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Serotonergic Modulation of the Activity of Mesencephalic Dopaminergic Systems: Therapeutic Implications
Abstract
Since their discovery in the mammalian brain, it has been apparent that serotonin (5-HT) and dopamine (DA) interactions play a key role in normal and abnormal behavior. Therefore, disclosure of this interaction could reveal important insights into the pathogenesis of various neuropsychiatric diseases including schizophrenia, depression and drug addiction or neurological conditions such as Parkinson’s disease and Tourette’s syndrome. Unfortunately, this interaction remains difficult to study for many reasons, including the rich and widespread innervations of 5-HT and DA in the brain, the plethora of 5-HT receptors and the release of co-transmitters by 5-HT and DA neurons. The purpose of this review is to present electrophysiological and biochemical data showing that endogenous 5-HT and pharmacological 5-HT ligands modify the mesencephalic DA systems’ activity. 5-HT receptors may control DA neuron activity in a state-dependent and region-dependent manner. 5-HT controls the activity of DA neurons in a phasic and excitatory manner, except for the control exerted by 5-HT2C receptors which appears to also be tonically and/or constitutively inhibitory. The functional interaction between the two monoamines will also be discussed in view of the mechanism of action of antidepressants, antipsychotics, anti-Parkinsonians and drugs of abuse.
... Different views have emerged on the respective role of DA and 5-HT in reward functions either opposing them or making them allies (Boureau and Dayan, 2011;Cools et al., 2011;Daw et al., 2002). The complexity of this relationship notably lies in the fact that there is a heterogeneous expression of 5 H T receptors in the VTA on both DA and non-DA neurons (De Deurwaerdere and Di Giovanni, 2017). The heterogeneous expression of receptors also holds true in other structures involved in reward processing (Hayes and Greenshaw, 2011). ...
... Critically, there are different 5-HT receptors present in the VTA and their expression depends on the neuronal type (i.e. DA vs non-DA neurons; for extensive reviews, see (De Deurwaerdere and Di Giovanni, 2017;Hayes and Greenshaw, 2011)). 5-HT1A, 5-HT2A, 5-HT2C and 5-HT3 are mostly expressed in DA neurons while 5 H T1A; 5-HT1B; 5-HT2A; 5 H T2C; 5 H T4−3; 5 H T 6 are expressed on non-DA cells, pre-sumably GABAergic cells in the VTA. ...
... It is clear that 5-HT impacts VTA DA activity, however, the effects are complex (De Deurwaerdere and Di Giovanni, 2017;De Deurwaerdère and Di Giovanni, 2020). Another report in-vivo in anesthetized rats notably highlighted this complexity. ...
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.
... Le ratio 5HT/Trp a même été proposé comme marqueur d'agressivité (25). Les inhibiteurs de recapture de la sérotonine, tel que la fluoxétine, sont largement utilisés dans les pathologies précitées, en particulier en tant qu'antidépresseurs (26). ...
... Hypertension is also linked to TRP metabolism since the over-expression of the kynureninase (KYNU) gene, which convert 3-hydroxykynurenine (3HK) into 3HA, but also KYN into anthranilic acid (AA) is involved in hypertension [25,26]. Indeed, a higher expression of KYNU mRNA in brainstem of spontaneously hypertensive rats (SHR) was shown compared with Wistar-Kyoto rats [25], strongly suggesting that the gene coding for KYNU is one of the genes contributing to central control of blood pressure in SHR. ...
... Indeed, a higher expression of KYNU mRNA in brainstem of spontaneously hypertensive rats (SHR) was shown compared with Wistar-Kyoto rats [25], strongly suggesting that the gene coding for KYNU is one of the genes contributing to central control of blood pressure in SHR. This is concordant with recent data reporting a rare variant KYNU gene in the Han Chinese Population, suffering from essential hypertension [26]. Another study showed that the gene of kynurenine aminotransferase-1 (KAT), which degrades KYN into KA, is mutated in SHR leading to a decreased activity of the enzyme and a lower concentration of KA in SHR than in Wistar-rats [27]. ...
Le métabolisme du tryptophane (Trp) a été investigué dans différentes pathologies, incluant les maladies cardiovasculaires, la cancérologie et les maladies neurodégénératives. Le Trp, acide aminé essentiel, est catabolisé en périphérie et au niveau central selon 2 voies : celle des kynurénines, quantitativement majoritaire et impliquée dans les cardiopathies et la tolérance immune, et celle de la sérotonine, connue pour son implication dans la dépression et le sommeil. Dans le cadre de ce travail, nous nous sommes intéressés à l’implication de cette voie métabolique dans la phénylcétonurie (PCU) et les maladies cardiovasculaires.Dans la première partie de ce travail, nous avons mis au point une technique analytique de dosage de 9 métabolites de la voie du Trp, incluant ses 2 voies cataboliques. La méthode proposée, en HPLC-MS/MS, est fiable, reproductible, peu coûteuse, avec un processus pré-analytique simple et une durée d’analyse de 15 min. Ses critères sont conformes aux exigences du laboratoire selon les recommandations de la norme NF EN ISO 15189.Dans la deuxième partie, nous nous sommes intéressés au métabolisme du Trp dans la phénylcétonurie (PCU ; OMIM 261600). Cette maladie, due à un déficit de la phénylalanine hydroxylase hépatique (PAH ; EC 1.14.16.1), entraine une accumulation de phénylalanine (Phe) associée à un déficit en tyrosine. Cette pathologie, causant principalement un profond retard mental (QI < 50), est traitable grâce à l’instauration le plus précocement possible d’un régime restreint en Phe.Plusieurs éléments rapprochent le métabolisme du Trp de celui de la Phe, que ce soient les transporteurs, cofacteurs et enzyme chaperone communs, ou les inhibitions de l’une des voies par des métabolites de l’autre voie. De plus, certains adultes atteints de PCU présentent des dysfonctions neuropsychologiques inexpliquées par leur concentration de Phe sanguine, ce qui pourrait être dû à des modifications de la voie métabolique du Trp, plusieurs kynurénines possédant des propriétés neuroactives.Nous avons mis en évidence une modification du métabolisme du Trp dans une population phénylcétonurique adulte française (n=151 patients), avec en particulier une diminution des concentrations sanguines de kynurénine (KYN) et d’acide 3-hydroxykynurénique (3HK) par rapport à notre population de référence (p-value < 0.0001), ces résultats étant modulés par le type de régime suivi.La troisième partie de notre travail a consisté en l’évaluation du métabolisme du Trp dans le contexte des maladies cardiovasculaires. La prévention de ces pathologies est un enjeu de santé publique majeur, et se base sur la maitrise des facteurs de risque, dont le syndrome d’apnées obstructives du sommeil (SAOS) qui touche 6 à 17% des adultes à travers le monde. Ce syndrome se caractérise par un collapsus pharyngé partiel ou total, une fragmentation du sommeil et une augmentation des efforts respiratoires et donc des séquences d’hypoxie – réoxygénations (hypoxie intermittente) responsables d’une inflammation de bas grade. Plusieurs études explorant les maladies cardiovasculaires et le métabolisme du Trp ont été publiées récemment, mais très peu apportaient un lien mécanistique. Nous présentons ici les prochaines études cliniques et pré-cliniques que nous souhaitons mener dans ce domaine, afin de caractériser les modifications du métabolisme du Trp dans le SAOS traité ou non, mais également lors de l’hypoxie intermittente (modèle animal du SAOS) ou lors d’un réentrainement à l’effort.Il est à présent évident que la voie métabolique du Trp est impliquée dans différentes conditions pathologiques. Nous avons mis en évidence lors de ce travail ses modifications dans la PCU. L’impact physiopathologique des modifications observées reste cependant à explorer dans de nombreuses pathologies.
... Serotonin (5-HT) and dopamine (DA) systems interact in the nervous system of multiple organisms across the animal kingdom. The importance of this interaction has been revealed by the analysis of the mechanisms of action of numerous psychotropic drugs including antipsychotics and antidepressant drugs in the treatment of schizophrenia or depression (De Deurwaerdère and Di Giovanni, 2017;Di Giovanni et al., 2008). Thereafter, some pathophysiological data showed alterations in one or the other system or both in neurodegenerative diseases. ...
... The brain localization of the different 5-HT receptors is summarized in Table 1. The relative expression of 5-HT receptors mRNA and binding sites and/or immunolabeling in brain areas containing substantial DA innervation and basal ganglia have been previously reported (De Deurwaerdere and Di Giovanni, 2017;Miguelez et al., 2014). ...
... This latter finding endows arguments for the concept that the endogenous 5-HT system impacts DA neuron function when DA neuron function is perturbated/activated (see below). But we cannot exclude that under some circumstances, endogenous 5-HT at the level of the SN stimulates the dendritic release of DA (or simply impairs DA reuptake as a competitor on the DAT) (Trent and Tepper, 1991), thereby reducing the excitability of DA neurons via D2 receptors (see De Deurwaerdere and Di Giovanni, 2017;Navailles and De Deurwaerdere, 2011) for a complement of information on the mechanisms triggered by exogenous 5-HT and relative compounds). ...
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.
... On the other hand, also 5-HT1A receptors seem to indirectly alter DA release due to a low density of 5-HT1A receptors in the nucleus accumbens. However, 5-HT1A receptors may control DA release by reducing the 5-HT neuron activity as a consequence of the stimulation of 5-HT1A autoreceptors in the dorsal raphe nucleus or by reducing pyramidal cell activity projecting to VTA neurons [32]. A similar effect on DA release in the nucleus accumbens exerted by psilocin, an active metabolite of psilocybin, was demonstrated by Sakashita et al. [33]. ...
... The low basal levels of DA and 5-HT in dialysates from hippocampal and amygdalar regions did not allow for the measurement of these monoamine levels after the administration of psilocybin and ketamine (see Deurwardère and Giovanni [32]). It has to be noted that the problems with the detection of hippocampal and amygdalar DA and 5-HT were potentially due to the shorter lengths of microdialysis probes capturing less monoamines from the surrounding tissue. ...
The pathophysiology of depression is related to the reduced volume of the hippocampus and amygdala and hypertrophy of the nucleus accumbens. The mechanism of these changes is not well understood; however, clinical studies have shown that the administration of the fast-acting antidepressant ketamine reversed the decrease in hippocampus and amygdala volume in depressed patients, and the magnitude of this effect correlated with the reduction in depressive symptoms. In the present study, we attempted to find out whether the psychedelic substance psilocybin affects neurotransmission in the limbic system in comparison to ketamine. Psilocybin and ketamine increased the release of dopamine (DA) and serotonin (5-HT) in the nucleus accumbens of naive rats as demonstrated using microdialysis. Both drugs influenced glutamate and GABA release in the nucleus accumbens, hippocampus and amygdala and increased ACh levels in the hippocampus. The changes in D2, 5-HT1A and 5-HT2A receptor density in the nucleus accumbens and hippocampus were observed as a long-lasting effect. A marked anxiolytic effect of psilocybin in the acute phase and 24 h post-treatment was shown in the open field test. These data provide the neurobiological background for psilocybin’s effect on stress, anxiety and structural changes in the limbic system and translate into the antidepressant effect of psilocybin in depressed patients.
... Another possibility is that the DRN and VTA interact with each other. Indeed, a growing number of studies have suggested that there are direct and indirect interactions among distinctive neuronal types between and within the DRN and VTA (di Giovanni et al., 2008;Tan et al., 2012;Watabe-Uchida et al., 2012;McDevitt et al., 2014;Ogawa et al., 2014;Beier et al., 2015;de Deurwaerdère and di Giovanni, 2017;Valencia-Torres et al., 2017;Xu et al., 2017;Li et al., 2019;Wang et al., 2019). ...
