs may play a more important role in the antidepressant properties of SSRIs relative to other 5-HT receptor subtypes [53]. Paradoxical similar antidepressant effects of both agonists and antagonists of the 5-HT2C receptor may be a result of diverse mechanisms that produce similar behavioral effects including stimulation of postsynaptic 5-HT receptors by 5-HT2C receptor agonists or facilitation of the release of other neurotransmitters by 5-HT2C receptor antagonists [2,54,55]. In addition, agomelatine, a 5-HT2C receptor antagonist and an agonist of melatonin receptors (MT1 and MT2), has shown antidepressant properties in several clinical and preclinical studies [56]. ...
Conventional serotonin-enhancing antidepressants including selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs) have shown effectiveness in the treatment of major depression, but their significant limitations such as slowness of action have led to intensive research efforts to develop new antidepressants. Increased synaptic neurotransmission of serotonin (5-hdroxytryptamine; 5-HT) through orchestration of stimulation and blockade of various subtypes of 5-HT receptors is involved in the mechanisms of action of SSRIs. Agonists at the 5-HT1A, 5-HT1B, 5-HT2C, 5-HT4, and 5-HT6 receptors and antagonists at the 5-HT1A, 5-HT2A, 5-HT2C, 5-HT3, 5- HT6, and 5-HT7 receptors have shown antidepressant properties in clinical and preclinical studies. However, paradoxical antidepressant-like effects of both agonists and antagonists at particular 5-HT receptors suggest the need to consider the neurochemical mechanisms of each 5-HT receptor subtype. Therefore, better knowledge of the involvement of individual 5-HT receptors in the mechanisms of action of currently used antidepressants as well as antidepressant effects of selective ligands of 5-HT receptor subtypes will provide opportunities for the development of future antidepressants with more rapid onset of action, fewer side effects, and better efficacy than SSRIs.
... M), serotonergic 5HT1A (k i 3.1 M) and 5HT2A (k i 15 M) receptors, and histamine H3 (k i 7.2 M) receptors [79]. Interactions at these receptors, each of which has been shown to modulate extracellular levels of monoamines [97][98][99][100], as well as glutamatergic transmission in the cortex [101][102][103][104], may contribute to the in vivo effects of pridopidine. Apart from the monoaminergic receptors, pridopidine has been reported to display moderate affinity at the sigma-1 receptor in vitro [105]. ...
Despite advances in understanding the pathophysiology of Huntington’s disease (HD), there are currently no effective pharmacological agents available to treat core symptoms or to stop or prevent the progression of this hereditary neurodegenerative disorder. Pridopidine, a novel small molecule compound, has demonstrated potential for both symptomatic treatment and disease modifying effects in HD. While pridopidine failed to achieve its primary efficacy outcomes (Modified motor score) in two trials (MermaiHD and HART) there were consistent effects on secondary outcomes (TMS). In the most recent study (PrideHD) pridiopidine did not differ from placebo on TMS, possibly due to a large enduring placebo effect.
This review describes the process, based on in vivo systems response profiling, by which pridopidine was discovered and discusses its pharmacological profile, aiming to provide a model for the system-level effects, and a rationale for the use of pridopidine in patients affected by HD. Considering the effects on brain neurochemistry, gene expression and behaviour in vivo, pridopidine displays a unique effect profile. A hallmark feature in the behavioural pharmacology of pridopidine is its state-dependent inhibition or activation of dopamine-dependent psychomotor functions. Such effects are paralleled by strengthening of synaptic connectivity in cortico-striatal pathways suggesting pridopidine has potential to modify phenotypic expression as well as progression of HD. The preclinical pharmacological profile is discussed with respect to the clinical results for pridopidine, and proposals are made for further investigation, including preclinical and clinical studies addressing disease progression and effects at different stages of HD.
... We start from three particular findings. First, 5-HT is involved in the prediction of aversive events, possibly as a form of opponent [1][2][3] to dopamine [4][5][6][7][8][9][10][11]. Second, 5-HT is involved in behavioral inhibition [12][13][14], preventing or curtailing ongoing actions in light of predictions of aversive outcomes. ...
Pavlovian predictions of future aversive outcomes lead to behavioral inhibition, suppression, and withdrawal. There is considerable evidence for the involvement of serotonin in both the learning of these predictions and the inhibitory consequences that ensue, although less for a causal relationship between the two. In the context of a highly simplified model of chains of affectively charged thoughts, we interpret the combined effects of serotonin in terms of pruning a tree of possible decisions, (i.e., eliminating those choices that have low or negative expected outcomes). We show how a drop in behavioral inhibition, putatively resulting from an experimentally or psychiatrically influenced drop in serotonin, could result in unexpectedly large negative prediction errors and a significant aversive shift in reinforcement statistics. We suggest an interpretation of this finding that helps dissolve the apparent contradiction between the fact that inhibition of serotonin reuptake is the first-line treatment of depression, although serotonin itself is most strongly linked with aversive rather than appetitive outcomes and predictions.
... 5-HT (serotonin)-1A agonists and partial agonists are identified to elicit the anticataleptogenic effects, 17,19,[41][42][43] which is positively correlated with the rank order of their intrinsic activity at 5-HT-1A receptors. 44 In order to find out the prospective role of somatodendritic and/or postsynaptic 5-HT-1A receptors in the modulation of haloperidol-induced catalepsy, we 4 46,47 Therefore, the administration of mianserin and mesulergine, 5-HT-2A/2C receptor antagonists (Figures 2 and 3), possibly releases DA neurons from the inhibitory effects of 5-HT to ameliorate parkinsonian-like effects of the neuroleptics drug. 20,48 This effect is illustrated in Figure 4. ...
Antipsychotic drugs are extensively prescribed for the treatment of schizophrenia and other related psychiatric disorders. These drugs produced their action by blocking dopamine (DA) receptors, and these receptors are widely present throughout the brain. Therefore, extended antipsychotic use also leads to severe extrapyramidal side effects. The short-term effects include parkinsonism and the later appearing tardive dyskinesia. Currently available treatments for these disorders are mostly symptomatic and insufficient, and are often linked with a number of detrimental side effects. Antipsychotic-drug-induced tardive dyskinesia prompted researchers to explore novel drugs with fewer undesirable extrapyramidal side effects. Preclinical studies suggest a role of 5-hydroxytryptamine (serotonin)-1A and 2A/2C receptors in the modulation of dopaminergic neurotransmission and motivating a search for better therapeutic strategies for schizophrenia and related disorders. In addition, adjunctive treatment with antioxidants such as vitamin E, red rice bran oil, and curcumin in the early phases of illness may prevent additional oxidative injury, and thus improve and prevent further possible worsening of related neurological and behavioral deficits in schizophrenia. This review explains the role of serotonergic receptors and oxidative stress, with the aim of providing principles for prospect development of compounds to improve therapeutic effects of antischizophrenic drugs.
... In general, the gross abnormalities in tissue contents of brain monoamines were not found but suggested an abnormal cortical filtering of stressful information (a blunted 5HT cortical response) and increased cortical tissue NA in all epileptic rats (Midzyanovskaya, 2006). It is proposed that subtle changes in the DAergic, NAergic and 5HTergic systems act in synergy in modulating susceptibility to stress and predisposition to depression (Alex and Pehek, 2007;Elhwuegi, 2004;Esposito, 2006;Juckel et al., 2003). ...
A great number of clinical observations show a relationship between epilepsy and depression. Idiopathic generalized epilepsy, including absence epilepsy, has a genetic basis. The review provides evidence that WAG/Rij rats can be regarded as a valid genetic animal model of absence epilepsy with comorbidity of depression. WAG/Rij rats, originally developed as an animal model of human absence epilepsy, share many EEG and behavioral characteristics resembling absence epilepsy
in humans, including the similarity of action of various antiepileptic drugs. Behavioral studies indicate that WAG/Rij rats exhibit depression-like symptoms: decreased investigative activity in the open field
test, increased immobility in the forced swimming test, and decreased sucrose consumption and preference (anhedonia). In addition, WAG/Rij rats adopt passive strategies in stressful situations, express some cognitive disturbances (reduced long-term memory), helplessness, and submissiveness, inability to make choice and overcome obstacles, which are typical for depressed patients. Elevated anxiety is not a characteristic (specific) feature of WAG/Rij rats, it is a characteristic for only a substrain of WAG/Rij rats susceptible to audiogenic seizures. Interestingly, WAG/Rij rats display a hyperresponse to amphetamine similar to anhedonic depressed patients. WAG/Rij rats are sensitive only to chronic, but not acute, antidepressant treatments, suggesting that WAG/Rij rats fulfill a criterion of predictive validity for a putative animal model of depression. However, more and different antidepressant drugs still await evaluation. Depression-like behavioral symptoms in WAG/Rij rats are evident at baseline conditions, not exclusively after stress. Experiments with foot-shock stress don't point towards higher stress sensitivity both at behavioral and hormonal level. However, freezing behavior (coping deficits) and blunted response of 5HT in the frontal cortex to uncontrollable sound stress suggest that WAG/Rij rats are vulnerable to some, but not to all types of stressors. We propose that genetic absence epileptic WAG/Rij rats have behavioral depression-like symptoms, are vulnerable to stress and might represent a model of chronic low-grade depression (dysthymia). Both 5HT and DAergic abnormalities detected in the brain of WAG/Rij rats are involved in modulation of vulnerability to stress and provocation of behavioral depression-like symptoms. The same neurotransmitter systems modulate SWDs as well. Recent studies suggest that the occurrence and
repetition of absence seizures are a precipitant of depression-like behavior. Whether the neurochemical changes are primary to depression-like behavioral alterations remains to be determined. In conclusion, the WAG/Rij rats can be considered as a genetic animal model for absence
epilepsy with comorbidity of dysthymia. This model can be used to investigate aetiology, pathogenic mechanisms and treatment of a psychiatric comorbidity, such as depression in absence epilepsy, to
reveal putative genes contributing to comorbid depressive disorder, and to screen novel psychotropic drugs with a selective and/or complex (dual) action on both pathologies.
... 5-HT 1A auto receptors desensitization leads to an increased 5-HT release which results in tonic activation of 5-HT 1A postsynaptic receptors in the hippocampus and 5-HT 2c in dopaminergic neuron (Haddjeri et al., 1998). Increased 5-HT 2C expression decreases dopamine release and 5-HT 2C receptor antagonism results in an increased extracellular dopaminergic response to many drugs (Bubaret al., 2006, Esposito et al., 2006). Previously it is reported that repeated administration of oral therapeutic doses of methylphenidate produces locomotor sensitization whereas sensitization and cognitive improvement are more pronounced at smaller doses (Alam and Najam., 2013). ...