... In another example, with model architecture "B, " when the connection from DRN 5-HT to DRN Glu neurons was inhibitory, it led to more restricted values in its connectivity strength (0-0.1 a.u.) and hence less robust than when it was excitatory (0-1 a.u.) (Supplementary Table 2). It has been reported that there are mixed findings of 5-HT on VTA DA neurons (de Deurwaerdère and di Giovanni, 2017). In our simulations, we found that an inhibitory connection from 5-HT to VTA DA neurons could lead to several degenerate models (architectures "A"-"D, " "I, " and "L"). ...
Degenerate neural circuits perform the same function despite being structurally different. However, it is unclear whether neural circuits with interacting neuromodulator sources can themselves degenerate while maintaining the same neuromodulatory function. Here, we address this by computationally modeling the neural circuits of neuromodulators serotonin and dopamine, local glutamatergic and GABAergic interneurons, and their possible interactions, under reward/punishment-based conditioning tasks. The neural modeling is constrained by relevant experimental studies of the VTA or DRN system using, e.g., electrophysiology, optogenetics, and voltammetry. We first show that a single parsimonious, sparsely connected neural circuit model can recapitulate several separate experimental findings that indicated diverse, heterogeneous, distributed, and mixed DRNVTA neuronal signaling in reward and punishment tasks. The inability of this model to recapitulate all observed neuronal signaling suggests potentially multiple circuits acting in parallel. Then using computational simulations and dynamical systems analysis, we demonstrate that several different stable circuit architectures can produce the same observed network activity profile, hence demonstrating degeneracy. Due to the extensive D2-mediated connections in the investigated circuits, we simulate the D2 receptor agonist by increasing the connection strengths emanating from the VTA DA neurons. We found that the simulated D2 agonist can distinguish among sub-groups of the degenerate neural circuits based on substantial deviations in specific neural populations’ activities in reward and punishment conditions. This forms a testable model prediction using pharmacological means. Overall, this theoretical work suggests the plausibility of degeneracy within neuromodulator circuitry and has important implications for the stable and robust maintenance of neuromodulatory functions.
... Moreover, there is functional connectivity of monoaminergic neurons-direct and indirect interconnections between 5-HT, NE and DA neurons are mediated through various receptor types which act on both autoreceptors and heteroreceptors. In particular, the impact of 5-HT systems on NE and DA neurotransmission were shown to be complex through 5-HT 2A and 5-HT 2C receptor-mediated mechanisms, respectively [20]. On the other hand, complex positive and negative influences of the NE system on 5-HT neurotransmission are mediated through α 1 -and α 2 -adrenergic receptors, respectively. ...
... The 5HT 1A receptor is an autoreceptor and its stimulation leads to inhibition of 5-HT release and subsequent inhibition of DA release in the prefrontal cortex (a decrease of DA in the prefrontal cortex is responsible for negative symptoms of schizophrenia). It is hypothesised that 5HT 1A receptor partial agonism may increase DA levels in the prefrontal cortex (minor effect of atypical antipsychotics on negative symptoms) [20,30]. It was also suggested that 5HT 2C agonism may result in antipsychotic effects without induction of extrapyramidal symptoms [9]. ...
Schizophrenia and depression are heterogeneous disorders. The complex pathomechanism of the diseases imply that medication responses vary across patients. Many psychotropic drugs are available but achieving optimal therapeutic effect can be challenging. The evidence correlates well with clinical observations, suggesting that new atypical antipsychotic drugs are effective against negative and cognitive symptoms of schizophrenia, as well as against affective symptoms observed in depression. The purpose of this review presents the background and evidence for the use of the new second/third-generation antipsychotics (aripiprazole, cariprazine, lurasidone, asenapine, brexpiprazole, lumateperone, pimavanserin) in treatment of schizophrenia and depression. We have first provided a brief overview of the major neurobiological underpinnings of schizophrenia and depression. We then shortly discuss efficacy, safety and limitations of ongoing pharmacotherapy used in depression and schizophrenia. Mainly, we have focused this review on the therapeutic potential of new atypical antipsychotic drugs—currently existing—to be effective in psychotic, as well as in affective disorders.
... 5HT3 receptors are cation selective ion channels, closely related to nicotinic acetylcholine receptors, and are highly expressed in mesocorticolimbic regions that are involved in sensory information processing, and assign context and salience to sensory inputs [8]. Distinct from other 5HT receptor subtypes, whose actions are G-protein coupled, 5HT3 receptors mediate fast synaptic neurotransmission and modulate the release of multiple neurotransmitters (dopamine, substance P, gamma-aminobutyric acid (GABA) and acetylcholine) through their expression on presynaptic terminals of non-serotonergic neurones [9,10] and post-synaptic GABAergic inter-neurones [11]. Although there is no evidence of a direct involvement of 5HT3 receptors in hallucinations, preclinical studies have shown antipsychotic and pro-cognitive effects of 5HT3 receptor antagonist ondansetron in animal models that are relevant for psychosis in humans [12]: Ondansetron attenuated amphetamine-induced dopamine release in mesocorticolimbic regions without inducing parkinsonism [9,10,13]; and reversed impairments in sensory gating and visual processing in the DBA/2 mouse model of α7-nicotinic cholinergic receptor depletion, by increasing hippocampal acetylcholine release [14,15]. ...
... Distinct from other 5HT receptor subtypes, whose actions are G-protein coupled, 5HT3 receptors mediate fast synaptic neurotransmission and modulate the release of multiple neurotransmitters (dopamine, substance P, gamma-aminobutyric acid (GABA) and acetylcholine) through their expression on presynaptic terminals of non-serotonergic neurones [9,10] and post-synaptic GABAergic inter-neurones [11]. Although there is no evidence of a direct involvement of 5HT3 receptors in hallucinations, preclinical studies have shown antipsychotic and pro-cognitive effects of 5HT3 receptor antagonist ondansetron in animal models that are relevant for psychosis in humans [12]: Ondansetron attenuated amphetamine-induced dopamine release in mesocorticolimbic regions without inducing parkinsonism [9,10,13]; and reversed impairments in sensory gating and visual processing in the DBA/2 mouse model of α7-nicotinic cholinergic receptor depletion, by increasing hippocampal acetylcholine release [14,15]. The latter findings extend to the secondgeneration 5HT3 antagonist tropisetron; a selective 5HT3 antagonist with additional partial α7-nicotinic receptor agonist activity [16]. ...
Ondansetron is a selective serotonin (5HT3) receptor antagonist that is under evaluation as an adjunctive treatment for schizophrenia, and a novel treatment for hallucinations in Parkinson’s disease. Ondansetron reverses sensory gating deficits and improves visuoperceptual processing in animal models of psychosis, but it is unclear to what extent preclinical findings have been replicated in humans. We systematically reviewed human studies that evaluated the effects of ondansetron and other 5HT3 receptor antagonists on sensory gating deficits or sensory processing. Of 11 eligible studies, eight included patients with schizophrenia who were chronically stable on antipsychotic medication; five measured sensory gating using the P50 suppression response to a repeated auditory stimulus; others included tests of visuoperceptual function. Three studies in healthy participants included tests of visuoperceptual and sensorimotor function. A consistent and robust finding (five studies) was that ondansetron and tropisetron (5HT3 antagonist and α7-nicotinic receptor partial agonist) improved sensory gating in patients with schizophrenia. Tropisetron also improved sustained visual attention in non-smoking patients. There was inconsistent evidence of the effects of 5HT3 antagonists on other measures of sensory processing, but interpretation was limited by the small number of studies, methodological heterogeneity and the potential confounding effects of concomitant medication in patients. Despite these limitations, we found strong evidence that selective 5HT3 antagonists (with or without direct α7-nicotinic partial agonist effects) improved sensory gating. Future studies should investigate how this relates to potential improvement in neurocognitive symptoms in antipsychotic naive patients with prodromal or milder symptoms, in order to understand the clinical implications.
... Therefore, it is possible that by controlling the 5-HT system, LED green light can reduce the pecking behaviour of Roman pink chickens. The 5-HT system consists of central neurotransmitters and peripheral signalling molecules, which can modulate DA levels in the brain [26]. The results of the current study demonstrated that the impact of LED green light significantly raised the DA levels in Roman pink and Hy-line brown embryos, suggesting greater foraging behaviour, which can be a natural antidote to damaging pecking [27,28]. ...
Background
The present study aimed to investigate the impact of the light-emitting diode (LED) green light alone or in combination with melatonin on pecking-related hormone regulation during incubation under normal and under hormonal stress conditions in breeder eggs. This study was divided into 2 experiments: In the first experiment effect of LED green light incubation on pecking-related hormones under normal conditions, on Hy-line brown (low pecking phenotype) and Roman pink (high pecking phenotype) eggs were tested. The 296 eggs of each strain were divided into two groups: LED green light incubation and dark incubation (control), each containing four replicates (37 eggs/replicate). The second experiment was conducted to evaluate the effect of LED green light incubation alone or in combination with melatonin under hormonal stress conditions on Roman pink eggs. A total of 704 Roman pink eggs were taken and divided into four groups, each consisting of 176 eggs. Each group was further divided into 2 subgroups, LED green light-regulated incubation and dark incubation with 88 eggs per subgroup, having 4 replicates of 22 eggs each. The groups were as follows: corticosterone solution injection (CI), corticosterone + melatonin mixed solution injection (CMI), Phosphate buffer solution injection (PI), and no injection (UI).
Results
Results of the first experiment revealed a higher level of serotonin hormone and lower corticosterone hormone in Hy-Line brown embryos compared to Roman pink embryos during dark incubation. The LED green light incubation significantly (P < 0.05) increased the level of 5-HT while decreasing the CORT level in Roman pink embryos indicating its regulatory effect on pecking-related hormones. Results of the second experiment showed that LED green light incubation significantly (P < 0.05) alleviated the CORT-induced hyperactivity of plasma 5-HT in Roman pink embryos. Furthermore, Melatonin (MLT) injection and LED green light together significantly (P < 0.05) reduced the hormonal stress caused by corticosterone injection in the eggs.
Conclusions
Overall, the LED green light regulatory incubation demonstrated a regulatory effect on hormones that influence pecking habits. Additionally, when coupled with MLT injection, it synergistically mitigated hormonal stress in the embryos. So, LED green light incubation emerged as a novel method to reduce the damaging pecking habits of poultry birds.
... Therefore, it is possible that by controlling the 5-HT system, LED green light can lessen the pecking and aggressive behaviour of Roman pink embryos. The 5-HT system consists of central neurotransmitters and peripheral signalling molecules, which can modulate DA levels in the brain [25]. The results of the current study demonstrated that the impact of LED green light signi cantly raised the DA levels in Roman pink and Hy-line brown embryos, suggesting greater foraging behaviour, which can be a natural antidote to aggressive pecking [26,27]. ...
Background
The present study aimed to investigate the impact of light emitting diode (LED) green light alone or in combination with melatonin on behaviour related hormones regulation during incubation under normal and under hormonal stress conditions in breeder eggs. This study divided into 2 experiments: In the first experiment LED green light effect on different hormone during incubation under normal condition, on Hy-line brown (low aggressive phenotype) and Roman pink (high aggressive phenotype) were tested. Total 296 eggs of each strain divided into two groups: LED green light incubation and dark incubation (control), each containing four replicates (37 eggs/replicate). Second experiment conducted to detect LED green light effect alone or in combination with melatonin during incubation under hormonal stress conditions. Total 704 eggs of Roman pink were taken and divided into four groups, each consisting of 176 eggs. Each group was further divided into 2 subgroups, LED green light-regulated incubation and dark incubation with 88 eggs per subgroup having 4 replicates of 22 eggs each. The groups were as follows: corticosterone solution injection (CI), corticosterone + melatonin mixed solution injection (CMI), Phosphate buffer solution injection (PI), and no injection (UI).