Methylphenidate, which inhibit dopamine transporter is effective in the treatment of ADHD (attention deficit hyperactivity disorder), but long term use of this drug is often associated with addiction and dependence. Locomotor sensitization development to psychostimulants like methylphenidate is an important contributor to drug abuse induced by psychostimulants. Different studies have shown that long term administration of drugs of abuse increases the effectiveness of 5-hydroxytryptamine (5-HT)-1A somatodendritic receptors. Repeated buspirone administration reduces the effectiveness of 5-HT1A somatodendritic receptors. This study was designed to determine that buspirone coadministration may reduce methylphenidate-induced sensitization. The motor activity was compared by using familiar and novel environments after long-term administration of methylphenidate, buspirone and their co-administration. Long term oral administration of methylphenidate at a dose of 2.0mg/kg/day enhanced motor activity in home cage i.e activity of familiar environment monitored at alternate day. Locomotor enhancing effects of methylphenidate were augmented on 13th day of drug administration suggesting sensitization induced by the drug. The sensitization effects were significant in home cage monitored on alternate day and also in an open field monitored weekly. Buspirone co-administration at a dose of 10mg/kg/day prevented methylphenidate-induced sensitization. It is suggested that the sensitization development to methylphenidate may oppose by buspirone co-administration due to the reduction in the sensitivity of 5-HT1A somatodendritic receptors. These findings may help extend future therapeutics in ADHD.
... Taken together, AV-extract possesses a clear antidepressant-like effect in all animal models used. It is generally accepted that improving brain monoaminergic functions is effective in treating depression, and the serotonergic, noradrenergic or dopaminergic systems have become the targets for development of antidepressants (Lambert et al., 2000;Esposito, 2006). The serotonergic system has long been implicated in the pathogenesis of anxiety and depression (Heninger et al., 1996). ...
... Tar has been found to diminish the ability of vitamin B6 to function in critical biochemical pathways such as tryptophan/serotonin metabolism [5,44]. Serotonin can modulate the dopaminergic and norepinephrine systems, and vice versa [9,27]. On the other hand, The Morris water maze test allows the parallel measurement of responses related to both conditioned and unconditioned fear in the same subject. ...
Color additives are used in a wide variety of foods, Food azo-colours tartrazine (Tar) is one of the most widely
used artificial foods, drugs and cosmetic yellow dyes, its E number is E102 while Curcumin (Cur, an active
ingredient of turmeric) is brightly yellow colored which routinely used as spice, food preservative and coloring
material in different parts of the world; its E number is E100. The present study aimed to Compare between
artificial yellow coloring additive Tar and natural one Cur (has the same color) on hyperactivity, learning and
memory and the possibility of using Cur instead of Tar or at least in combined with Tar to protect against Tar
behavioral disorder in weanling rats. To characterized biochemical and behavioral parameters the study was
assessed the effect of Tar (1%, 3%) alone or in combination with Cur (200 mg/kg/b.wt) for 8 weeks on Open
field test to assess the potential hyperactivity and Morris water maze test to assess learning and memory.
Furthermore, biomarkers of oxidative stress malondialdhyde (MDA, end product of lipid peroxides), nitric
oxides (NO, as nitrite to nitrate ratio), GSH (reduced glutathione), and oxidized glutathione (GSSG) in addition
to some neurotransmitter, monoamines [dopamine (DA), norepinephrine (NE) and serotonin (5-HT)] were also
measured in three different brain areas (frontal cortex, Striatum and hippocampus).These brain regions are important because they are involved in important behavioral functions, such as emotion,
motivation, learning and memory. The results indicated that Tar extract significantly enhanced active behavioral
response. Tar-treated rats showed hyperactivity in open field test presented by increasing horizontal locomotion
as well as depletion in learning and memory by increased the escape latency in Morris water maze test and
decreased the retention latency in probe test. Tar alone disturb oxidative stress marker by causing significant
increase in serum NO and serum and tissue MDA and GSSG while it caused significant decrease in serum and
tissue GSH as well as it inhibited neurotransmitters releases especially in striatum and hippocampus area. While
combined treatment of Cur significantly ameliorated all the behavioral and biochemical alterations in serum and
different brain regions of Tar-treated weanling rats. This study provides scientific evidence that there is a
relationship between Tar and inflection of hyperactivity and depletion in learning and memory in weanling rats
while coadministration of Cur attenuates the potential hazards of Tar.
... The elevation of serotonin concentration in the frontal cortex was accompanied by a drop in DA concentration, which can be ascribed to a very complex serotonin-DA interaction (Esposito 2006;Alex and Pehek 2007;Di Giovanni et al. 2008). In the latter case, the interaction may involve terminal 5-HT 1A/B receptors located on endings of the dopaminergic neurons projecting from the ventral tegmental area and exerting local inhibitory control of DA release (Pauwels 1997;Lanfumey and Hamon 2004;Di Giovanni et al. 2008). ...
We aimed to demonstrate that the cytochrome P450 2D (CYP2D)-mediated synthesis of serotonin from 5-methoxytryptamine (5-MT), shown in vitro for cDNA-expressed CYP2D-isoforms and brain microsomes, can happen in the brain in vivo. We measured serotonin tissue content in brain regions after 5-MT injection into the raphe nuclei (Model-A), and its extracellular concentration in rat frontal cortex and striatum using an in vivo microdialysis (Model-B) in male Wistar rats. The measurements were performed in naïve and PCPA (tryptophan hydroxylase inhibitor)-pretreated animals in the absence/presence of the CYP2D inhibitor quinine. 5-MT injected into the raphe nuclei of PCPA-treated rats increased the tissue concentration of serotonin, while quinine diminished serotonin level in some brain structures of those animals (Model-A). 5-MT given locally through a microdialysis probe markedly increased extracellular serotonin concentration and changed dopamine concentration in the frontal cortex and striatum (Model-B). Quinine given jointly with 5-MT prevented the 5-MT-induced increase in cortical serotonin in naïve rats, and in striatal serotonin in PCPA-treated animals. Quinine alone had no effect on serotonin concentration. The obtained results indicate that the CYP2D-catalyzed alternative pathway of serotonin synthesis from 5-MT may happen in the brain in vivo and set a new target for the action of psychotropics. This article is protected by copyright. All rights reserved.
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... The ability of NS18283 to increase 5-HT, NE and DA outflows to a similar extent within the ACC was unexpected; however, given that it has a more unbalanced profile (IC50 = 0.72, 10 and 150 nmol/L for inhibition of 5-HT, NE and DA reuptake in cortex, hippocampus and striatum, respectively). It is conceivable that blockade of 5-HT and NE transporters could have indirect effects on DA outflow given that the ACC dopaminergic system receives dense noradrenergic and serotonergic innervations ( Adell and Artigas, 2004;Esposito, 2006). In other brain regions, e.g., 5-HT exerts an inhibitory influence on DA neurotransmission via the 5-HT2C receptor-mediated activation of gamma-aminobutyric acid (GABA) interneurons, decreasing dopaminergic neuronal firing in the ventral tegmental area (VTA) ). ...
Background: Chronic neuropathic pain can lead to anxiety and depression. Drugs that block reuptake of serotonin, norepinephrine and/or dopamine are widely used to treat depression, and have emerged as useful drugs in the treatment of neuropathic pain. This study compared the acute antinociceptive effects of NS18283, a novel triple monoamine reuptake inhibitor (MRI) with indatraline, venlafaxine and escitalopram in a mouse model of neuropathic pain. Method: Neuropathic pain-like behaviours were induced in mice by repeated injections of oxaliplatin (OXA), and assessed using the von Frey hair test, the cold plate test and the thermal preference plate test. Anxio/depressive phenotype and antidepressant-like properties of compounds were assessed by the novelty suppressed feeding test and the tail suspension test, respectively. Results: In vivo microdialysis experiments showed that each MRI increased extracellular serotonin, norepinephrine and/or dopamine levels in the cingulate cortex, in agreement with their in vitro reuptake inhibitory properties. Indatraline (3 mg/kg) reversed the full repertoire of OXA-induced neuropathic hypersensitivity. NS18283 (10 mg/kg) reversed OXA-induced mechano-hypersensitivity and cold allodynia. Venlafaxine (16 mg/ kg) and escitalopram (4 mg/kg) only reversed cold allodynia and mechano-hypersensitivity, respectively. All MRIs produced antidepressant-like activity in anxio/depressive phenotype of OXA mice. Conclusions: Acute administration of drugs that enhance the activity of serotonin, norepinephrine and dopamine neurotransmission within nociceptive pathways may provide a broader spectrum of antinociception than dual or selective reuptake inhibitors in animal models of neuropathic pain. Whether similar observations would occur after repeated administration of such compounds in an attempt to simulate dosing in humans, or be compromised by dopaminergic-mediated adverse effects warrants further investigation.
... Important synaptic contacts occur not only between axon terminals but also between cell bodies of dopamine-containing and serotonin-containing neurons (see Haleem, 2013). It is therefore not surprising that changes in the activity of one of these neuronal systems can modulate the activity of the other, as demonstrated by a number of pharmacological studies (Bubar and Cunningham, 2006;Dremencov et al., 2006;Esposito, 2006;Haleem, 2006;Werkman et al., 2006;Alex and Pehek, 2007;Navailles and De Deurwaerdère, 2011). ...
Dysfunctions of the basal ganglia are associated with a number of neurological and psychiatric conditions including Parkinson's disease and schizophrenia. Current treatments of these disorders are mostly symptomatic and inadequate, and are often associated with a number of unwanted side-effects. The striatum, the terminal region of the nigrostriatal dopamine pathway, is the main input nucleus of the basal ganglia, and dopamine neurotransmission through the nigrostriatal pathway plays a crucial role in the modulation of basal ganglia output and mediated behaviors. Evidence suggests a role of 5-hydroxytryptamine (5-HT; serotonin)-1A receptors in the modulation of dopamine neurotransmission and in improving pharmacotherapy in schizophrenia and Parkinson's disease. This review concerns the role of 5-HT1A receptors in the modulation of nigrostriatal dopamine neurotransmission, with the aim of providing guidelines for future research to improve pharmacotherapy. The current state of knowledge suggests that drugs simultaneously targeting dopamine D2 and 5-HT1A receptors may improve pharmacotherapy for schizophrenia and Parkinson's disease. Activation of somatodendritic 5-HT1A receptors in the dorsal raphe nucleus has an important role in the alleviation of extrapyramidal symptoms and levodopa-induced dyskinesia induced by antipsychotic treatment. Drugs acting exclusively through dopamine D2 and 5-HT1A receptors are highly needed to validate the potential role of 5-HT1A receptors in improving therapeutics for Parkinson's disease and schizophrenia.
... Moreover, the underlying causes of these disorders are complex and may also involve other neurotransmitter systems including the noradrenalin and dopamine systems (D'Aquila et al., 2000; Ressler and Nemeroff, 2000). Serotonin can modulate the dopaminergic and noradrenalin systems, and vice versa (Iyer and Bradberry, 1996;Esposito, 2006;Salomon et al., 2006). ...