Results
Results from the first experiment revealed the higher level of serotonin hormone (related to calmness of behaviour) and lower of corticosterone hormone (related to aggressive behaviour) in Hy-Line brown embryos compares to those of Roman pink embryos during dark incubation. The LED green light incubation significantly increased the level of 5-HT while decreasing the CORT level in Roman pink embryos indicating its regulatory effect on behaviour related hormones. Results of the second experiments showed that LED green light incubation alleviated the CORT-induced hyperactivity of plasma 5-HT in Roman pink embryos. Furthermore, Melatonin (MLT) injection and LED green light together reduced the hormonal stress caused by corticosterone injection in the eggs.
Conclusions
Overall, the LED green light regulatory incubation demonstrated a regulatory effect on hormones related to behaviour. Additionally, when coupled with MLT injection, it synergistically mitigated hormonal stress in the embryos. So, LED green light incubation emerged as novel sustainable system to reduce the aggressive behviour and improve the productivity of the poultry birds.
... The interplay of the 5-HT system with several other classical neurotransmitter systems makes the wide range of brain processes mediated by 5-HT neurotransmission in the CNS more complicated. 5-HT exerts its effects on regulating the neurotransmitter release of these neurons by activating serotonergic receptors on cholinergic, dopaminergic, GABAergic, or glutamatergic neurons [8,9]. Additionally, 5-HT neurons also engage in co transmission, which is the release of several classical neurotransmitters by a single neuron. ...
Serotonin affects immunological regulation, hemostasis, vasoconstriction, gut motility, and is linked to several diseases. During peristalsis, serotonin (5-HT) is released from the gut mucosa and is largely generated by enterochromaffin cells (ECs) rather than gut microbes. Gut bacteria can stimulate the production of 5-HT. Serotonin in the blood that is retained within the platelets contributes to the production of clots and platelet aggregation. It binds to receptors such as 5HT2A, producing platelet aggregation and neuronal excitement. It regulates vasoconstriction via 5HT1D in cranial blood arteries. Atherosclerosis, thrombosis, and hypertension are some cardiovascular conditions liked to serotonin dysregulation. Serotonin imbalances in the gut influence gut motility and absorption, leading to conditions such as irritable bowel syndrome (IBS). 5-HT receptor subsets (5-HT1, 5HT2B, 5-HT3, 5-HT4, and 5-HT7) in gut are promising therapeutic targets. Serotonin in the Central Nervous System (CNS) controls a variety of behavioral and cognitive activities. 5-HTRs, including 5-HT1A and 5-HT2A, can have conflicting effects on pyramidal neuron firing. The chapter comprehends 5HTRs' involvement in the blood, gut, and brain, emphasizing its significance in modulating a variety of biological activities. Further investigation must be conducted to better comprehend the complexity of serotonin signaling to develop innovative treatment techniques that target serotonin receptor networking.
... In our present study, we further investigated the serotonin receptor subtypes that mediate the SSRI potentiation of methylphenidate-induced gene regulation in the striatum. There are at least 14 serotonin receptor subtypes, some of which are expressed in serotonin neurons (5-HT1A) and/ or in striatal neurons themselves [74,75]. Thus, there likely are multiple and complex mechanisms by which serotonin can modulate the molecular effects of dopamine action in striatal neurons. ...
Selective serotonin reuptake inhibitors (SSRIs), including fluoxetine, are frequently combined with medical psychostimulants such as methylphenidate (Ritalin), for example, in the treatment of attention-deficit hyperactivity disorder/depression comorbidity. Co-exposure to these medications also occurs with misuse of methylphenidate as a recreational drug by patients on SSRIs. Methylphenidate, a dopamine reuptake blocker, produces moderate addiction-related gene regulation. Findings show that SSRIs such as fluoxetine given in conjunction with methylphenidate potentiate methylphenidate-induced gene regulation in the striatum in rats, consistent with a facilitatory action of serotonin on addiction-related processes. These SSRIs may thus increase methylphenidate’s addiction liability. Here, we investigated the effects of a novel SSRI, vilazodone, on methylphenidate-induced gene regulation. Vilazodone differs from prototypical SSRIs in that, in addition to blocking serotonin reuptake, it acts as a partial agonist at the 5-HT1A serotonin receptor subtype. Studies showed that stimulation of the 5-HT1A receptor tempers serotonin input to the striatum. We compared the effects of acute treatment with vilazodone (10–20 mg/kg) with those of fluoxetine (5 mg/kg) on striatal gene regulation (zif268, substance P, enkephalin) induced by methylphenidate (5 mg/kg), by in situ hybridization histochemistry combined with autoradiography. We also assessed the impact of blocking 5-HT1A receptors by the selective antagonist WAY-100635 (0.5 mg/kg) on these responses. Behavioral effects of these drug treatments were examined in parallel in an open-field test. Our results show that, in contrast to fluoxetine, vilazodone did not potentiate gene regulation induced by methylphenidate in the striatum, while vilazodone enhanced methylphenidate-induced locomotor activity. However, blocking 5-HT1A receptors by WAY-100635 unmasked a potentiating effect of vilazodone on methylphenidate-induced gene regulation, thus confirming an inhibitory role for 5-HT1A receptors. Our findings suggest that vilazodone may serve as an adjunct SSRI with diminished addiction facilitating properties and identify the 5-HT1A receptor as a potential therapeutic target to treat addiction.
... Preclinical studies have shown the antipsychotic effects of 5-HT 3 antagonism in animal models. [36,37] 5HT 3 antagonism reduced dopamine release in the mesolimbic system in animal models and has not been found to cause or worsen parkinsonism. [37,38] In addition, 5-HT 3 antagonists modulate nicotinic cholinergic and GABAergic receptors, which are disrupted in PD patients with cognitive and behavioral abnormalities [22,39,40] Basic science studies have explored the effect of ondansetron, a highly selective 5-HT 3 receptor antagonist, on motor fluctuation in animal models of PD. [41][42][43] Furthermore, one of these studies explored the efficacy of ondansetron in ameliorating psychosis-like behavior in parkinsonian marmosets. ...
Psychosis is a debilitating non-motor symptom of Parkinson’s disease that commonly manifests with illusions, presence/passage hallucinations, and well-formed visual hallucinations. Parkinson’s
disease psychosis (PDP) is associated with several negative repercussions such as increased caregiver distress and high rates of nursing home placement, healthcare expenditure, and mortality.
Several neurotransmitters have been implicated in the pathogenesis of PDP; these include dopamine, acetylcholine, and serotonin. Most antipsychotics have a variable degree of dopamine-blocking property that may worsen parkinsonism or result in the emergence of other drug-induced movement disorders. Therefore, atypical antipsychotics with minimal dopamine-blocking property (quetiapine, clozapine) are commonly prescribed to treat PDP. Pimavanserin, which modulates serotonergic transmission
(5-HT2A inverse agonist), is the only drug approved by the US Food and Drug Administration to treat PDP; however, it is not globally available. Therefore, it is crucial to continue the search for effective
pharmacotherapy of PDP. Other serotonergic targets of interest include selective 5-HT3 receptor antagonist ondansetron. Licensed for use as an antiemetic, open-label studies on ondansetron in the
1990s have shown encouraging results in the treatment of hallucinations in PD. However, ondansetron was not further studied in PDP as it was cost-prohibitive. In this article, we highlight the role of abnormal serotonergic transmission in the pathogenesis of PDP, revisit the studies that investigated the role of ondansetron in treating PDP, and discuss its potential as an effective therapeutic option for PDP.
... Serotonin receptors (5-HTRs) can modulate the dopamine release as well [64], and serotonin inhibition of dopamine function may also contribute to AIP [26,27]. Among the various 5-HTRs, the 5-HT2AR and 5-HT2CR have been the most extensively studied, since various antipsychotic drugs, especially atypical antipsychotics, have a high affinity for these receptors. ...
Antipsychotic-induced parkinsonism (AIP) is the most common type of extrapyramidal side effect (EPS), caused by the blockage of dopamine receptors. Since dopamine availability might influence the AIP risk, the dopamine transporter (DAT) and serotonin receptors (5-HTRs), which modulate the dopamine release, may be also involved in the AIP development. As some of the individual differences in the susceptibility to AIP might be due to the genetic background, this study aimed to examine the associations of SLC6A3, HTR2C and HTR6 gene polymorphisms with AIP in haloperidol-treated schizophrenia patients. The Extrapyramidal Symptom Rating Scale (ESRS) was used to evaluate AIP as a separate entity. Genotyping was performed using a PCR, following the extraction of blood DNA. The results revealed significant associations between HTR6 rs1805054 polymorphism and haloperidol-induced tremor and rigidity. Additionally, the findings indicated a combined effect of HTR6 T and SLC6A3 9R alleles on AIP, with their combination associated with significantly lower scores of ESRS subscale II for parkinsonism, ESRS-based tremor or hyperkinesia and ESRS subscales VI and VIII. These genetic predictors of AIP could be helpful in better understanding its pathophysiology, recognizing the individuals at risk of developing AIP and offering personalized therapeutic strategies for the patients suffering from this EPS.
... Dopamine (DA) is another prominent modulatory neurotransmitter conserved in vertebrates, the functions of which include motor control and motivation-related behavior such as reward and punishment learning (Wise, 2004;Puig et al., 2014). Both the 5-HT and DA systems are involved in processes of motivation-related behavior and interact with each other (Boureau and Dayan, 2011;De Deurwaerdere and Di Giovanni, 2017;Yagishita, 2020;Beyeler et al., 2021;De Deurwaerdere and Di Giovanni, 2021;Peters et al., 2021). To understand the phylogenetic continuity of the neural basis for cognition and emotion, it is necessary to deepen our understanding of the neural circuits that control cognitive and emotional behaviors in animals other than mammals. ...
Serotonin (5-hydroxytryptamine, 5-HT) is a phylogenetically conserved modulator of numerous aspects of neural functions. Serotonergic neurons in the dorsal and median raphe nucleus provide ascending innervation to the entire forebrain and midbrain. Another important neural modulatory system exists in the midbrain, the dopaminergic system, which is associated to reward processing and motivation control. Dopaminergic neurons are distributed and clustered in the brain, classically designated as groups A8–A16. Among them, groups A8–A10 associated with reward processing and motivation control are located in the midbrain and projected to the forebrain. Recently, midbrain dopaminergic neurons were shown to be innervated by serotonergic neurons and modulated by 5-HT, with the crosstalk between serotonergic and dopaminergic systems attracting increased attention. In birds, previous studies revealed that midbrain dopaminergic neurons are located in the A8-A10 homologous clusters. However, the detailed distribution of dopaminergic neurons and the crosstalk between serotonergic and dopaminergic systems in the bird are poorly understood. To improve the understanding of the regulation of the dopaminergic by the serotonergic system, we performed in situ hybridization in the chick brainstem. We prepared RNA probes for chick orthologues of dopaminergic neuron-related genes; tyrosine hydroxylase (TH) and dopa decarboxylase (DDC), noradrenaline related genes; noradrenaline transporter (NAT) and dopamine beta-hydroxylase (DBH), and serotonin receptor genes; 5-HTR1A, 5-HTR1B, 5-HTR1D, 5-HTR1E, 5-HTR1F, 5-HTR2A, 5-HTR2B, 5-HTR2C, 5-HTR3A, 5-HTR4, 5-HTR5A, and 5-HTR7. We confirmed that the expression of tyrosine hydroxylase (TH) and NAT was well matched in all chick dopaminergic nuclei examined. This supported that the compensation of the function of dopamine transporter (DAT) by NAT is a general property of avian dopaminergic neurons. Furthermore, we showed that 5-HTR1A and 5-HTR1B were expressed in midbrain dopaminergic nuclei, suggesting the serotonergic regulation of the dopaminergic system via these receptors in chicks. Our findings will help us understand the interactions between the dopaminergic and serotonergic systems in birds at the molecular level.