The current research aimed to determine the influence of different doses of exposure to tartrazine on levels of hyperactivity, anxiety, depression and anti-social behaviours in rats. Forty five weanling male Wistar rats were randomly assigned into 3 groups of 15, divided on 2 replicates and administered our treatment daily in drinking water at different concentrations; 0, 1% and 2.5% for a 16 weeks period. Different animal models of anxiety; open field, elevated plus maze and dark-light transition tests were employed in our study. Tests for depression as well as social interaction were also used. Tartrazine-treated rats showed hyperactivity in open field test presented by increased horizontal locomotion. Anxiogenic effect of tartrazine was evidently observed during open field, elevated plus-maze and dark-light transition tests. Furthermore, tartrazine intake significantly promoted depression as expressed by prolonged immobilization during forced swim test. Impairment in social interaction test was also detected signifying the relevance of administered dose especially on numbers of bouts of social contacts. This study provides sufficient scientific evidence that a causal link truly exists between tartrazine and inflection of hyperactivity, anxiety and depression-like behaviours in rats and points to the hazardous impact of tartrazine on public health.
... A considerable amount of data suggests that decreased 5-HT-function can enhance or reduce impulsive behavior, depending on the 5-HT-receptor subtypes and the behavioral tasks used (WINSTANLEY ET AL. 2006). However, due to the fact that different tests of impulsivity probe different cognitive processes (EVENDEN AND RYAN 1999) it is still unclear what generalizations towards 5-HT 2 -receptor involvement can be made on the basis of measurements of impulsive behavior. ...
... The ability of NS18283 to increase 5-HT, NE and DA outflows to a similar extent within the ACC was unexpected; however, given that it has a more unbalanced profile (IC50 = 0.72, 10 and 150 nmol/L for inhibition of 5-HT, NE and DA reuptake in cortex, hippocampus and striatum, respectively). It is conceivable that blockade of 5-HT and NE transporters could have indirect effects on DA outflow given that the ACC dopaminergic system receives dense noradrenergic and serotonergic innervations (Adell and Artigas, 2004;Esposito, 2006). In other brain regions, e.g., 5-HT exerts an inhibitory influence on DA neurotransmission via the 5-HT2C receptor-mediated activation of gamma-aminobutyric acid (GABA) interneurons, decreasing dopaminergic neuronal firing in the ventral tegmental area (VTA) (Di . ...
Background
Chronic neuropathic pain can lead to anxiety and depression. Drugs that block reuptake of serotonin, norepinephrine and/or dopamine are widely used to treat depression, and have emerged as useful drugs in the treatment of neuropathic pain. This study compared the acute antinociceptive effects of NS18283, a novel triple monoamine reuptake inhibitor (MRI) with indatraline, venlafaxine and escitalopram in a mouse model of neuropathic pain.Method
Neuropathic pain-like behaviours were induced in mice by repeated injections of oxaliplatin (OXA), and assessed using the von Frey hair test, the cold plate test and the thermal preference plate test. Anxio/depressive phenotype and antidepressant-like properties of compounds were assessed by the novelty suppressed feeding test and the tail suspension test, respectively.ResultsIn vivo microdialysis experiments showed that each MRI increased extracellular serotonin, norepinephrine and/or dopamine levels in the cingulate cortex, in agreement with their in vitro reuptake inhibitory properties. Indatraline (3 mg/kg) reversed the full repertoire of OXA-induced neuropathic hypersensitivity. NS18283 (10 mg/kg) reversed OXA-induced mechano-hypersensitivity and cold allodynia. Venlafaxine (16 mg/kg) and escitalopram (4 mg/kg) only reversed cold allodynia and mechano-hypersensitivity, respectively. All MRIs produced antidepressant-like activity in anxio/depressive phenotype of OXA mice.Conclusions
Acute administration of drugs that enhance the activity of serotonin, norepinephrine and dopamine neurotransmission within nociceptive pathways may provide a broader spectrum of antinociception than dual or selective reuptake inhibitors in animal models of neuropathic pain. Whether similar observations would occur after repeated administration of such compounds in an attempt to simulate dosing in humans, or be compromised by dopaminergic-mediated adverse effects warrants further investigation.
... funciones importantes en el cerebro y están relacionados con enfermedades neuropsiquiátricas como la enfermedad de Parkinson y la depresión; se ha demostrado que el desequilibrio en la síntesis y liberación de ellos es la base fisiopatológica para este tipo de enfermedades (71)(72)(73). La liberación de estos neurotransmisores se encuentra influenciada por múltiples factores biológicos, dependiendo del tejido cerebral donde se encuentren. El ON es un importante regulador de la liberación de estas monoaminas y es así como Hanbauer y colaboradores (74) reportaron que la aplicación de NO exógeno producía liberación de dopamina en cultivos neuronales. ...
Major depression is one of the world's most prevalent psychiatric diseases. On the other hand, cardiovascular diseases are the first cause of death in Colombia, and epidemiologic observations lead to say that depression and cardiovascular diseases have a bidirectional relationship. The endothelium, with the production of nitric oxide, maintains the vascular tone, inhibits smooth muscle growth, white cell migration and adhesion and has an antiadhesive platelet effect. Therefore, low nitric oxide levels are related with endothelial dysfunction and with a higher cardiovascular risk. It is also well known that this gas has effects over the monoaminergic
Background
Pharmacogenomics describes the link between gene variations (polymorphisms) and drug responses. In view of the implementation of precision medicine in personalized healthcare, pharmacogenetic tests have recently been introduced in the clinical practice. However, the translational aspects of such tests have been limited due to the lack of robust population-based evidence.
Materials
In this paper we present a novel pharmacogenetic panel (iDNA Genomics-PGx–CNS or PGx–CNS), consisting of 24 single nucleotide polymorphisms (SNPs) on 13 genes involved in the signaling or/and the metabolism of 28 approved drugs currently administered to treat diseases of the Central Nervous System (CNS). We have tested the PGx–CNS panel on 501 patient-derived DNA samples from a southeastern European population and applied biostatistical analyses on the pharmacogenetic associations involving drug selection, dosing and the risk of adverse drug events (ADEs).
Results
Results reveal the occurrences of each SNP in the sample and a strong correlation with the European population. Nonlinear principal component analysis strongly indicates co-occurrences of certain variants. The metabolization efficiency (poor, intermediate, extensive, ultra-rapid) and the frequency of clinical useful pharmacogenetic, associations in the population (drug relevance), are also described, along with four exemplar clinical cases illustrating the strong potential of the PGx–CNS panel, as a companion diagnostic assay. It is noted that pharmacogenetic associations involving copy number variations (CNVs) or the HLA gene were not included in this analysis.
Conclusions
Overall, results illustrate that the PGx–CNS panel is a valuable tool supporting therapeutic medical decisions, urging its broad clinical implementation.
Fluoxetine is a widely prescribed antidepressant that has been frequently detected in aquatic environments and is associated with a series of neurological, behavioural and neuroendocrine disruptions in nontarget organisms. However, studies on its effects in fish under realistic environmental conditions are still limited. In this study, we determined the influences of an environmentally relevant concentration of fluoxetine (100 ng/L) on crucian carp (Carassius auratus) in the presence of dissolved organic matter (DOM). Endpoints that were assessed included accumulation of fluoxetine and metabolite formation as well as related biological responses involving neurotransmission and metabolic processes. Fluoxetine was significantly bioconcentrated in the fish brain and liver and largely transformed to the active metabolite norfluoxetine. Brain neurotransmission processes related to serotonin and choline and liver metabolic status were simultaneously altered. DOM added at 1 mg/L had no effect on the accumulation of fluoxetine or its metabolites in different tissues of the fish. However, at 10 mg/L DOM facilitated fluoxetine and norfluoxetine accumulation in the liver, brain, kidney, gill and bile tissues of the fish. The neuroendocrine-disrupting effects on fish caused by fluoxetine were also enhanced by the co-addition of DOM at 10 mg/L. Binding with fluoxetine and the inhibition of metabolic functions caused by DOM may be responsible for this increase in effects. These findings imply that at high concentrations DOM can increase the toxicity of environmentally relevant concentrations of fluoxetine to fish.
The miniature sensor has become one of the most popular tools for electroactive biomarker molecule sensing, but the challenge for preparing microelectrodes of hybrid materials still exists. In this contribution, we report a novel strategy for constructing a hybrid nitrogen-doped graphene microelectrode (NGR ME) to efficiently and reliably detect neurotransmitters. The construction procedure is a simple, green, easy-to-operate multistep assembly sequence coated on a customizable micro/nanoscale substrate. Meanwhile, polydopamine (PDA) is a biologically friendly polymer and playing multiple roles. It starts from classic adhesion ability on micro/nanoscale substrates, and its rich amino functional groups electrostatically adsorbed with graphene oxide (GO). Finally, it provided a nitrogen source for nitrogen atom doping in hybrid graphene materials. Since the self-assembled multilayers undergo a pyrolysis process, the synergistic interaction between the multilayers has endowed the microelectrodes excellent electrical conductivity and electrocatalytic performance. This work demonstrates our approach to designing microelectrodes with customizable sizes, proving that it can be used for neurotransmitter sensing with high sensitivity, excellent selectivity and low detection limit (0.69 nM for DA, 6.5 nM for 5-HT), and also can be implanted into a cannula to make a portable and micro-volume device for detecting real human serum samples, which demonstrates promising prospects in clinical diagnosis.
The serotonin receptor subtypes 2 comprises 5-HT2A, 5-HT2B and 5-HT2C that are Gq-coupled receptors and display distinct pharmacological properties. Although co-expressed in some brain regions and involved in various neurological disorders, their functional interactions have not been studied yet. We report that 5-HT2 receptors can form homo and heterodimers when expressed alone or co-expressed in transfected cells. Co-immunoprecipitation and bioluminescence resonance energy transfer studies confirmed that 5-HT2C receptors interact with either 5-HT2A or 5-HT2B receptors. Although heterodimerization with 5-HT2C receptors does not alter 5-HT2C Gαq-dependent inositol-phosphate signaling, 5-HT2A- or 5-HT2B-receptor-mediated signaling was totally blunted. This feature can be explained by a dominance of 5-HT2C on 5-HT2A and 5-HT2B receptor binding: in 5-HT2C-containing heterodimers, ligands bind and activate exclusively the 5-HT2C protomer. This dominant effect on the associated protomer was also observed in neurons, supporting a physiological relevance of 5-HT2 receptors heterodimerization in-vivo. Accordingly, exogenous expression of an inactive form of the 5-HT2C receptor in the Locus ceruleus is associated with decreased 5-HT2A-dependent noradrenergic transmission. These data demonstrate that 5-HT2 receptors can form functionally asymmetric heterodimers in-vitro and in-vivo that must be considered when analyzing the physiological or pathophysiological roles of serotonin in tissues where 5-HT2 receptors are co-expressed.
Various previous studies show that a dysfunction of the central dopaminergic neurotransmission is involved in a series of neuropsychiatric disorders, including schizophrenia, depression, bipolar disorder and ADHD. The neurocognitive and psychopathological manifestations of central dopaminergic dysfunction - on a motivational, psychomotors and executive level - have lately been put into a relationship with neuroanatomical and neurofunctional sites. The dorsal and ventral striatum, as well as cortical regions such as the limbic and prefrontal cortex, among other locations are in the focus of current research interests. This article presents current genetic, molecular-biologic and imaging findings, specifying the prominent role of dopaminergic transmission as well as the interaction of dopamine with other transmitters in the pathogenesis of some of the most important psychiatric disorders. We emphasize insights which might be crucial for the development of new therapeutic approaches.
Selected findings are noticed about the role and function of serotonin receptors followed by disclosure of mechanisms of action of antidepressants affecting primary serotonergic system; specifically, by antidepressants classified as selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs). Following of these findings, mechanisms of receptor and postreceptor action of serotonin antagonist and reuptake inhibitors (SARIs) can be clarified, which is demonstrated on example of multifunctional drug trazodone. The delay in onset of therapeutic efficiency of antidepressants is a function of the drugs, rather than the disease. Research into the biological characteristics of depression and its treatment may yield faster-acting antidepressants.
La depressione rappresenta uno dei principali disturbi non motori della malattia di Parkinson. Essa colpisce circa il 40% dei parkinsoniani e partecipa alla disabilità e all’alterazione della qualità di vita. La depressione è preponderante ai due estremi della malattia: all’inizio, a volte precedendo i sintomi motori, e allo stadio del declino e delle fluttuazioni motorie. La diagnosi di depressione rimane clinica e si basa sui criteri del Diagnostic and Statistical Manual of Mental Disorders, 4aedizione (DSM IV). Si tratta di un processo delicato, data l’esistenza di una certa sovrapposizione semeiologica tra sindrome parkinsoniana, depressione e apatia; quest’ultima è spesso osservata nei parkinsoniani sia in associazione con la depressione che in quanto sindrome a sé. Depressione, apatia e rischio di suicidio aumentato fanno parte delle complicanze psichiatriche osservate nei parkinsoniani trattati con stimolazione bilaterale ad alta frequenza del nucleo subtalamico. Sul piano fisiopatologico, sono in causa dei fattori psicologici e organici. Nuove ipotesi privilegiano l’implicazione preferenziale di un malfunzionamento dei sistemi noradrenergico e dopaminergico centrali all’interno della rete limbica, relativamente a quella del sistema serotoninergico. Sul piano terapeutico, nel corso dell’ultimo decennio, un numero crescente di studi ha rilevato il potenziale terapeutico antidepressivo degli agonisti dopaminergici, e l’ottimizzazione del trattamento dopaminergico si è, così, rivelata una tappa importante e necessaria prima della prescrizione degli antidepressivi tradizionali. Tuttavia, la scelta dei diversi antidepressivi disponibili resta attualmente empirica e, negli anni a venire, la realizzazione di nuovi studi controllati in doppio cieco, poco numerosi, a tutt’oggi, diviene necessaria per definire una condotta da tenere nel trattamento dei disturbi depressivi nella malattia di Parkinson. In conclusione, la depressione nella malattia di Parkinson è frequente e di origine multifattoriale, richiedendo, nei casi più complessi, una collaborazione stretta tra neurologi, psichiatri e psicologi.
This chapter discusses the various types of antidepressant drugs. Nearly all antidepressants currently in use act by increasing the concentrations of the monoamine neurotransmitters serotonin [5-hydroxytryptamine (HT)], norepinephrine (NE), and/or dopamine (DA), primarily by inhibition of reuptake mechanisms. Selective serotonin reuptake inhibitors (SSRIs) include fluoxetine, paroxetine, sertraline, and escitalopram. Serotonin and NE reuptake inhibitors (SNRIs) include venlafaxine and duloxetine. The “atypical” antidepressant buproprion has been reported to inhibit the NE transporter (NET) and the DA transporter (DAT). Although new SSRIs continue to be identified, only those possessing additional receptor modulating properties are discussed in the chapter.
The effect of prolonged administration of the potent and specific 5-HT uptake inhibitor citalopram on behavioural measures of dopaminergic and serotonergic activity has been studied in rats. Administration of citalopram in the diet at a daily dose of 99 mumol/kg led to supersensitivity to d-amphetamine-induced hypermotility and stereotypy and to subsensitivity to apomorphine-induced hypomotility 2 h after withdrawal. Forepaw clonus induced by 5-methoxy-N,N-dimethyltryptamine was decreased 2 h and 24 h after withdrawal and the number of head shakes induced by 1-5-HTP and citalopram were decreased 24 h after withdrawal. The d-amphetamine potentiation was still seen after 24 h, whereas the response had returned to normal 3 and 7 days after withdrawal. The content of amphetamine in three different brain regions was about 50% higher compared with controls 24 h after withdrawal of prolonged citalopram administration. At this time citalopram had been eliminated, and citalopram itself could not affect amphetamine metabolism. Other experiments indicated a linear relation between d-amphetamine brain concentration and motility level. Thus, a 50% increase in citalopram-treated rats cannot alone account for 3-fold increase in d-amphetamine-induced motility. Potentiation of d-amphetamine-induced hypermotility was also found after citalopram in a daily dietary dose of 25 mumol/kg for 13 days and after oral bolus injection (49 mumol/kg twice daily for 14 days). Acute citalopram injection had no effect in any of these models. The results suggest increased responsiveness of dopaminergic mechanisms mediating hypermotility, and decreased sensitivity of dopamine receptors mediating sedation (proposed autoreceptors). Sensitivity of 5-HT receptors was also decreased. The mechanisms by which citalopram induces d-amphetamine supersensitivity as well as subsensitivity to apomorphine and 5-HT agonists are presently unknown, since no changes in dopaminergic and serotonergic receptor binding have been found after an identical dose regimen.
The effect of prolonged administration of the clinically effective and specific serotonin (5-HT)-uptake-inhibitor, citalopram, has been studied in rats on behavioural measures of dopaminergic (DA) and serotonergic activity and on DA D-2, 5-HT2, alpha 1- and beta-adrenergic receptor number and affinity in vitro. Thirteen days treatment with citalopram in the diet (40 mg/kg/day) did not change receptor binding for either of the ligands studied, although citalopram was detected in high concentrations in brain and plasma and induced a 75% depletion of 5-HT in whole blood. This citalopram dose-regimen was followed by a potentiated hypermotility response to d-amphetamine. Also DA-dependent hypermotility induced by methylphenidate and (+)-3-PPP was increased. In contrast, the 5-HT2-receptor mediated head shake syndrome induced by 1-5-HTP or quipazine was decreased after prolonged citalopram treatment. Two weeks oral bolus treatment (10 mg/kg once or twice daily) with the 5-HT-uptake-inhibitors citalopram, fluoxetine, zimelidine, cyanimipramine or paroxetine induced d-amphetamine potentiation, whereas amitriptyline, nortriptyline, imipramine, iprindole, and mianserin treatment showed no effect. It is suggested that d-amphetamine potentiation induced by citalopram is mainly dependent on DA mechanisms, and that this profile is characteristic for preferential 5-HT-uptake-inhibitors. The lack of correlation between behavioural effect and receptor changes was important. Since citalopram has been shown to have clinical antidepressant activity, it is concluded that down-regulation of beta-adrenoceptors is not a prerequisite for antidepressant action.
The effects of long- and short-term administration of the tricyclic antidepressant desipramine on intracranial self-stimulation in rats were studied with electrodes in the A10 region of the dopamine-containing cell bodies of the ventromedial tegmentum. Long-term desipramine administration resulted in a significant shift to the left in the ascending portion of the rate--current intensity function, indicating that the activity of the mesolimbic dopamine system was enhanced. These findings point to a possible dopaminergic mechanism of action of antidepressants and support speculations concerning the role of dopamine-containing neurons in the pathophysiology of depression.
Chronic sequential exposure to a variety of mild stressors has previously been found to cause an antidepressant-reversible decrease in the consumption of palatable sweet solutions, associated with abnormalities of dopaminergic neurotransmission in the nucleus accumbens. In the present study, 5 weeks of treatment with imipramine (10 mg/kg b.i.d.) reversed the decreased sucrose intake of rats exposed to chronic mild stress. Stress also caused a decrease in D2-receptor binding in the limbic forebrain (but not the striatum), which was completely reversed by imipramine. In nonstressed animals, imipramine decreased D1-receptor binding in both regions. However, in stressed animals, imipramine did not significantly alter D1-receptor binding in either area. Stress alone slightly increased D1-receptor binding, in striatum only. Scatchard analysis showed that all changes in receptor binding resulted from changes in receptor number (Bmax) rather than receptor affinity (KD). The results support the hypothesis that changes in D2-receptor function in the nucleus accumbens are responsible for chronic mild stress-induced anhedonia and its reversal by antidepressant drugs. They do not support the hypothesis that the sensitization of D2-receptors seen following chronic antidepressant treatment is caused by a down-regulation of D1-receptors.
Chronic exposure to very mild unpredictable stress has previously been found to reduce or abolish the acquisition of place preference conditioning. In the present study, chronic mild stress was found to abolish the acquisition of preferences for a distinctive environment paired with systemic administration of amphetamine (0.5 mg/kg) or quinpirole (100-400 micrograms/kg) or with quinpirole (0.75 micrograms) administered bilaterally within the nucleus accumbens. The locomotor stimulant effects of quinpirole (100-400 micrograms/kg) were also attenuated in stressed animals. The result suggest that decreased sensitivity to reward following chronic mild stress results from a decreased sensitivity of dopamine D2 receptors within the nucleus accumbens.
SB 242084 is the most potent and selective 5-HT(2C) receptor antagonist thus far available. Thus, SB 242084 has high affinity for the cloned human 5-HT(2C) receptor with a pK(i) of 9.0, a much lower affinity for the human cloned 5-HT(2B) (pK(i) 7.0) and 5-HT(2A) (pK(i) 6.8) receptors, and low affinity for other 5-HT, dopamine, and adrenergic receptors. In the 5-HT-stimulated PI hydrolysis model of 5-HT(2C) receptor function, SB 242084 was found to be a competitive antagonist with a pK(B) of 9.3. A series of in vivo studies have shown that SB 242084 is a very effective antagonist of behavioral responses mediated by 5-HT(2C) receptors such as penile erections, and the hypophagic and hypolocomotor effect of mCPP in rats. In addition, this compound has anxiolytic-like properties. Moreover, SB 242084 increases the basal activity of dopaminergic neurons in the VTA and the in vivo DA release in the nucleus accumbens, and it is capable of blocking the inhibitory effects of mCPP and RO 60-0175 on mesolimbic dopaminergic activity. These data are consistent with the evidence that 5-HT(2C) receptors exert an inhibitory control upon the mesolimbic dopaminergic system. Taken together, the available data on SB 242084 might have implication for the possible use of this compound in the treatment of anxiety, depression, and the negative symptoms of schizophrenia.