... compensated for by enhancing the level of DA signaling. Meanwhile, 5-HT regulates the activity of DA neurons as well as the release of DA from the presynaptic membrane in the mesencephalon by acting on 5-HTR 2A of the DA neurons or 5-HTR 2C of the GABA neurons 29,30 . Therefore, sulpiride also indirectly up-regulated 5-HT synthase TPH by inhibiting the DA signaling system. ...
The presence of drugs in surface and groundwaters adversely affects the physiological function of non-target organisms due special activities that can pose a serious threats to various forms of aquatic life. Psychotropic drugs are one of the most commonly used drugs in the world. Hence, the aim of this study was to investigate the effect of environmentally-relevant concentrations of the antipsychotic drugs, sulpiride and clozapine, on dopaminergic (DAergic) and serotonergic (5-HTergic) neurotransmitter systems in the brain of zebrafish. Adult zebrafish (AB strain) were exposed to the environmentally-relevant concentrations of sulpiride, clozapine, or a mixture of sulpiride and clozapine. The effects of the drugs on the mRNA and protein levels of major functional molecules in DAergic and 5-HTergic systems were then analyzed in the telencephalon and diencephalon. Both drugs induced abnormal mRNA and protein levels of important functional molecules of the DA and 5-HT signaling pathways in both telencephalon and diencephalon, as shown by the abnormal transcriptional levels of TH, DAT, DR D1, DR D2, MAO, TPH, serotonin transporter (SERT), 5-HTR 1AA, 5-HTR 1B, 5-THR 2AA, and 5-HTR 2B, and the abnormal translational levels of DAT, DR D2, SERT, 5-HTR 1A, 5-HTR 1B, and 5-HTR 2B. In addition, we observed a specificity in the adverse effects of these antipsychotic drugs, in terms of doses and brain parts. Compared to their effects alone, the drug mixture had a weaker effect on the DA and 5-HT systems, suggesting an antagonistic interaction between sulpiride and clozapine. Our findings suggest that sulpiride and clozapine interfere with DAergic and 5-HTergic neurotransmitter systems in the telencephalon and diencephalon of zebrafish, resulting in possible effects on brain functions and posing a serious threat to the health of zebrafish.
... In addition, the activation of 5-HTR1 receptors in the pre-synaptic membrane inhibits neuronal activity and leads to decreased transmitter release (including 5-HTR1A, which regulates neuronal firing, and 5-HTR1B, which regulates 5-HT release) [52]. The 5-HT receptors may control the activity of DA neurons in a state-and region-dependent manner [53]. Therefore, clozapine antagonizes 5-HTR2A, DRD1, DRD2, and DRD3 in the octopus brain tissue, resulting in decreased DA synthesis, decreased signaling activity of the DA neurotransmitter system, downregulation of the transcription of functional molecules, and increased protein expression levels of the 5-HT neurotransmitter system. ...
Pharmaceuticals and personal care products (PPCPs) from specific activities often enter surface and groundwater, adversely affecting the physiological functions of non-target organisms and posing a serious threat to a wide range of aquatic organisms. Therefore, the aim of this study was to investigate the effects of environmentally relevant concentrations of the antipsychotic drugs sulpiride and clozapine on dopaminergic (DAergic) and serotonergic (5-hydroxytryptaminergic, i.e., 5-HTergic) neurotransmitter systems in the brain of a short-arm octopus (Octopus ochellatus). Octopus ochellatus adults were exposed to environmentally relevant concentrations of sulpiride, clozapine, or a mixture of sulpiride and clozapine. The effects of the drug on the transcription and expression levels of major functional molecules in the DAergic and 5-HTergic systems of the brain were analyzed. By antagonizing the dopamine receptor D2 (DRD2) or 5-hydroxytryptamine receptor 2A (5-HTR2A), the two drugs induced abnormal transcription and expression levels of important functional molecules in the brain’s DA and 5-HT signaling pathways. In addition, dose-dependent adverse reactions were observed with these antipsychotics. Our results suggest that sulpiride and clozapine interfere with DAergic and 5-HTergic neurotransmitter systems in the brain of Amphioctopus fangsiao (O. ochellatus), possibly affecting brain functions, such as reproduction, predation, camouflage, learning, and memory. As a result, they pose a serious threat to the health of Amphioctopus fangsiao.
... Our study spotlights the hypothesis that lack of Snord115 remodels slightly monoaminergic function in the brain, yet it does not highlight a specific functional domain in which Snord115-KO mice could be strongly defective: the cocaine-induced reward response and locomotor hyperactivity, binge-like eating and repetitive digging behaviors remained unaffected. Given that these behaviors are regulated by 5-HT, sometimes in an opposite manner compared to DA (80), net changes in behavioral responses are likely to be meager because the 5-HT neurons also display higher activity. Despite higher rates of neuronal discharges, adaptive mechanisms in Snord115-KO mice (e.g. ...
The neuronal-specific SNORD115 has gathered interest because its deficiency may contribute to the pathophysiology of Prader-Willi syndrome (PWS), possibly by altering post-transcriptional regulation of the gene encoding the serotonin (HTR2C) receptor. Yet, Snord115-KO mice do not resume the main symptoms of PWS and only subtle altered A-to-I RNA editing of Htr2c mRNAs were uncovered. Because HTR2C signaling fine-tunes the activity of monoaminergic neurons, we addressed the hypothesis that lack of Snord115 alters monoaminergic systems. We first showed that Snord115 was expressed in both monoaminergic and non-monoaminergic cells of the ventral tegmental area (VTA) and the dorsal raphe nucleus (DRN) harboring cell bodies of dopaminergic and serotonergic neurons, respectively. Measuring the tissue level of monoamines and metabolites, we found very few differences except that the content of homovanillic acid—a metabolite of dopamine—was decreased in the orbitofrontal and prefrontal cortex of Snord115-KO mice. The latter effects were, however, associated with a few changes of monoamine tissue content connectivity across the 12 sampled brain regions. Using in vivo single cell extracellular recordings, we reported that the firing rate of VTA dopaminergic neurons and DRN serotonergic neurons was significantly increased in Snord115-KO mice. These neural circuit dysfunctions were not, however, associated with apparent defects in binge eating, conditioned place preference to cocaine, cocaine-induced hyperlocomotion or compulsive behavior. Altogether, our multiscale study shows that the absence of Snord115 impacts on central monoaminergic circuits to an extent that does not elicit gross behavioral abnormalities.
... Active pyramidal cells stimulate neurons in VTA, resulting in an increased DA release in the frontal cortex. Alternatively, psilocybin-activated 5-HT2A receptors located in pyramidal cells may be responsible for an increase in cortical DA release [47]. Thus, the stimulation of descending excitatory projection by 5-HT1A or 5-HT2A receptors could enhance glutamate release in VTA, subsequently stimulating glutamate receptors and increasing DA release in the frontal cortex. ...
Clinical studies provide evidence that ketamine and psilocybin could be used as fast-acting antidepressants, though their mechanisms and toxicity are still not fully understood. To address this issue, we have examined the effect of a single administration of ketamine and psilocybin on the extracellular levels of neurotransmitters in the rat frontal cortex and reticular nucleus of the thalamus using microdialysis. The genotoxic effect and density of glutamate receptor proteins was measured with comet assay and Western blot, respectively. An open field test, light–dark box test and forced swim test were conducted to examine rat behavior 24 h after drug administration. Ketamine (10 mg/kg) and psilocybin (2 and 10 mg/kg) increased dopamine, serotonin, glutamate and GABA extracellular levels in the frontal cortex, while psilocybin also increased GABA in the reticular nucleus of the thalamus. Oxidative DNA damage due to psilocybin was observed in the frontal cortex and from both drugs in the hippocampus. NR2A subunit levels were increased after psilocybin (10 mg/kg). Behavioral tests showed no antidepressant or anxiolytic effects, and only ketamine suppressed rat locomotor activity. The observed changes in neurotransmission might lead to genotoxicity and increased NR2A levels, while not markedly affecting animal behavior.
... The reduction of the DOPAC/DA ratio was not expected because WIN 55,212-2 has been consistently reported to enhance DA neuronal activity and DA release in the NAc, although preferentially in the shell (Tanda et al., 1997;Polissidis et al., 2013). The reduction in DOPAC/DA ratio in GAERS is perhaps connected to the strong increase in 5-HT tissue content in the SN that is known to mediate DA cell inhibition (Di De Deurwaerdère and Di Giovanni, 2017). The increase in 5-HT and NA levels driven by WIN 55,212-2 might depend on the potentiation of the excitatory effect of CB1Rs of the 5-HT dorsal raphe nucleus (Bambico et al., 2007) and NA locus coeruleus neurons (Gobbi et al., 2005), respectively, compared to NEC rats. ...
Childhood absence epilepsy (CAE) is characterized by absence seizures, which are episodes of lack of consciousness accompanied by electrographic spike-wave discharges. About 60% of children and adolescents with absence seizures are affected by major neuropsychological comorbidities, including anxiety. Endocannabinoids and monoamines are likely involved in the pathophysiology of these CAE psychiatric comorbidities. Here, we show that the synthetic cannabinoid receptor type 1/2 (CB1/2R) agonist WIN 55,212-2 (2 mg/kg) has a strain-dependent effect on anxiety-like and motor behavior when assess in the hole board test and cerebral monoaminergic levels in Genetic Absence Epilepsy Rats from Strasbourg (GAERS) and their non-epileptic control (NEC) rat strain. Using quantitative and Temporal pattern (T-pattern) analyses, we found that WIN 55,212-2 did not affect the emotional status of GAERS, but it was anxiolytic in NEC. Conversely, WIN 55,212-2 had a sedative effect in GAERS but was ineffective in NEC. Moreover, vehicle-treated GAERS more motivated to explore by implementing more complex and articulated strategies. These behavioral changes correlate with the reduction of 5-HT in the hippocampus and substantia nigra (SN) and noradrenaline (NA) in the entopeduncular nucleus (EPN) in vehicle-treated GAERS compared to NEC rats, which could contribute to their low anxiety status and hypermotility, respectively. On the other hand, the increased level of NA in the EPN and 5-HT in the SN is consistent with an activation of the basal ganglia output-mediated motor suppression observed in WIN 55,212-2-treated GAERS rats. These data support the view of a strain-dependent alteration of the endocannabinoid system in absence epilepsy by adding evidence of a lower emotional responsiveness and a basal ganglia hypersensitivity to cannabinoids in GAERS compared to NEC rats.
... As such, 5-HT 2C receptor antagonists reduced these effects and unmasked an increase in c-Fos expression in the subthalamic nucleus. The theatre of the 5-HT 2C receptor/dopamine transmission is much more widespread than initially thought [12]. ...
Serotonin (5-HT) is an attractive neurotransmitter system, in terms of physiology, physiopathology, and medicines [...]
... Bullied children with the SS genotype are at greater risk for developing emotional problems at age 12 than those children with the SL or LL genotype [97]. In humans and various animals, the 5-HTergic system regulates aggression via innervating the midbrain and hypothalamic dopaminergic neurons [98][99][100]. The midbrain dopamine storage capacity is negatively correlated with aggression [101]; individuals who have a low dopamine transmission capacity show more impulsive aggression in response to provocation [101]. ...