This study investigated, using microdialysis in freely-moving rats, the role of serotonin (5-HT) and 5-HT2 receptor subtypes in the enhancement of striatal dopamine (DA) release induced by various doses of haloperidol.The subcutaneous injection of 0.01, 0.1 or 1 mg/kg haloperidol dose-dependently increased DA outflow (160, 219 and 230% of baseline, respectively). The effect of 0.01 mg/kg haloperidol was, respectively, potentiated by the 5-HT uptake inhibitor citalopram (1 mg/kg, s.c.; +35%) and reduced by the 5-HT1A receptor agonist 8-OH-DPAT (0.025 mg/kg, s.c.; −32%). Also, it was reduced by the 5-HT2A antagonist SR 46349B (0.5 mg/kg, s.c.; −40%) or by the 5-HT2A/2B/2C antagonist ritanserin (1.25 mg/kg, i.p.; −34%), and potentiated by the 5-HT2B/2C antagonist SB 206553 (5 mg/kg, i.p; +78%). Further, only this latter compound significantly modified basal dopamine release by itself (+26%). Dopamine released by 0.1 mg/kg haloperidol was enhanced (+100%) by citalopram, decreased (−61%) by SR 4634B, but unaltered by SB 206553. Finally, none of the compounds used were able to modify the enhancement of dopamine release induced by 1 mg/kg haloperidol.These results show that central 5-HT2A and 5-HT2C receptors exert an opposite (respectively excitatory and inhibitory) influence on DA release. Moreover, they suggest that the 5-HT2A-dependent modulation depends on the degree of central DA receptor blockade.
THE depletion by reserpine of storage in the body of 5-hydroxytryptamine (`Serotonin') and of the catechol amines is now well established1-3. In reserpinized animals the peripheral part of the adrenergic system does not function owing to lack of the transmitter2. This is presumably true also of the central part of the adrenergic system. However, it remains to be proved to what extent the central action of reserpine may be attributed to changes in brain catechol amines and/or 5-hydroxytryptamine.
We evaluated the topographic relations between tyrosine hydroxylase (TH)- and/or aromatic l-amino acid decarboxylase (AADC)-immunoreactive neurons in the arcuate nucleus (AN), as well as between TH- and/or AADC-immunoreactive axons in the median eminence (ME) in rats at the 21st embryonic day, 9th postnatal day, and in adulthood. The double-immunofluorescent technique in combination with confocal microscopy was used. Occasional bienzymatic neurons but numerous monoenzymatic TH- or AADC-immunoreactive neurons were observed in fetuses. There was almost no overlap in the distribution of monoenzymatic neurons, and therefore few appositions were observed in between. In postnatal animals, numerous bienzymatic neurons appeared in addition to monoenzymatic neurons. They were distributed throughout the AN resulting in the increased frequency of appositions. Furthermore, specialized-like contacts between monoenzymatic TH- and AADC-immunoreactive neurons appeared. The quantification of the fibers in the ME showed that there were large specific areas of the monoenzymatic TH-immunoreactive fibers and bienzymatic fibers in fetuses, followed by the gradual reduction of the former and the increase of the latter to adulthood. The specific area of the monoenzymatic AADC-immunoreactive fibers in fetuses was rather low, and thereafter increased progressively to adulthood. The fibers of all the types were in apposition in the ME at each studied age. Close topographic relations between the neurons containing individual complementary enzymes of dopamine synthesis at the level of cell bodies and axons suggest functional interaction in between.
The differential projections from the dorsal raphe and median raphe nuclei of the midbrain were autoradiographically traced in the rat brain after 3H-proline micro-injections. Six ascending fiber tracts were identified, the dorsal raphe nucleus being the sole source of four tracts and sharing one with the median raphe nucleus. The tracts can be classified as those lying within the medial forebrain bundle (dorsal raphe forebrain tract and the median raphe forebrain tract) and those lying entirely outside (dorsal raphe arcuate tract, dorsal raphe periventricular tract, dorsal raphe cortical tract, and raphe medial tract). The dorsal raphe forebrain tract lies in the ventrolateral aspect of the medial forebrain bundle (MFB) and projects mainly to lateral forebrain areas (e.g., basal ganglion, amygdala, and the pyriform cortex). The median raphe forebrain tract lies in the ventromedial aspect of the MFB and projects to medial forebrain areas (e.g., cingulate cortex, medial septum, and hippocampus). The dorsal raphe cortical tract lies ventrolaterally to the medial longitudinal fasciculus and projects to the caudate-putamen and the parieto-temporal cortex. The dorsal raphe periventricular tract lies immediately below the midbrain aqueduct and projects rostrally to the periventricular region of the thalamus and hypothalamus. The dorsal raphe arcuate tract curves laterally from the dorsal raphe nucleus to reach the ventrolateral edge of the midbrain and projects to ventrolateral geniculate body nuclei and the hypothalamic suprachiasmatic nuclei. Finally, the raphe medial tract receives fibers from both the median and dorsal raphe nuclei and runs ventrally between the fasciculus retroflexus and projects to the interpeduncular nucleus and the midline mammillary body.
Further studies were done to test whether the fiber tracts travelling in the MFB contained 5-HT. Unilateral (left) injections of 5,7-dihydroxytryptamine (5 μgm/400 nl) 18 days before midbrain raphe microinjections of 3H-proline produced a reduction in the grain concentrations in all the ascending fibers within the MFB. Furthermore, pharmacological and behavioural evidence was obtained to show that the 5-HT system had been unilaterally damaged; these animals displayed preferential ipsilateral turning in a rotameter which was strongly reversed to contralateral turning after 5-hydroxytryptophan administration.
The results show that DR and MR nuclei have numerous ascending projections whose axons contain the transmitter 5-HT. The results agree with the neuroanatomical distribution of the 5-HT system previously determined biochemically, histochemically, and neurophysiologically. The midbrain serotonin system seems to be organized by a series of fiber pathways. The fast transport rate in these fibers was found to be about 108 mm/day.
Chronic exposure to mild unpredictable stress has previously been found to depress the consumption of palatable sweet solutions. In the present study this effect was reversed by chronic (9 weeks) treatment with the atypical antidepressants, fluoxetine and maprotiline (5 mg/kg/day); the non-antidepressant chlordiazepoxide was ineffective. Stressed animals were also subsensitive to food reward in the place conditioning procedure; however, fluoxetine and maprotiline treated animals showed normal place preference conditioning. Acute pretreatment with raclopride (100 g/kg) selectively reversed the recovery of sucrose drinking in antidepressant-treated stressed animals. These results extend previous reports of the efficacy of tricyclic antidepressants in this paradigm, and support the hypothesis of a dopaminergic mechanism of antidepressant action.
Rats subjected chronically (12 weeks) to a variety of mild, unpredictable stressors showed a reduced consumption of sucrose or a sucrose/saccharin mixture in two-bottle consumption tests (sweet solution versus water). The deficit was apparent within 2 weeks of stress; normal behaviour was restored by chronic (7 weeks) treatment with the tricyclic antidepressants desmethylimipramine (DMI) or amitriptyline (AMI). Acute administration of the dopamine D1 receptor antagonist SCH-23390 1 week after withdrawal, or the dopamine D2 receptor antagonist sulpiride 2 weeks after withdrawal, were without effect in vehicle-treated stressed animals, and in non-stressed animals. However, the DA antagonists selectively reversed the improvement of performance in DMI- or AMI-treated stressed animals. This suggests that an increase in functional activity at DA synapses is the mechanism of action of DMI and AMI in this model.
In control rats small doses of apomorphine (25 to 100 μg/kg) decreased motor activity and reduced DOPAC content in the caudate nucleus. A larger dose (500 μg/kg) increased motor activity and elicited stereotypy. Chronic treatment with imipramine, amitryptiline and mianserine (10, 10 and 2.5 mg/kg twice daily for 10 days respectively) counteracted or reversed the effect of small doses of apomorphine on motor activity, left DOPAC content unchanged and potentiated the central stimulant response to the larger dose of apomorphine. Changes in apomorphine responses were observed after ten but not after two days of imipramine treatment and persisted unaltered up to 4 days after imipramine withdrawal. It is suggested that chronic treatment with antidepressants induces persistent subsensitivity in presynaptic dopamine receptors. The relevance of the findings in the therapeutic effect of these drugs is discussed.
The highly selective 5-HT2 receptor antagonist, MDL 100,907, was used to explore the role of serotonin in the stimulation of dopaminergic function produced by the amphetamine analogue 3,4-methylenedioxymethamphetamine (MDMA). MDL 100,907 blocked MDMA-stimulated dopamine synthesis in vivo without affecting basal synthesis. The long-term deficits in 5-HT concentrations believed to be a consequence of MDMA-induced dopamine release were also blocked by MDL 100,907 over the same dose range. In vivo microdialysis confirmed that 5-HT2 receptor blockade with MDL 100,907 attenuated MDMA-induced increases in extracellular concentrations of striatal dopamine. In contrast to its effect on MDMA-induced synthesis, MDL 100,907 did not alter dopamine synthesis stimulated by haloperidol or reserpine. In vivo dopamine release produced by haloperidol was also unaffected by MDL 100,907. The results suggest a permissive role for 5-HT2 receptors in the activation of the dopamine system which occurs during states of high serotonergic activity or during conditions of elevated dopamine efflux with high D2 receptor occupancy.
The effect of repeated treatment (5 and 10 mg/kg,po, twice daily, 14 days) with sertraline and citalopram (antidepressants which selectively inhibit the reuptake of 5-hydroxytryptamine (5-HT)) on the responsiveness of different 5-HT receptors to their agonists, was examined in rats and mice. Sertraline and citalopram (both at a dose 5 and 10 mg/kg) antagonized (the first one more potently) the hypothermia induced in mice by 8-OH-DPAT (a 5-HT1A agonist), but not the behavioural syndrome induced in rats by this substance. The m-chlorophenylpiperazine-induced hypothermia in mice (a 5-HT1B effect) was increased by sertraline and citalopram (only in a dose of 10 mg/kg). Both antidepressants, given repeatedly (as well acutely) attenuated exploratory hypoactivity induced in rats by m-chlorophenylpiperazine (a 5-HT1C effect). L-5-HTP-induced head twitches in mice (5-HT2 effect) were antagonized dose-dependently by both repeated sertraline and citalopram. Both antidepressants (citalopram only in higher dose) reduced the fenfluramine-induced hyperthermia in rats (5-HT2 effect).
The results indicate that sertraline and citalopram given repeatedly decrease the responsiveness of 5-HT1A (presynaptic) and 5-HT2 receptors but increase the responsiveness of 5-HT1B receptors to respective agonists.
A hypothesis implicating dopamine in depression was proposed over 15 years ago (Randrup et al 1975). The identification of multiple new subtypes of dopamine receptors and evolving views regarding the function of the dopamine systems in the brain require a reexamination of this hypothesis. Results from studies in depression, Parkinson's disease, and animal models of depression suggest a deficiency of dopamine in depression. Dopamine precursors, dopamine agonists, and dopamine reuptake inhibitors show therapeutic efficacy in depression. Electroconvulsive therapy (ECT) and standard pharmacological antidepressants enhance dopamine function. Studies using receptor-specific drugs in clinical trials and neuroimaging studies are needed to further clarify the role of dopamine in depression.
Drugs of abuse are very powerful reinforcers, and even in conditions of limited access (where the organism is not dependent) these drugs will motivate high rates of operant responding. This presumed hedonic property and the drugs' neuropharmacological specificity provide a means of studying the neuropharmacology and neuroanatomy of brain reward. Three major brain systems appear to be involved in drug reward--dopamine, opioid and GABA. Evidence suggests a midbrain-forebrain-extrapyramidal circuit with its focus in the nucleus accumbens. Data implicating dopamine and opioid systems in indirect sympathomimetic and opiate reward include critical elements in both the nucleus accumbens and ventral tegmental areas. Ethanol reward appears to depend on an interaction with the GABAA receptor complex but may also involve common elements such as dopamine and opioid peptides in this midbrain-forebrain-extrapyramidal circuit. These results suggest that brain reward systems have a multidetermined neuropharmacological basis that may involve some common neuroanatomical elements.
There is accumulating evidence that some antidepressant treatments can increase the functional output of the meso-accumbens dopaminergic system. For example, chronic administration of tricyclic antidepressant drugs such as imipramine and desipramine (DMI) enhances the locomotor stimulant effects of d-amphetamine. Subsensitivity of inhibitory dopamine (DA) autoreceptors and supersensitivity of postsynaptic DA receptor mechanisms are among the mechanisms that have been suggested to underlie these observations. The present experiments investigated the effects of acute and chronic DMI treatment on interstitial DA concentrations in the nucleus accumbens and striatum using in vivo microdialysis in awake freely moving rats (48 h following implantation of a microdialysis probe). Neither acute (5 mg/kg b.i.d. for 2 days followed by 72 h withdrawal) nor chronic (5 mg/kg b.i.d. for 21 days followed by 72 h withdrawal) DMI influenced the ability of apomorphine (25 micrograms/kg s.c.) to decrease extracellular concentrations of DA or its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the nucleus accumbens. In contrast, d-amphetamine (1.5 mg/kg s.c.)-induced increases in extracellular DA were significantly enhanced in the nucleus accumbens of the chronic but not the acute DMI group. This effect was at least partially regionally selective, as significant effects were not observed in the striatum. In accordance with previous reports, the locomotor stimulant effects of d-amphetamine were also enhanced in the chronic DMI groups. DMI itself failed to alter the interstitial concentrations of DA and its metabolites in the nucleus accumbens of the control and chronic DMI groups. These results provide in vivo neurochemical confirmation that chronically administered DMI does not produce DA autoreceptor subsensitivity. They also demonstrate that chronic DMI-induced increases in the locomotor stimulant effects of d-amphetamine are accompanied by a selective potentiation of the effects of this stimulant on interstitial DA concentrations in the nucleus accumbens.
The effects of sulpiride isomers injected into the nucleus accumbens on the anti-immobility activity of desipramine in rats were studied to clarify the role of dopamine receptors. (-)-Sulpiride 100 ng/0.5 microliters injected bilaterally into the nucleus accumbens 5 min before testing reduced the effect of a 7-day treatment with 10 mg/kg per day desipramine in the swimming test but 5 micrograms/0.5 microliter (+)-sulpiride injected in the same area had no effect. Fluphenazine, 5 micrograms/0.5 microliter, or 6-hydroxydopamine-induced depletion of dopamine in the nucleus accumbens also reduced the anti-immobility effect of desipramine. The data further support the hypothesis that dopamine transmission in the nucleus accumbens has a permissive role in the effect of desipramine in the forced swimming test.
Studies have shown an increased responsiveness of the dopaminergic system after repeated administration of a variety of antidepressant drugs. In the present study, the effect of repeated administration (twice daily for 14 days) of imipramine and mianserin on the affinity of dopamine D2-receptors for quinpirole, a D2-agonist, and on the quinpirole-induced locomotor hyperactivity was examined in rats. Repeated doses of imipramine and mianserin increased the affinity of quinpirole for [3H]spiperone binding sites in membranes prepared from the limbic system but not the striatum. The locomotor hyperactivity induced by quinpirole was enhanced by chronic treatment with both antidepressants. The data indicate that the enhanced responsiveness of the dopaminergic system in rats, observed after chronic treatment with antidepressants, may result from an increased affinity of agonists at D2-receptors in the mesolimbic system.
Neurons in rat central nervous system (CNS) that express 5-HT1c receptor mRNA have been localized by in situ hybridization histochemistry. The 5-HT1c receptor is expressed in a wide variety of cortical and subcortical neurons including hippocampal pyramidal neurons, neurons within most of the central monoaminergic cell groups, neurons in thalamic sensory relay nuclei, and neurons involved in the central processing and regulation of nociceptive transmission. Therefore, the 5-HT1c receptor is a prominent but poorly characterized central subclass of serotonin (5-HT) receptor. The distribution of the 5-HT1c receptor within the CNS is considerably more widespread than that of the structurally and functionally related 5-HT2 receptor.
The effect of desipramine (DMI) was studied after its repeated administration (10 mg/kg p.o., twice daily, 14 days) to rats, on the action of dopamine and d-amphetamine injected bilaterally into the nucleus accumbens. DMI, applied repeatedly but not acutely, prevented the sedative effect of dopamine and enhanced its stimulating action, as assessed by the open-field test. Repeated administration of DMI also enhanced d-amphetamine-induced locomotor hyperactivity. The number of [3H]SCH 23390 binding sites (D-1) in the limbic system decreased while the number of [3H] spiperone ones (D-2) remained unchanged. The results indicate that, like other antidepressant drugs studied earlier, DMI enhances neurotransmission in the dopamine mesolimbic system (nucleus accumbens) of the rat.
Bilateral injections of 1 microgram sulpiride in the rat nucleus accumbens antagonized the effect of a seven-day treatment with 20 mg kg-1 day-1 imipramine or amitriptyline in the swimming test. The data suggest that dopamine mechanisms in the limbic regions of the rat brain are involved in the effect of repeated treatment with imipramine and amitriptyline in that test.
Bilateral injections of 5 or 1 (but not 0.5) micrograms sulpiride into the nucleus accumbens reduced the effect of a 7-day treatment with 10 mg/kg/day desipramine in the forced swimming test. Bilateral injections of 5 or 1 micrograms sulpiride in the caudate-putamen did not modify the anti-immobility effect of desipramine. The data support the hypothesis that dopamine mechanisms in the limbic regions of the brain of the rat are involved in the effect of repeated treatment with desipramine in the forced swimming test.
It was demonstrated that the influence of i.v. administered probenecid on HVA concentration in CSF was less pronounced in a group of retarded depression than in a group of non-retarded depression and a non-depressive control group. The figures corresponded to that found in Parkinson patients.
These findings suggest a decreased consumption of dopamine in the brain in retarded depression. This might be understood as an indication that, disorders of cerebral dopamine metabolism are related not so much to a specific nosological entity as to a given motor status, possibly that of hypokinesia.
The neurotransmitter metabolites 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA) and 4-hydroxy-3-methoxyphenyl glycol (HMPG) in cerebrospinal fluid (CSF) were measured by mass fragmentography in 83 patients with melancholia (diagnosed by the Newcastle Inventory and the Research Diagnostic Criteria), and 66 healthy volunteer controls. After adjustment by analysis of covariance for differences between the subject groups in body height, age and sex distribution, significantly (P less than 0.001) lower concentrations of 5-HIAA and HVA were found in the melancholia patients than in the controls. HMPG did not differ between the groups. The differences could not be accounted for by differences in timing or examination techniques, and not by previously administered drugs (all patients were drug-free at the examination, but a minority had taken small amounts of psychotropic drugs prior to the wash-out period). The differences persisted after excluding the suicidal patients. There were no clear-cut differences between unipolar and bipolar patients. It is suggested that the reduced concentrations of 5-HIAA and HVA in the melancholic patients may be due to altered serotonin and/or dopamine functions in the central nervous system, which may be connected with an increased vulnerability to certain types of affective illness.
A series of experiments was performed to evaluate the mechanism(s) by which chronic administration of desipramine (DMI) facilitates the locomotor stimulant action of d-amphetamine, a response thought to be dependent on the mesolimbic dopaminergic system. Prior lesions of central noradrenergic or serotonergic neurons, induced by neonatal treatment with 6-hydroxydopamine (6-OHDA) or intraventricular injections of 5,7-dihydroxytryptamine (5,7-DHT) respectively, failed to block DMI-induced facilitation of amphetamine hypermotility. Chronic administration of DMI did not significantly influence specific [3H]spiperone binding in the striatum or the nucleus accumbens. In other experiments it was found that chronic administration of some (amitryptyline, imipramine, mianserin, iprindole) but not all (zimelidine, nomifensine, fluoxetine) antidepressants enhanced the locomotor response to d-amphetamine. The weak anticholinergic effects of the latter compounds suggest that the positive results obtained with the former drugs may be related to their anticholinergic properties. This hypothesis is consistent with the observation that chronic administration of scopolamine also increased the locomotor response to d-amphetamine. The results suggest that the facilitation by chronic DMI of amphetamine-induced locomotor activity is not mediated by primary actions of this tricyclic antidepressant on central noradrenergic or serotonergic systems. In addition, the results argue against an effect of DMI on dopamine receptors as measured by [3H]spiperone binding. Instead, the facilitation of the amphetamine response by some of these antidepressant compounds may be related to their anticholinergic effects.(ABSTRACT TRUNCATED AT 250 WORDS)
The effects of acute and chronic administration of desipramine (DMI) on a number of behaviors thought to be dependent on central dopaminergic (DA) systems were examined in the rat. Chronic but not acute administration of DMI potentiated the locomotor response to d-amphetamine within a narrow dosage range. The potentiation of the amphetamine response was observed up to 5 days after cessation of chronic DMI but had nearly returned to baseline by 10 days. Neither amphetamine- nor apomorphine-induced stereotypy was affected by chronic DMI. Chronic administration of iprindole but not fluoxetine potentiated amphetamine-induced locomotor activity. Chronic DMI administration did not affect the concentration or distribution of [3H]d-amphetamine in the brain. Furthermore, residual anticholinergic effects of DMI did not appear to be responsible for the potentiated amphetamine response. Chronic administration of DMI did not significantly influence the hypomotility induced by low doses of apomorphine. The increased locomotor activity and rearing produced by moderate doses of apomorphine were significantly increased by chronic DMI administration. The results suggest that chronic DMI may produce supersensitivity of postsynaptic receptors in the mesolimbic DA projection, a system that has been associated with the mediation of amphetamine- and apomorphine-induced increases in locomotor activity. There was no evidence for subsensitivity of presynaptic DA receptors after DMI. The findings are discussed with reference to the possible role of central DA neurons in the antidepressant mechanism of action of the tricyclic compounds.