Tryptophan, as the sole precursor of serotonin, mainly derived from diets, is essential for neurodevelopment and immunomodulation. Gestational tryptophan fluctuation may account for the maternal-fetal transmission in determining neuroembryogenesis with long-lasting effects on psychological development. Personality disorders and social exclusion are related to psychosocial problems, leading to impaired social functioning. However, it is not clear how the fluctuation in mother-child transmission regulates the neuroendocrine development and gut microbiota composition in progeny due to that tryptophan metabolism in pregnant women is affected by multiple factors, such as diets (tryptophan-enriched or -depleted diet), emotional mental states (anxiety, depression), health status (hypertension, diabetes), and social support as well as stresses and management skills. Recently, we have developed a non-mammal model to rationalize those discrepancies without maternal effects. This perspective article outlines the possibility and verified the hypothesis in bully-victim research with this novel model: (1). Summarizes the effects of the maternal tryptophan administration on the neuroendocrine and microbial development in their offspring; (2). Highlights the inconsistency and limitations in studying the relationship between gestational tryptophan exposure and psychosocial development in humans and viviparous animals; and (3). Evidences that embryonic exposure to tryptophan and its metabolite modify bullying interactions in the chicken model. With the current pioneer researches on the biomechanisms underlying the bully-victim interaction, the perspective article provides novel insights for developing appropriate intervention strategies to prevent psychological disorders among individuals, especially those who experienced prenatal stress, by controlling dietary tryptophan and medication therapy during pregnancy.
... The persistence of behavioral and affective changes in cocaine addiction likely reflects long-term adaptations in neural systems that support continued drug use [7]. These may include alterations in brain connectivity [8], signaling [9], neuronal plasticity [10], or neurotransmitter and neuromodulator dynamics [11][12][13]. The molecular mechanisms underlying these adaptive responses to repeated drug exposure are poorly characterized, but appear to involve transcriptional adaptations [14,15]. ...
Cocaine addiction is a complex pathology inducing long-term neuroplastic changes that, in turn, contribute to maladaptive behaviors. This behavioral dysregulation is associated with transcriptional reprogramming in brain reward circuitry, although the mechanisms underlying this modulation remain poorly understood. The endogenous cannabinoid system may play a role in this process in that cannabinoid mechanisms modulate drug reward and contribute to cocaine-induced neural adaptations. In this study, we investigated whether cocaine self-administration induces long-term adaptations, including transcriptional modifications and associated epigenetic processes. We first examined endocannabinoid gene expression in reward-related brain regions of the rat following self-administered (0.33 mg/kg intravenous, FR1, 10 days) cocaine injections. Interestingly, we found increased Cnr1 expression in several structures, including prefrontal cortex, nucleus accumbens, dorsal striatum, hippocampus, habenula, amygdala, lateral hypothalamus, ventral tegmental area, and rostromedial tegmental nucleus, with most pronounced effects in the hippocampus. Endocannabinoid levels, measured by mass spectrometry, were also altered in this structure. Chromatin immunoprecipitation followed by qPCR in the hippocampus revealed that two activating histone marks, H3K4Me3 and H3K27Ac, were enriched at specific endocannabinoid genes following cocaine intake. Targeting CB1 receptors using chromosome conformation capture, we highlighted spatial chromatin re-organization in the hippocampus, as well as in the nucleus accumbens, suggesting that destabilization of the chromatin may contribute to neuronal responses to cocaine. Overall, our results highlight a key role for the hippocampus in cocaine-induced plasticity and broaden the understanding of neuronal alterations associated with endocannabinoid signaling. The latter suggests that epigenetic modifications contribute to maladaptive behaviors associated with chronic drug use.
... To date, the interaction between serotonergic and dopaminergic systems is still under investigation. Many studies conducted so far claim an involvement of the 5-HT system in the modulation of the activity of dopaminergic neurons and in the regulation of corticostriatal synaptic transmission (De Deurwaerdere and Di Giovanni, 2017;Ogawa and Watabe-Uchida, 2018). The 5-HT afferents arising from the dorsal raphe nucleus innervate all components of the basal ganglia circuitry (Cavaccini et al., 2018). ...
Introduction
Plasticity at corticostriatal synapses is a key substrate for a variety of brain functions – including motor control, learning and reward processing – and is often disrupted in disease conditions. Despite intense research pointing toward a dynamic interplay between glutamate, dopamine (DA), and serotonin (5-HT) neurotransmission, their precise circuit and synaptic mechanisms regulating their role in striatal plasticity are still unclear. Here, we analyze the role of serotonergic raphe-striatal innervation in the regulation of DA-dependent corticostriatal plasticity.
Methods
Mice (males and females, 2–6 months of age) were housed in standard plexiglass cages at constant temperature (22 ± 1 °C) and maintained on a 12/12 h light/dark cycle with food and demineralized water ad libitum. In the present study, we used a knock-in mouse line in which the green fluorescent protein reporter gene (GFP) replaced the I Tph2 exon (Tph2eGFP mice), allowing selective expression of GFP in the whole 5-HT system, highlighting both somata and neuritis of serotonergic neurons. Heterozygous, Tph2+/GFP, mice were intercrossed to obtain experimental cohorts, which included Wild-type (Tph2+/+), Heterozygous (Tph2+/GFP), and Mutant serotonin-depleted (Tph2GFP/GFP) animals.
Results
Using male and female mice, carrying on different Tph2 gene dosages, we show that Tph2 gene modulation results in sex-specific corticostriatal abnormalities, encompassing the abnormal amplitude of spontaneous glutamatergic transmission and the loss of Long Term Potentiation (LTP) in Tph2GFP/GFP mice of both sexes, while this form of plasticity is normally expressed in control mice (Tph2+/+). Once LTP is induced, only the Tph2+/GFP female mice present a loss of synaptic depotentiation.
Conclusion
We showed a relevant role of the interaction between dopaminergic and serotonergic systems in controlling striatal synaptic plasticity. Overall, our data unveil that 5-HT plays a primary role in regulating DA-dependent corticostriatal plasticity in a sex-related manner and propose altered 5-HT levels as a critical determinant of disease-associated plasticity defects.
... Studies show that there is a decrease in these receptors in the hippocampus of individuals with depressive disorders, as well as in animals submitted to chronic stress and elevated glucocorticoid levels. On the other hand, treatment with antidepressant drugs promotes increased sensitivity of these receptors in the limbic system in post-synaptic structures and this increase in sensitivity of receptors would be directly related to the manifestation of the antidepressant effect of these substances (De Deurwaerd ere and Di Giovanni, 2017;Petrunich-Rutherford et al., 2018). Thus, it is important to evaluate the interaction between RO and the serotonergic system and specifically the 5HT1A receptors. ...
Rose oxide (RO) is a monoterpene found in rose oil fragrances. This monoterpene has been reported to possess anti-inflammatory activity, however, little is known regarding its pharmacological activity. The present study was carried out to evaluate its antidepressant action and possible mechanisms of action. Analysis of ADMET pharmacokinetic properties (absorption, distribution, metabolism, excretion and toxicity) of rose oxide was performed by computational prediction analysis. Behavioral tests were performed to assess the interaction between rose oxide and the central nervous system and antidepressant effect that includes: forced swim test (FST), tail suspension test (TST), open field test (OFT) and rota-rod test. The results of pharmacokinetic and toxicological properties indicate that rose oxide could be used orally, since it has good intestinal absorption as well as pharmacological and toxicological properties that can be similar to pharmacological compounds (regular hepatic metabolism and low toxicity). Treatment with 50 mg/kg of rose oxide was able to decrease the immobility time of animals not affected by FST and TST and was not able to alter the motor activity of the OFT and rota-rod test, suggesting modulation and antidepressant activity. Docking data suggest that rose oxide can bind to receptors in the serotonergic pathway. The results described here suggest that rose oxide has antidepressant activity, modulating the serotonergic pathway.
Psychedelics belong to the oldest psychoactive drugs. They arouse recent interest due to their therapeutic applications in the treatment of major depressive disorder, substance use disorder, end-of-life anxiety,= and anxiety symptoms, and obsessive–compulsive disorder. In this review, the current state of preclinical research on the mechanism of action, neurotoxicity, and behavioral impact of psychedelics is summarized. The effect of selective 5-HT2A receptor agonists, 25I- and 25B-NBOMe, after acute and repeated administration is characterized and compared with the effects of a less selective drug, psilocybin. The data show a significant effect of NBOMes on glutamatergic, dopaminergic, serotonergic, and cholinergic neurotransmission in the frontal cortex, striatum, and nucleus accumbens. The increases in extracellular levels of neurotransmitters were not dose-dependent, which most likely resulted from the stimulation of the 5-HT2A receptor and subsequent activation of the 5-HT2C receptors. This effect was also observed in the wet dog shake test and locomotor activity. Chronic administration of NBOMes elicited rapid development of tolerance, genotoxicity, and activation of microglia. Acute treatment with psilocybin affected monoaminergic and aminoacidic neurotransmitters in the frontal cortex, nucleus accumbens, and hippocampus but not in the amygdala. Psilocybin exhibited anxiolytic properties resulting from intensification of GABAergic neurotransmission. The data indicate that NBOMes as selective 5-HT2A agonists exert a significant effect on neurotransmission and behavior of rats while also inducing oxidative DNA damage. In contrast to NBOMes, the effects induced by psilocybin suggest a broader therapeutic index of this drug.
Resumen
Introducción
el complejo parkinsonismo-demencia-esclerosis lateral amiotrófica fue descrito por primera vez en las islas de Guam. Esta patología presentó su pico de incidencia en los años 50. Debido a la rareza de la asociación, informamos sobre un caso clínico que la presenta. El objetivo fue describir las implicaciones nosológicas y patogénicas de este trastorno neurodegenerativo, ya que no es frecuente encontrar esta asociación en nuestra población.
Caso clínico
presentamos un caso de origen latinoamericano que inicialmente se manifestó con síntomas sistémicos de más de 6 años de evolución, con posteriores alteraciones cognitivas. Después presentó alteraciones de la marcha y síntomas motores sugestivos de parkinsonismo con datos atípicos y datos de enfermedad de motoneurona. Se hicieron estudios de extensión que confirmaron hallazgos compatibles con afectación en motoneurona superior e inferior. Observamos mutación en gen POLG, relacionada con síndrome de depleción mitocondrial.
Conclusiones
a pesar del conocimiento de esta asociación, es una entidad cuyo diagnóstico clínico puede ser muy difícil de obtener. Además, no se han identificado del todo los mecanismos moleculares, se han excluido los genes más comunes relacionados con parkinsonismos y esclerosis lateral amiotrófica e incluso se intentó localizar el locus, sin lograr resultados certeros. Desafortunadamente al ser una enfermedad neurodegenerativa el pronóstico es fatal, sin que haya tratamiento modificador de la enfermedad.