The relationship between the dorsal raphe neurons projecting to the caudate-putamen and those projecting to the substantia nigra was investigated using a fluorescent retrograde double labeling technique in the rat. The majority of the dorsal raphe neurons projecting to the substantia nigra were found to project also to the caudate-putamen. In addition, a large population of dorsal raphe neurons innervating the caudate-putamen but not the substantia nigra was seen. The cells projecting to the substantia nigra were situated primarily in the dorsal part of the dorsal raphe, whereas those projecting to the caudate-putamen were located throughout the dorsal raphe.
Dopamine (DA) has largely been ignored in considering possible mechanisms underlying the therapeutic effects of tricyclic anti-depressants (TCA). Most previous work done has focused on the ability of some TCAs to block the in vitro re-uptake of DA--an effect which unfortunately requires very high doses. Recently, however, Serra et al. proposed that TCAs may exert their therapeutic effects by inducing a subsensitivity of presynaptic receptors located on the dendrites and soma of DA neurones (DA autoreceptors). This hypothesis was directly tested by examining the influence of TCAs on the demonstrated ability of the DA agonist, apomorphine, to depress selectively the spontaneous activity of single DA cells. We now report that repeated administration of both typical and atypical TCAs induces a progressive subsensitivity of DA autoreceptors, and that this gradual augmentation of DA autoreceptor subsensitivity depends on the passage of time rather than daily TCA administration. The latter finding suggests that daily drug administration may not be therapeutically necessary.
Microinfusion of serotonin (5-hydroxytryptamine; 5-HT) into the ventral tegmental area enhances the release of dopamine in the nucleus accumbens, a major target of midbrain dopamine neurons. We examined the synaptic basis for 5-HT modulation of neurons in the ventral tegmental area which either (i) project to the nucleus accumbens or (ii) contain the catecholamine synthesizing enzyme tyrosine hydroxylase, a marker of dopamine neurons in this brain region. In the first study, immunoperoxidase labeling of 5-HT in the ventral tegmental area was combined with retrograde transport of gold particles following unilateral injections of the tracer into the nucleus accumbens of adult rats. The gold particles had been previously coupled to wheat germ agglutinin conjugated to inactive horseradish peroxidase. Gold particles were enlarged for visualization using a silver enhancement procedure. By brightfield microscopy, retrogradely labeled neurons contained black punctate granules within their perikarya and proximal processes. The labeled cells were scattered ipsilateral to the injection within the paranigral and parabrachial subdivisions of the ventral tegmental area. Both regions also contained 5-HT immunoreactive varicosities. By electron microscopy, irrespective of the ventral tegmental subdivision, 5-HT labeling was seen primarily in unmyelinated axons and axon terminals. The terminals contained small, clear and large dense core vesicles and ranged from 0.3 micron to 1.4 microns in cross-sectional diameter. 22% (n = 250) of the axon terminals containing 5-HT immunoreactivity formed synaptic contacts with neurons containing the retrograde label. Of these 5-HT terminals, 16% formed asymmetric type contacts and 6% formed symmetric junctions on the retrogradely labeled neurons. The remaining 5-HT terminals were either apposed to (but lacked recognized synapses on) perikarya and large dendrites containing the retrogradely transported protein-gold tracer or contacted unlabeled neurons. In the second set of experiments combining immunoperoxidase of 5-HT and immunogold silver for tyrosine hydroxylase, 32% (n = 250) of the 5-HT-labeled terminals formed synaptic junctions with perikarya or dendrites containing tyrosine hydroxylase immunoreactivity. Of these 5-HT terminals, 23% formed asymmetric type junctions. The remainder were either symmetric or lacked recognized membrane densities. The prominence of asymmetric junctions formed by 5-HT-labeled terminals on neurons projecting to the nucleus accumbens and those containing tyrosine hydroxylase in the ventral tegmental area suggests a cellular basis for serotonergic excitation of mesoaccumbens dopamine neurons. Additionally, the multiplicity of junctions formed by 5-HT terminals on targets with or without retrograde labeling or tyrosine hydroxylase immunoreactivity is consistent with known diverse physiological actions of 5-HT in the tegmental area.
The ventral tegmental area receives a gamma-aminobutyric acid (GABA) innervation from the nucleus accumbens and contains GABA immunoreactive neurons believed to be interneurons. We combined the immunocytochemical detection of retrogradely transported Fluoro-Gold (FG) from the nucleus accumbens (Acb) with the detection of GABA within the same section of tissue in the ventral tegmental area (VTA) of the rat brain to determine whether there might also be reciprocal GABAergic projections in the mesolimbic pathway. Immunoperoxidase labeling for FG and immunogold-silver labeling for GABA were most readily distinguished within perikarya and dendrites in sections examined by electron microscopy. Ultrastructural observations indicated that 36% (n = 110) of the FG-labeled perikarya and dendrites also contained GABA immunoreactivity. The present results provide the first evidence that GABA is contained in a subpopulation of neurons in the mesolimbic pathway from the VTA to the Acb. The reciprocity of this circuitry may provide an important feedback loop thus facilitating inhibition of motor activity.
The effects of the 5-HT2 receptor agonists 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) and 5-methoxy-N,N-dimethyltryptamine (5-MeODMT) on 3,4-methylenedioxymethamphetamine (MDMA)-induced dopamine release and 5-HT depletion in the striatum were studied. The MDMA-induced increase in the extracellular concentration of dopamine in the striatum was enhanced significantly in rats treated with either DOI (2 mg/kg, ip.) or 5-MeODMT (15 mg/kg, ip.), as assessed using in vivo microdialysis. Neither DOI nor 5-MeODMT alone altered the extracellular concentration of dopamine in the striatum. The striatal concentration of 5-HT was decreased, but not significantly, 7 days following a single administration of MDMA (10 mg/kg, sc.). However, 7 days following the concomitant treatment with DOI and MDMA the striatal concentration of 5-HT was significantly less than that in rats treated with MDMA alone or the vehicle-treated controls. It is concluded that activation of 5-HT2 receptors is an important determinant of the acute increase in extracellular dopamine and, consequently, the long-term depletion of brain 5-HT produced by MDMA.
Chronic treatment with selective 5-HT reuptake inhibitors (SSRI) are therapeutic in obsessive compulsive disorder, depression, anxiety, bulimia nervosa and migraine. In the present study the possibility that SSRI's act by desensitizing 5-HT2C/5-HT2B receptors was assessed using a putative in vivo model of 5-HT2C/5-HT2B receptor function, mCPP-induced hypolocomotion. mCPP (2, 4 and 6 mg/kg i.p. 20 min pretest) reduced locomotion and rears in rats treated acutely or chronically with saline. Acute oral administration of the SSRI's fluoxetine (10 mg/kg), paroxetine (10 mg/kg), or clomipramine (70 mg/kg) or the noradrenaline reuptake inhibitor, desipramine (10 mg/kg), all 1 hr pretest, did not prevent mCPP-induced hypolocomotion. In contrast, chronic treatment with the SSRI's paroxetine and fluoxetine (both 10 mg/kg p.o. daily x 21 days), significantly attenuated the effect of mCPP (4 and 6 mg/kg i.p.) on locomotion and rears 24 hr after the last pretreatment dose. Chronic clomipramine (70 mg/kg p.o. daily x 21 days) also significantly attenuated the effect of mCPP (4 mg/kg i.p.) on rears and tended to reduce the hypolocomotor response. However, chronic treatment with desipramine, (10 mg/kg p.o. daily x 21) had no effect on any of the parameters measured. As chronic fluoxetine and paroxetine did not reduce brain mCPP levels (determined by HPLC 30 min after 4 mg/kg i.p.) the results suggest that chronic SSRI's, but not desipramine, reduce 5-HT2C/5-HT2B receptor responsivity. If this occurs in man, it may mediate or contribute to their reported therapeutic efficacy in depression, anxiety, bulimia, migraine and alcoholism. It may also be of particular relevance to their unique efficacy in OCD.
The current classification for 5-HT2 receptors accommodates three subtypes. In addition to the originally defined 5-HT2 receptor, sanctuary is now provided for the structurally related 5-HT1c receptor (now 5-HT2c) and at least one atypical 5-HT receptor subtype. The strong functional union of this family is reflected in the paucity of ligands that will discriminate between its subtypes and prompts some re-evaluation of the activities of compounds which may now be regarded as nonselective for the receptor subtypes in this class. In this article, Gordon Baxter and colleagues examine the pharmacology of both officially recognized and atypical 5-HT2 receptor subtypes. A number of novel selective agents are highlighted, some of which may prove useful for 5-HT2 receptor classification and, ultimately, clarify the mechanistic basis for current and future therapeutic strategies which target this receptor family.
The effects of pretreatments on behavioural responses to activation of 5-HT1C receptors by m-chlorophenylpiperazine (mCPP) were investigated. The hypo locomotor and anxiogenic effects of mCPP (social interaction test) were influenced neither by previous housing (single versus grouped) nor by restraint (2 h, 24 h previously). In the absence of mCPP, 24 h group housing led to decreased social interaction and the restraint procedure led to significant decreases of feeding and locomotion. The hypophagic effect of mCPP was unaffected by previous restraint. However, chronic pretreatment with mCPP (2.5 mg/kg per day IP x 14) or with the antidepressant 5-HT reuptake inhibitor sertraline (5 mg/kg per day SC x 14) attenuated all three behaviours. The above findings are discussed with respect to published data on effects of pretreatments on responses to the activation of 5-HT1C receptors.
This study investigated the possible involvement of 5HT1C receptors in the development of depressive states and in the mode of action of antidepressants. The effects of repeated unpredictable mild stress (a regimen known to induce an anhedonic state in the rat) and of chronic administration of either of two recognized antidepressant treatments (sleep deprivation or inhibition of monoamine oxidase type A) in rats were studied on a 5HT1C receptor initiated response, i.e. mCPP-induced penile erection. A 3-week period of repeated, but unpredictable exposure to mild stressors induced a shift to the left of the dose-response curve for mCPP-induced penile erection. In contrast, 72-h REM sleep deprivation resulted in a shift to the right of the mCPP dose-response curve and 10-day administration of the monoamine oxidase type A inhibitor moclobemide (20 mg/kg IP bid) also resulted in a decreased number of mCPP-induced penile erections. These findings support the hypothesis that neuronal activities initiated via 5HT1C receptor stimulation may play a role in the pathophysiology and treatment of depression.