The hypothalamic neuropeptide oxytocin (OT) is well known for its prosocial, anxiolytic, and ameliorating effects on various psychiatric conditions, including alcohol use disorder (AUD). In this chapter, we will first introduce the basic neurophysiology of the OT system and its interaction with other neuromodulatory and neurotransmitter systems in the brain. Next, we provide an overview over the current state of research examining the effects of acute and chronic alcohol exposure on the OT system as well as the effects of OT system manipulation on alcohol-related behaviors in rodents and humans. In rodent models of AUD, OT has been repeatedly shown to reduce ethanol consumption, particularly in models of acute alcohol exposure. In humans however, the results of OT administration on alcohol-related behaviors are promising but not yet conclusive. Therefore, we further discuss several physiological and methodological limitations to the effective application of OT in the clinic and how they may be mitigated by the application of synthetic OT receptor (OTR) agonists. Finally, we discuss the potential efficacy of cutting-edge pharmacology and gene therapies designed to specifically enhance endogenous OT release and thereby rescue deficient expression of OT in the brains of patients with severe forms of AUD and other incurable mental disorders.KeywordsAlcohol use disorderDopamineOxytocinOxytocin receptorStress axisVasopressin
Depression induced by weightlessness exposure in spaceflight has seriously affected astronauts’ psychology and flight missions, but the preventive and treatment methods remain limited. Here, we used systems pharmacology to identify the potential bioactive compounds from Hippophae rhamnoides L. (HR) for treating depression caused by weightlessness. First, isorhamnetin was screened out as a potential drug in HR for treating depression. Further, the therapeutic effect of isorhamnetin was investigated in depression induced by weightlessness using the hindlimb unloading (HLU) rat model. We found that treatment with isorhamnetin notably shortened immobility time during forced swimming tests and tail suspension tests in HLU rats. The hematoxylin-eosin staining results revealed that isorhamnetin could ameliorate morphological damage to the hippocampus of HLU-induced rats. Moreover, exposure to HLU caused increased corticosterone (CORT) and adrenocorticotropic hormone (ACTH) concentrations in serum. Administration with isorhamnetin for four weeks reduced the ACTH and CORT content in HLU rats. The 5-hydroxytryptamine and dopamine content in hippocampus were reduced in HLU rats, which were increased after isorhamnetin-treatment. Conclusively, isorhamnetin can alleviate the depression and hippocampus damage induced by weightlessness. Our study identified that isorhamnetin could be a natural bioactive drug for depression.
Serotonin (5-hydroxytryptamine, 5-HT) is a phylogenetically conserved neurotransmitter and modulator. Neurons utilizing serotonin have been identified in the central nervous systems of all vertebrates. In the central serotonergic system of vertebrate species examined so far, serotonergic neurons have been confirmed to exist in clusters in the brainstem. Although many serotonin-regulated cognitive, behavioral, and emotional functions have been elucidated in mammals, equivalents remain poorly understood in non-mammalian vertebrates. The purpose of this review is to summarize current knowledge of the anatomical organization and molecular features of the avian central serotonergic system. In addition, selected key functions of serotonin are briefly reviewed. Gene association studies between serotonergic system related genes and behaviors in birds have elucidated that the serotonergic system is involved in the regulation of behavior in birds similar to that observed in mammals. The widespread distribution of serotonergic modulation in the central nervous system and the evolutionary conservation of the serotonergic system provide a strong foundation for understanding and comparing the evolutionary continuity of neural circuits controlling corresponding brain functions within vertebrates. The main focus of this review is the chicken brain, with this type of poultry used as a model bird. The chicken is widely used not only as a model for answering questions in developmental biology and as a model for agriculturally useful breeding, but also in research relating to cognitive, behavioral, and emotional processes. In addition to a wealth of prior research on the projection relationships of avian brain regions, detailed subdivision similarities between avian and mammalian brains have recently been identified. Therefore, identifying the neural circuits modulated by the serotonergic system in avian brains may provide an interesting opportunity for detailed comparative studies of the function of serotonergic systems in mammals.
Introduction
Psilocybin is one of the most extensively studied psychedelic drugs with a broad therapeutic potential. Despite the fact that its psychoactivity is mainly attributed to the agonism at 5-HT2A receptors, it has high binding affinity also to 5-HT2C and 5-HT1A receptors and indirectly modulates the dopaminergic system. Psilocybin and its active metabolite psilocin, as well as other serotonergic psychedelics, induce broadband desynchronization and disconnection in EEG in humans as well as in animals. The contribution of serotonergic and dopaminergic mechanisms underlying these changes is not clear. The present study thus aims to elucidate the pharmacological mechanisms underlying psilocin-induced broadband desynchronization and disconnection in an animal model.
Methods
Selective antagonists of serotonin receptors (5-HT1A WAY100635, 5-HT2A MDL100907, 5-HT2C SB242084) and antipsychotics haloperidol, a D2 antagonist, and clozapine, a mixed D2 and 5-HT receptor antagonist, were used in order to clarify the underlying pharmacology.
Results
Psilocin-induced broadband decrease in the mean absolute EEG power was normalized by all antagonists and antipsychotics used within the frequency range 1–25 Hz; however, decreases in 25–40 Hz were influenced only by clozapine. Psilocin-induced decrease in global functional connectivity and, specifically, fronto-temporal disconnection were reversed by the 5-HT2A antagonist while other drugs had no effect.
Discussion
These findings suggest the involvement of all three serotonergic receptors studied as well as the role of dopaminergic mechanisms in power spectra/current density with only the 5-HT2A receptor being effective in both studied metrics. This opens an important discussion on the role of other than 5-HT2A-dependent mechanisms underlying the neurobiology of psychedelics.
Parkinson's disease (PD) is characterized mainly by motor dysfunctions due to the progressive loss of dopaminergic neurons. However, PD patients experience a multitude of debilitating non-motor symptoms, including depression, which may have deleteriously detrimental effects on life. Depression is multifactorial and exhibits a bimodal progression in PD, but its underlying molecular mechanisms are poorly understood. Studies demonstrating the pathophysiology of depression in PD and the specific treatment strategies for depression-like symptoms in PD patients are largely lacking, often underrated, under-recognized and, consequently, inadequately/under-treated. Nevertheless, reports suggest that the incidence of depression is approximately 20%-30% of PD patients and may precede the onset of motor symptoms. Diagnosing depression in PD becomes difficult due to the clinical overlap in symptomatology between the two diseases, and the nigrostriatal dysfunction alone is insufficient to explain depressive symptoms in PD. Therefore, the current study provides an overview of the molecular mechanisms underlying the development of depression in PD and new insights into developing current antidepressant strategies to treat depression in PD. This review will identify and understand the molecular pathological mechanisms of depression in PD that will fundamentally help tailoring therapeutic interventions for depressive symptoms in PD.
Myopia is a refractive disorder arising from a mismatch between refractive power and relatively long axial length of the eye. With its dramatically increasing prevalence, myopia has become a pervasive social problem. It is commonly accepted that abnormal visual input acts as an initiating factor of myopia. As the first station to perceive visual signals, the retina plays an important role in myopia etiology. The retina is a fine-layered structure with multitudinous cells, processing intricate visual signals via numerous molecular pathways. Accordingly, dopaminergic mechanisms, contributions of rod and cone photoreceptors, myopic structural changes of retinal pigment epithelium (RPE) and neuro-retinal layers have all suggested a vital role of retinal dysfunction in myopia development. Herein, we separately discuss myopia-related retinal dysfunction and current dilemmas by different levels, from molecules to cells, with the hope that the comprehensive delineation could contribute to a better understanding of myopia etiology, indicate novel therapeutic targets, and inspire future studies.
The activity of monoamine oxidases (MAOs) in the brain is often associated with neurodegenerative diseases. The study of MAOs in vivo or ex vivo is generally performed using MAO inhibitors and rarely using substrates. We present a pharmacological approach using intracerebral microdialysis to study the activity of MAO in the striatum and the prefrontal cortex of rats. It consists of applying ascending concentrations of 3-methoxytyramine (3-MT) as a substrate via the probes and measuring the indirect product homovanillic acid generated by MAO activity. We present herein the methodologies comprising our in-house stereotaxic procedures in rats, the microdialysis perfusion system and the substrate application, and the neurochemical analysis of the samples.Key words3-MethoxytyramineHomovanillic acidMonoamine oxidasesHigh pressure liquid chromatographyElectrochemical detectionReverse microdialysis
Objective
The aim of the present study was to investigate whether serotonin1B (5-HT1B) receptor-adenylate cyclase (AC)-protein kinase A (PKA) signal pathway in the lateral habenula (LHb) is involved in Parkinson’s disease-related depression in sham-lesioned and substantia nigra pars compacta (SNc)-lesioned rats.
Methods
The sucrose preference and forced swim tests were used to measure depressive-like behaviors. In vivo electrophysiology and microdialysis were performed to observe the firing activity of LHb neurons and GABA and glutamate release in the LHb, respectively. Western blotting was used to analyze protein expression of 5-HT1B receptors, AC and phosphorylated PKA at threonine 197 site (p-PKA-Thr197) in the LHb.
Results
Unilateral 6-hydroxydopamine lesions of the SNc in rats induced depressive-like behaviors. Intra-LHb injection of 5-HT1B receptor agonist CP93129 produced antidepressant-like effects and the antagonist SB216641 induced depressive-like behaviors in sham-lesioned and SNc-lesioned rats. Further, pretreatment with AC inhibitor SQ22536 and PKA inhibitor KT5720 blocked the behavioral effects of CP93129 in the two groups of rats, respectively. CP93129 decreased the firing rate of LHb neurons and release of GABA and glutamate, but increased the GABA/glutamate ratio, while SB216641 induced the opposite effects. Compared with sham-lesioned rats, effects of CP93129 and SB216641 on the depressive-like behaviors, electrophysiology, and microdialysis were decreased in SNc-lesioned rats, which were associated with decreased expression of 5-HT1B receptors, AC and p-PKA-Thr197 in the LHb.
Conclusion
5-HT1B receptor-AC-PKA signal pathway in the LHb is involved in the regulation of depressive-like behaviors, and depletion of DA reduces activity of 5-HT1B receptor-AC-PKA signal pathway.
Adenosine deaminases acting on RNAs convert adenosines (A) to inosines (I) in structured or double- stranded RNAs. In mammals, this process is widespread. In the human transcriptome more than a million different sites have been identified that undergo an ADAR-mediated A to I exchange (1). Inosines have an altered base pairing potential due to the missing amino group when compared to the original adenosine. Consequently, inosines prefer to base pair with guanosines but can also base pair with uracil or adenine (2). This altered base pairing potential not only affects protein decoding at the ribosome but also influences the folding of RNAs and the proteins that can associate with it. Consequently, an A to I exchange can also affect RNA processing and turnover (3, 4). All of these events will interfere with gene expression and therefore, can also affect cellular and organismic physiology. As double-stranded RNAs are a hallmark of viral pathogens RNA-editing not only affects RNA-processing, coding and gene expression but also controls the antiviral response to double-stranded RNAs. Most interestingly, recent advances in our understanding of ADAR enzymes reveal multiple layers of regulation by which ADARs can control antiviral programs. In this review we focus on the recoding of mRNAs where the altered translation products lead to physiological changes. We also address recent advances in our understanding of the multiple layers of antiviral responses and innate immune modulations mediated by ADAR1.
The hippocampal region receives a dense serotoninergic innervation originating from both medial and dorsal raphe nuclei. This innervation regulates hippocampal activity through the activation of distinct receptor families that are expressed in excitatory and inhibitory neurons, terminals of several afferent neurotransmitter systems, and glial cells. Preclinical and clinical studies indicate that hippocampal dysfunctions are involved in learning and memory deficits, dementia, Alzheimer's disease, epilepsy and mood disorders such as anxiety, depression and post-traumatic syndrome disorder, whereas the hippocampus participates also in the therapeutic mechanisms of numerous medicines. Not surprisingly, several drugs acting via 5-HT mechanisms are efficacious to some extent in some diseases and the link between 5-HT and the hippocampus although clear remains difficult to untangle. For this reason, we review reported data concerning the distribution and the functional roles of the 5-HT receptors in the hippocampal region in health and disease. The impact of the 5-HT systems on the hippocampal function is such that the research of new 5-HT mechanisms and drugs is still very active. It concerns notably drugs acting at the 5-HT1A,2A,2C,4,6 receptor subtypes, in addition to the already existing drugs including the selective serotonin reuptake inhibitors.
The serotonergic system of the central nervous system (CNS) has been implicated in a broad range of physiological functions and behaviors, such as cognition, mood, social interaction, sexual behavior, feeding behavior, sleep-wake cycle and thermoregulation. Serotonin (5-hydroxytryptamine, 5-HT) establishes a plethora of interactions with neurochemical systems in the CNS via its numerous 5-HT receptors and autoreceptors. The facets of this control are multiple if we consider the molecular actors playing a role in the autoregulation of 5-HT neuron activity including the 5-HT1A, 5-HT1B, 5-HT1D, 5-HT2B, 5-HT7 receptors as well as the serotonin transporter. Moreover, extrinsic loops involving other neurotransmitters giving the other 5-HT receptors the possibility to impact 5-HT neuron activity. Grasping the complexity of these interactions is essential for the development of a variety of therapeutic strategies for cognitive defects and mood disorders. Presently we can illustrate the plurality of the mechanisms and only conceive that these 5-HT controls are likely not uniform in terms of regional and neuronal distribution. Our understanding of the specific expression patterns of these receptors on specific circuits and neuronal populations are progressing and will expand our comprehension of the function and interaction of these receptors with other chemical systems. Thus, the development of new approaches profiling the expression of 5-HT receptors and autoreceptors should reveal additional facets of the 5-HT controls of neurochemical systems in the CNS.
Parkinson's disease (PD) is commonly treated with dopaminergic medication, which enhances some, while impairing other cognitive functions. It can even contribute to impulse control disorder and addiction. We describe the history of research supporting the dopamine overdose hypothesis, which accounts for the large within-patient variability in dopaminergic medication effects across different tasks by referring to the spatially non-uniform pattern of dopamine depletion in dorsal versus ventral striatum. However, there is tremendous variability in dopaminergic medication effects not just within patients across distinct tasks, but also across different patients. In the second part of this chapter we review recent studies addressing the large individual variability in the negative side effects of dopaminergic medication on functions that implicate dopamine, such as value-based learning and choice. These studies begin to unravel the mechanisms of dopamine overdosing, thus revising the strict version of the overdose hypothesis. For example, the work shows that the canonical boosting of reward-versus punishment-based choice by medication is greater in patients with depression and a non-tremor phenotype, which both implicate, among other pathology, more rather than less severe dysregulation of the mesolimbic dopamine system. Future longitudinal cohort studies are needed to identify how to optimally combine different clinical, personality, cognitive, neural, genetic and molecular predictors of detrimental medication effects in order to account for as much of the relevant variability as possible. This will provide a useful tool for precision neurology, allowing individual and contextual tailoring of (the dose of) dopaminergic medication in order to maximize its cognitive benefits, yet minimize its side effects.
L-3,4-dihydroxyphenylalanine (L-DOPA) is the mainstay treatment for Parkinson’s disease, but its effectiveness during early disease is marred by the eventual development of L-DOPA induced dyskinesia. In hemi-parkinsonian rats, the serotonin type 3 (5-HT3) antagonists ondansetron and granisetron alleviated dyskinesia induced by L-DOPA without impeding its anti-parkinsonian action; in parkinsonian marmosets, ondansetron alleviated dyskinesia and enhanced L-DOPA anti-parkinsonian action. Here, we sought to gain insight into the mechanisms governing the anti-dyskinetic action of 5-HT3 antagonists and measured their levels across different brain, using [³H]GR65630 autoradiographic binding. Brain sections were chosen from 6-hydroxydopamine (6-OHDA)-lesioned rats exhibiting abnormal involuntary movements (AIMs), as well as L-DOPA-naïve 6-OHDA and sham-lesioned animals. [³H]GR65630 binding increased in the ipsilateral subthalamic nucleus of 6-OHDA-lesioned rats with mild and severe AIMs, (3-fold changes, P < 0.001). [³H]GR65630 binding also increased in the ipsilateral entopeduncular nucleus and thalamus of 6-OHDA-lesioned rats with severe AIMs (75% and 88%, P < 0.05). AIMs scores negatively correlated with [³H]GR65630 binding in the ipsilateral dorsolateral striatum and contralateral subthalamic nucleus (P < 0.05). These results suggest that alterations in 5-HT3 mediated neurotransmission may contribute to the pathophysiology of L-DOPA induced dyskinesia.
Serotonin (5-HT) is important in some nicotine actions in the CNS. Among all the 5-HT receptors (5-HTRs), the 5-HT2CR has emerged as a promising drug target for smoking cessation. The 5-HT2CRs within the lateral habenula (LHb) may be crucial for nicotine addiction. Here we showed that after acute nicotine tartrate (2 mg/kg, i.p.) exposure, the 5-HT2CR agonist Ro 60-0175 (5–640 µg/kg, i.v.) increased the electrical activity of 42% of the LHb recorded neurons in vivo in rats. Conversely, after chronic nicotine treatment (6 mg/kg/day, i.p., for 14 days), Ro 60-0175 was incapable of affecting the LHb neuronal discharge. Moreover, acute nicotine exposure increased the 5-HT2CR-immunoreactive (IR) area while decreasing the number of 5-HT2CR-IR neurons in the LHb. On the other hand, chronic nicotine increased both the 5-HT2CR-IR area and 5-HT2CR-IR LHb neurons in the LHb. Western blot analysis confirmed these findings and further revealed an increase of 5-HT2CR expression in the medial prefrontal cortex after chronic nicotine exposure not detected by the immunohistochemistry. Altogether, these data show that acute and chronic nicotine exposure differentially affect the central 5-HT2CR function mainly in the LHb and this may be relevant in nicotine addiction and its treatment.
Almost 35% of patients with Parkinson’s are affected by depression. Much before the occurrence of motor symptoms, various nonmotor symptoms such as depression arise in Parkinson’s disease patients. The pathophysiology of depression in Parkinson’s patients is still unknown but the change in neurotransmitter pathways is one of the major reasons behind it. Alteration in noradrenergic, serotonergic, and dopaminergic pathways in Parkinson’s patients might assist to enlighten reason behind the incidence of depression. Not only drugs working on dopamine systems but also noradrenergic and serotonin systems may help to reduce depression in the patient. The current review describes the mechanism underlying biochemical changes that occur in the noradrenergic, serotonergic and dopaminergic system of Parkinson’s patient with depression.
Flexible electrochemical sensors based on electroactive materials have emerged as powerful analytical tools for biomedical applications requiring bioanalytes detection. Within this context, 3D printing is a remarkable technology for developing electrochemical devices, due to no design constraints, waste minimization, and batch manufacturing with high reproducibility. However, the fabrication of 3D printed electrodes is still limited by the in‐house fabrication of conductive filaments, which requires the mixture of the electroactive material with melted of thermoplastic polymer (e.g., polylactic acid, PLA). Herein, a simple approach is presented for preparing electrochemical dopamine (DA) biosensors. Specifically, the surface of 3D‐printed PLA specimens, which exhibit an elastic modulus and a tensile strength of 3.7 ± 0.3 GPa and 47 ± 1 MPa, respectively, is activated applying a 0.5 m NaOH solution for 30 min and, subsequently, poly(3,4‐ethylenedioxythiophene) is polymerized in situ using aqueous solvent. The detection of DA with the produced sensors has been demonstrated by cyclic voltammetry, differential pulse voltammetry, and chronoamperometry. In summary, the obtained results reflect that low‐cost electrochemical sensors, which are widely used in medicine and biotechnology, can be rapidly fabricated using the proposed approach that, although based on additive manufacturing, does not require the preparation of conductive filaments.
The serotonergic system of the central nervous system (CNS) has been implicated in a broad range of physiological functions and behaviors, such as cognition, mood, social interaction, sexual behavior, feeding behavior, sleep-wake cycle and thermoregulation. Serotonin (5-hydroxytryptamine, 5-HT) establishes a plethora of interactions with neurochemical systems in the CNS via its numerous 5-HT receptors and autoreceptors. The facets of this control are multiple if we consider the molecular actors playing a role in the autoregulation of 5-HT neuron activity including the 5-HT1A, 5-HT1B, 5-HT1D, 5-HT2B, 5-HT7 receptors as well as the serotonin transporter. Moreover, extrinsic loops involving other neurotransmitters giving the other 5-HT receptors the possibility to impact 5-HT neuron activity. Grasping the complexity of these interactions is essential for the development of a variety of therapeutic strategies for cognitive defects and mood disorders. Presently we can illustrate the plurality of the mechanisms and only conceive that these 5-HT controls are likely not uniform in terms of regional and neuronal distribution. Our understanding of the specific expression patterns of these receptors on specific circuits and neuronal populations are progressing and will expand our comprehension of the function and interaction of these receptors with other chemical systems. Thus, the development of new approaches profiling the expression of 5-HT receptors and autoreceptors should reveal additional facets of the 5-HT controls of neurochemical systems in the CNS.
The brainstem is a neglected brain area in neurodegenerative diseases, including Alzheimer's and Parkinson's disease, frontotemporal lobar degeneration and autonomic dysfunction. In Depression, several observations have been made in relation to changes in one particular the Dorsal Raphe Nucleus (DRN) which also points toward as key area in various age-related and neurodevelopmental diseases. The DRN is further thought to be related to stress regulated processes and cognitive events. It is involved in neurodegeneration, e.g., amyloid plaques, neurofibrillary tangles, and impaired synaptic transmission in Alzheimer's disease as shown in our autopsy findings. The DRN is a phylogenetically old brain area, with projections that reach out to a large number of regions and nuclei of the central nervous system, particularly in the forebrain. These ascending projections contain multiple neurotransmitters. One of the main reasons for the past and current interest in the DRN is its involvement in depression, and its main transmitter serotonin. The DRN also points toward the increased importance and focus of the brainstem as key area in various age-related and neurodevelopmental diseases.
This review describes the morphology, ascending projections and the complex neurotransmitter nature of the DRN, stressing its role as a key research target into the neural bases of depression.
The hippocampal region receives a dense serotoninergic innervation originating from both medial and dorsal raphe nuclei. This innervation regulates hippocampal activity through the activation of distinct receptor families that are expressed in excitatory and inhibitory neurons, terminals of several afferent neurotransmitter systems, and glial cells. Preclinical and clinical studies indicate that hippocampal dysfunctions are involved in learning and memory deficits, dementia, Alzheimer's disease, epilepsy and mood disorders such as anxiety, depression and post-traumatic syndrome disorder, whereas the hippocampus participates also in the therapeutic mechanisms of numerous medicines. Not surprisingly, several drugs acting via 5-HT mechanisms are efficacious to some extent in some diseases and the link between 5-HT and the hippocampus although clear remains difficult to untangle. For this reason, we review reported data concerning the distribution and the functional roles of the 5-HT receptors in the hippocampal region in health and disease. The impact of the 5-HT systems on the hippocampal function is such that the research of new 5-HT mechanisms and drugs is still very active. It concerns notably drugs acting at the 5-HT1A,2A,2C,4,6 receptor subtypes, in addition to the already existing drugs including the selective serotonin reuptake inhibitors.