The receptors through which serotonin (5-hydroxytryptamine, 5-HT) produces its effects have been the subject of intense investigation, initially using both in vivo and in vitro pharmacological methods, and later radioligand binding. These approaches allowed a preliminary classification of 5-HT receptors, but the identification on subtypes was limited by the selectivity on the available agonists and antagonists. Bradley et al. (1986) distinguished three main classes of 5-HT receptors: 5-HT 1 , 5-HT 2 and 5-HT 3 . 5-HT 3 receptors were activated by the selective agonist 2-methyl-5-HT and blocked by selective antagonists such as (-)cocaine, MDL72222 and tropisetron (ICS 205-930)
Intracellular recordings were made with conventional microelectrodes and with whole-cell patch-clamp electrodes from neurons of the rat ventral tegmental area and substantia nigra zona compacta in vitro. Neurons were distinguished as principal cells and secondary cells; it is known from previous work that most principal cells contain dopamine whereas secondary cells do not. 5-Hydroxytryptamine (5-HT; 3-100 microM) depolarized (or evoked an inward current at -60 mV) 46% of 153 principal cells; a small proportion (11%) of cells were hyperpolarized (or showed outward current at -60 mV). Secondary cells were equally likely to be depolarized (or inward current at -60 mV, 30% of 80 cells) or hyperpolarized (or outward current at -60 mV, 28%). approximately 40% of each type of cell were unaffected by 5-HT. Depolarizing responses of 5-HT were mimicked by (+/-)-1-(2,5-dimethoxy-4-iodophenyl)- 2-aminopropane (DOI) and blocked by ketanserin. Hyperpolarizing responses were mimicked by dipropyl-5-carboxamidotryptamine and reversed polarity at the K+ equilibrium potential. Inhibitory postsynaptic potentials (or currents) mediated at GABAA receptors occurred spontaneously in some principal cells; they were reversibly blocked by tetrodotoxin and bicuculline. 5-HT either increased or decreased the frequency of these synaptic potentials but did not change their mean amplitude or decay time.(ABSTRACT TRUNCATED AT 250 WORDS)
Because of their similarities, serotonin 5-HT2, 5-HT1C, and the recently described 5-HT2F receptors have been classified as members of the 5-HT2 receptor family, and they have been renamed 5-HT2A, 5-HT2C and 5-HT2B, respectively. The regional distribution and cellular localization of mRNA coding for the members of 5-HT2 receptor family were investigated in consecutive tissue sections from the rat brain by in situ hybridization histochemistry. No evidence for the expression of 5-HT2B receptor was found. High levels of 5-HT2A (formerly 5-HT2) receptor mRNA were observed only in few areas, as the frontal cortex, piriform cortex, ventro-caudal part of CA3, medial mammillary nucleus, the pontine nuclei and the motor cranial nerve nuclei in the brainstem, and the ventral horn of the spinal cord. The distribution of 5-HT2A receptor mRNA is generally in good agreement with that of the corresponding binding sites, although discrepancies were sometimes observed. 5-HT2C (formerly 5-HT1C) mRNA was present at very high levels in the choroid plexuses. However, very high levels were also seen in many other brain regions, as the retrosplenial, piriform and entorhinal cortex, anterior olfactory nucleus, lateral septal nucleus, subthalamic nucleus, amygdala, subiculum and ventral part of CA3, lateral habenula, substantia nigra pars compacta, several brainstem nuclei and the whole grey matter of the spinal cord. These results confirm and extend previous observations that 5-HT2C receptor mRNA is present in many brain areas in addition to those autoradiographically shown to have the corresponding binding sites and that 5-HT2C receptor subtype is a principal 5-HT receptor in the brain. From the comparison between their distributions, 5-HT2A and 5-HT2C receptor mRNAs appeared to be expressed in distinct but overlapping sets of brain regions. Both mRNAs coexisted at high levels in the anterior olfactory nucleus, piriform cortex, endopiriform nucleus, claustrum, pyramidal cell layer of the ventral part of CA3, taenia tecta, substantia nigra pars compacta, and several brainstem nuclei. In other regions both mRNAs were present but with different distributions, as the caudate-putamen. These results are also discussed in relation to the physiological meaning of the existence of two so similar receptor subtypes in the brain.
A variety of antidepressants of different chemical classes were tested for their in vivo and in vitro activity at 5-HT1C receptors in the brain. Conventional tricyclic antidepressants (imipramine, desipramine, maprotiline, clomipramine, trimipramine, amitriptyline, nortriptyline, doxepin, amoxapine, oxaprotiline) and two atypical antidepressants (mianserin and trazodone) were found to display affinity for 5-HT1C receptors in the nanomolar range. Antidepressants of other chemical classes and mechanisms of action (serotonin uptake inhibitors: fluoxetine, citalopram, sertraline, fluvoxamine; noradrenaline-dopamine uptake inhibitors: nomifensine, bupropion, amineptine; or monoamine oxidase inhibitors: moclobemide, iproniazid) had affinities in the micromolar range for 5-HT1C receptors, except fluoxetine. When tested in an in vivo functional model revealing agonistic or antagonistic properties at 5-HT1C receptors, all antidepressants displaying high affinity for this receptor type (except fluoxetine, clomipramine, trimipramine and oxaprotiline) were antagonists at 5-HT1C receptors. Antidepressants with lower 5-HT1C receptor affinity (except nomifensine) were inactive in this functional in vivo model. Antagonism at brain 5-HT1C receptors is a component of the antiserotonergic properties of a number of established antidepressants, especially of the tricyclic class.
5-Hydroxytryptamine (5HT)1C and 5HT2 receptors display paradoxical down-regulation when exposed to receptor antagonists in vivo, a property that is unique to these two subtypes of serotonin (5HT) receptors. Because of the absence of cell culture model systems, the mechanisms involved in this paradoxical down-regulation have been difficult to explore. The present study focuses on the regulation of 5HT1C receptors in primary cultures of rat choroid plexus epithelial cells. Exposure of the epithelial cell cultures to 100 nM mianserin, a receptor antagonist, or (-)-1-(4-bromo-2,5-dimethoxyphenyl)-2-aminopropane, an agonist, for 72 hr caused a loss of 5HT1C receptor binding sites, as determined by [3H]mesulergine binding to crude membrane preparations. No significant changes in Kd values were observed. Neither the agonist nor antagonist caused a significant change in binding sites after 24 hr. A solution hybridization assay was used to determine whether the down-regulation by mianserin or (-)-1-(4-bromo-2,5-dimethoxyphenyl)-2-aminopropane was accompanied by a decrease in the steady state level of 5HT1C receptor mRNA. These studies showed that neither treatment caused an alteration in the levels of 5HT1C receptor mRNA. Thus, it is possible to reproduce the in vivo regulatory effects of drugs on 5HT1C receptors in choroid plexus epithelial cells in culture, including the atypical down-regulation by receptor antagonists. Using this cell culture model system, indirect transynaptic effects and decreases in receptor mRNA levels have been ruled out as mechanisms accounting for the down-regulation.
This study was designed to investigate the predictive validity of a recently described chronic mild-stress-induced anhedonia model of depression. In an intracranial self-stimulation (ICSS) paradigm, rats were allowed to self-stimulate in the ventral tegmental area. Stimulation frequency thresholds for ICSS responses were determined prior to, during, and after a 19-day period of exposure to a variety of mild, intermittent, unpredictable stressors. After nine days of mild stress, stimulation threshold was significantly increased, suggesting a gradual decrease in the rewarding properties of brain stimulation. This anhedonic state lasted throughout the stress period and slowly disappeared over a 10-day period after termination of the stress regimen. This stress-induced increase in ICSS threshold was not observed in rats that were stressed and concomitantly treated with the reversible inhibitor of monoamine oxidase type A (RIMA) moclobemide (20 mg/kg, b.i.d.). In nonstressed animals treated with vehicle or moclobemide, no significant change in ICSS occurred during the course of the experiment. These experimental results reinforce the value of this animal model with respect to its predictive and construct validity.
The 5-hydroxytryptamine1C (5-HT1C) receptor shares many features with the 5-HT2 receptor. To determine if the regulation of the sites is also similar we studied the effects of chronic treatment with drugs active at 5-HT1C/2 receptors on [3H]mesulergine-labelled 5-HT1C binding sites in spinal cord. The 5-HT receptor agonists 1-(3-chlorophenyl)piperazine (m-CPP) (-38%), 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) (-35%), quipazine (-27%) and m-trifluoromethylphenylpiperazine (TFMPP) (-27%) significantly down-regulated spinal 5-HT1C sites with chronic injection compared to vehicle treatment. The 5-HT receptor antagonists methiothepin (-71%), mianserin (-24%), methysergide (-21%), and cyproheptadine (-27%) also induced down-regulation, and ritanserin and metergoline further reduced [3H]mesulergine specific binding to undetectable levels. There were no significant changes in Kd to implicate presence of residual drug except for mianserin, methiothepin, and TFMPP. Pindolol and spiperone had no significant effects. In acute dose-response studies, injection of a single dose of DOI did not result in a significant change in any receptor parameters. The capacity of a drug to lower Bmax correlated significantly with its pKd (r = 0.84, P < 0.0007). This drug regulation pattern for 5-HT1C sites of down-regulation by both 5-HT1C/2 receptor agonists and antagonists is similar to that for 5-HT2 receptors and is consistent with the classification of 5-HT1C and 5-HT2 receptors in the same superfamily.
A variety of antidepressants of different chemical classes were tested for their in vivo and in vitro activity at 5-HT1C receptors in the brain. Conventional tricyclic antidepressants (imipramine, desipramine, maprotiline, clomipramine, trimipramine, amitriptyline, nortriptyline, doxepin, amoxapine) as well as mianserin and trazodone were found to display high to low nanomolar affinity for 5-HT1C receptors. Antidepressants of other chemical classes and with other mechanisms of action (affecting amine uptake systems: fluoxetine, citalopram, sertraline, fluvoxamine, nomifensine, amineptine; or monoamine oxidase inhibitors: moclobemide, iproniazid) had negligible affinities (micromolar range) for 5-HT1C receptors, except fluoxetine. When tested in an in vivo rat model thought to reveal functional agonistic or antagonistic properties at 5-HT1C receptors, all antidepressants displaying high affinity for this receptor type (except clomipramine and trimipramine) were antagonists at 5-HT1C receptors. Antidepressants with a lower affinity for 5-HT1C receptors (except nomifensine) were inactive in this functional in vivo model. Taken together, these results suggest that antagonism at brain 5-HT1C receptors is a component of the antiserotonergic properties of a number of established antidepressants. In addition, the study confirmed that 5-HT1A receptors functionally interact with 5-HT1C receptors, which suggests that some degree of activity at 5-HT1A receptors may also be an important property for antidepressant activity.