Intracellular recordings were made from presumed dopamine-containing neurons in slices cut from the midbrain of the rat. Focal electrical stimulation produced a hyperpolarizing synaptic potential that was reduced by 75–95% by the GABAB-receptor antagonist 2-hydroxysaclofen (300 microM). 5-HT (3–100 microM) reduced the amplitude of the GABAB synaptic potential by 20–74%, with a 50% reduction at 10 microM, but did not reduce the amplitude of synaptic potentials mediated by GABAA receptors. 5-HT acted presynaptically because hyperpolarizations produced by exogenously administered GABA (1 mM) in picrotoxin (100 microM) were not affected by 5-HT (30 microM). (+/-)-Cyanopindolol (100 nM), a 5-HT1B antagonist, blocked the effect of 5-HT (10 microM); spiperone (1 microM), which is an antagonist at 5-HT1A and 5-HT2 receptors, had no effect. The amplitude of the GABAB synaptic potential was reduced by the 5-HT1B receptor agonists 1-[3-(trifluoromethyl)- phenyl]-piperazine (300 nM) and 7-trifluoromethyl-4-(4-methyl-1- piperazinyl)-pyrrolo[1,2-a]quinoxaline (1 microM), but not by the 5- HT1A agonist N,N-dipropyl-5-carboxamidotryptamine (1 microM) or the 5- HT2 agonist (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-amino-propane (10 microM). We conclude that 5-HT activates presynaptic 5-HT1B receptors that inhibit the release of GABA onto GABAB but not GABAA receptors.
Background and purpose:
L-DOPA is still the most efficacious pharmacological treatment for Parkinson's disease. Its efficacy is counteracted after years of treatment by motor complications and notably L-DOPA-induced dyskinesia in the majority of patients. Evidence suggests that the serotonergic system is involved in the therapeutic and side effects of L-DOPA. Here, we investigate if long-term L-DOPA treatment alters the activity of dorsal raphe nucleus (DRN) and its reactivity to serotonergic drugs.
Experimental approach:
We explored the responses of serotonergic neurons to acute and chronic L-DOPA treatment using in vivo electrophysiological single unit-extracellular recordings in the 6-OHDA-lesion rat model of Parkinson's disease.
Key results:
The results showed that neither acute nor chronic L-DOPA administration (6 mg kg(-1) s.c.) altered the properties of serotonergic-like neurons. Furthermore, no correlation was found between the activity of these neurons and the magnitude of L-DOPA-induced dyskinesia. In dyskinetic rats, the inhibitory response induced by the 5-HT1A agonist 8-OH-DPAT (0.0625-16 µg kg(-1) , i.v.) was preserved. Nonetheless, L-DOPA impaired the ability of the serotonin reuptake inhibitor fluoxetine (0.125-8 mg kg(-1) , i.v) to inhibit DRN neuron firing rate in dyskinetic animals.
Conclusions and implications:
Although serotonergic neurons are responsible for the dopaminergic effects of L-DOPA, we provide evidence that the effect of L-DOPA is not related to changes of the activity of DRN neurons. Rather, L-DOPA might dampen the efficacy of drugs that normally enhance serotonin extracellular levels.
Astrocytes contribute to pathogenesis of neuropsychiatric disorders, including major
depression. Stimulation of astroglial 5-HT2B receptors transactivates epidermal growth
factor receptors (EGFRs) and regulates gene expression. Previously we reported that
expression of 5-HT2B receptors in cortical astrocytes is down-regulated in animals, which
developed anhedonia in response to chronic stress; moreover this down-regulation
as well as anhedonia, are reversed by chronic treatment with fluoxetine. In this study
we have investigated whether astrocytic 5-HT2B receptor is involved in anhedonia in
C57BL/6 mice model of Parkinson’ disease (PD) induced by intraperitoneal injection of
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) for 7 days. The MPTP treatment
induced anhendonia in 66.7% of animals. The appearance of depressive behavior
was accompanied with motor deficiency and decrease of tyrosine hydroxylase (TH)
expression. Expression of mRNA and protein of 5-HT2B receptor in animals that became
anhedonic decreased to 77.3 and 79.3% of control groups, respectively; in animals that
received MPTP but did not develop anhedonia the expression of 5-HT2B receptor did
not change. Experiments with FACS-sorted isolated cells demonstrated that decrease
in 5-HT2B receptor expression was confined to astrocytes, and did not occur in
neurons. Fluoxetine corrected MPTP-induced decrease of 5-HT2B receptor expression
and depressive behavior. Our findings indicate that regulation of gene expression of 5-
HT2B receptors in astroglia may be associated with pathophysiological evolution of PDinduced
depression.
Bivalve molluscs such as Perna perna display temporal cycles of reproduction that result from the complex interplay between endogenous and exogenous signals. The monoamines serotonin, dopamine and noradrenaline represent possible endocrine and neuronal links between these signals allowing the molluscs to modulate reproductive functions in conjunction with environmental constraints. Here, we report a disruption of the reproductive cycle of mussels collected from two of three sites along the Moroccan atlantic coast soiled by industrial or domestic waste. Using high pressure liquid chromatography, we show that the temporal pattern of monoamine content in the gonads, pedal and cerebroid ganglia varied throughout the reproductive cycle (resting, developing, maturing, egg-laying) of mussels from the unpolluted site. Marked modification of monoamine tissue content was found between sites, notably in noradrenaline content of the gonads. Discriminant statistics revealed a specific impact of mussel location on the temporal variations of noradrenaline and serotonin levels in gonads and cerebroid ganglia. Correlation analyses showed profound and temporal changes in the monoamine content between organs and ganglia, at the two sites where the reproduction was disrupted. We suggest that environmental constraints lead to profound changes of monoaminergic systems, which thereby compromises the entry of mussels into their reproductive cycle.
The dorsal raphe nucleus (DRN) represents one of the most sensitive reward sites in the brain. However, the exact relationship between DRN neuronal activity and reward signaling has been elusive. In this review, we will summarize anatomical, pharmacological, optogenetics, and electrophysiological studies on the functions and circuit mechanisms of DRN neurons in reward processing. The DRN is commonly associated with serotonin (5-hydroxytryptamine; 5-HT), but this nucleus also contains neurons of the neurotransmitter phenotypes of glutamate, GABA and dopamine. Pharmacological studies indicate that 5-HT might be involved in modulating reward- or punishment-related behaviors. Recent optogenetic stimulations demonstrate that transient activation of DRN neurons produces strong reinforcement signals that are carried out primarily by glutamate. Moreover, activation of DRN 5-HT neurons enhances reward waiting. Electrophysiological recordings reveal that the activity of DRN neurons exhibits diverse behavioral correlates in reward-related tasks. Studies so far thus demonstrate the strong power of DRN neurons in reward signaling and at the same time invite additional efforts to dissect the roles and mechanisms of different DRN neuron types in various processes of reward-related behaviors.
© 2015 Luo et al.; Published by Cold Spring Harbor Laboratory Press.
Imbalance between the dopamine and serotonin (5-HT) neurotransmitter systems has been implicated in the comorbidity of Parkinson's disease (PD) and psychiatric disorders. L-DOPA, the leading treatment of PD, facilitates the production and release of dopamine. This study assessed the action of L-DOPA on monoamine synaptic transmission in mouse brain slices. Application of L-DOPA augmented the D2-receptor-mediated inhibitory postsynaptic current (IPSC) in dopamine neurons of the substantia nigra. This augmentation was largely due to dopamine release from 5-HT terminals. Selective optogenetic stimulation of 5-HT terminals evoked dopamine release, producing D2-receptor-mediated IPSCs following treatment with L-DOPA. In the dorsal raphe, L-DOPA produced a long-lasting depression of the 5-HT1A-receptor-mediated IPSC in 5-HT neurons. When D2 receptors were expressed in the dorsal raphe, application of L-DOPA resulted in a D2-receptor-mediated IPSC. Thus, treatment with L-DOPA caused ectopic dopamine release from 5-HT terminals and a loss of 5-HT-mediated synaptic transmission.
Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
Desensitization and blockade of 5-HT2C receptors (5-HT2CR) have long been thought to be central in the therapeutic action of antidepressant drugs. However, besides behavioral pharmacology studies, there is little in vivo data documenting antidepressant-induced 5-HT2CR desensitization in specific brain areas.
Mice lacking the 5-HT reuptake carrier (5-HTT(-/-)) were used to model the consequences of chronic 5-HT reuptake inhibition with antidepressant drugs. The effect of this mutation on 5-HT2CR was evaluated at the behavioral (social interaction, novelty-suppressed feeding and 5-HT2CR-induced hypolocomotion tests), the neurochemical and the cellular (RT-qPCR, mRNA editing and c-fos-induced expression) levels.
Although 5-HTT(-/-) mice had an anxiogenic profile in the novelty-suppressed feeding test, they displayed less 5-HT2CR-mediated anxiety in response to the agonist m-chlorophenylpiperazine in the social interaction test. In addition, 5-HT2CR-mediated inhibition of stress-induced increase in 5-HT turnover, measured in various brain areas, was markedly reduced in 5-HTT(-/-) mutants. These indices of tolerance to 5-HT2CR stimulation were associated neither with altered levels of 5-HT2CR protein and mRNA nor with changes in pre-mRNA editing in the frontal cortex. However, basal c-fos mRNA production in cells expressing 5-HT2CR was higher in 5-HTT(-/-) mutants, suggesting an altered basal activity of these cells following sustained 5-HT reuptake carrier inactivation. Furthermore, the increased c-fos mRNA expression in 5-HT2CR-like immune-positive cortical cells observed in wild-type mice treated acutely with the 5-HT2CR agonist RO-60,0175, was absent in 5-HTT(-/-) mutants.
Such blunted responsiveness of the 5-HT2CR system, observed at the cell signaling level, probably contributes to moderate the anxiety phenotype of 5-HTT(-/-) mice.
© The Author 2014. Published by Oxford University Press on behalf of CINP.
In advanced stages of Parkinson's disease, serotonergic terminals take up l-DOPA and convert it to dopamine. Abnormally released dopamine may participate in the development of l-DOPA-induced dyskinesias. Simultaneous activation of 5-HT1A and 5-HT1B receptors effectively blocks l-DOPA-induced dyskinesias in animal models of dopamine depletion, justifying a clinical study with eltoprazine, a 5-HT1A/B receptor agonist, against l-DOPA-induced dyskinesias in patients with Parkinson's disease. A double-blind, randomized, placebo-controlled and dose-finding phase I/IIa study was conducted. Single oral treatment with placebo or eltoprazine, at 2.5, 5 and 7.5 mg, was tested in combination with a suprathreshold dose of l-DOPA (Sinemet®) in 22 patients with Parkinson's disease (16 male/six female; 66.6 ± 8.8 years old) with l-DOPA-induced dyskinesias. A Wilcoxon Signed Ranked Test was used to compare each eltoprazine dose level to paired randomized placebo on the prespecified primary efficacy variables; area under the curve scores on Clinical Dyskinesia Rating Scale for 3 h post-dose and maximum change of Unified Parkinson's Disease Rating Scale part III for 3 h post-dose. Secondary objectives included effects on maximum Clinical Dyskinesia Rating Scale score, area under the curve of Rush Dyskinesia Rating Scale score for 3 h post-dose, mood parameters measured by Hospital Anxiety Depression Scale and Montgomery Asberg Depression Rating Scale along with the pharmacokinetics, safety and tolerability profile of eltoprazine. A mixed model repeated measures was used for post hoc analyses of the area under the curve and peak Clinical Dyskinesia Rating Scale scores. It was found that serum concentrations of eltoprazine increased in a dose-proportional manner. Following levodopa challenge, 5 mg eltoprazine caused a significant reduction of l-DOPA-induced dyskinesias on area under the curves of Clinical Dyskinesia Rating Scale [-1.02(1.49); P = 0.004] and Rush Dyskinesia Rating Scale [-0.15(0.23); P = 0.003]; and maximum Clinical Dyskinesia Rating Scale score [-1.14(1.59); P = 0.005]. The post hoc analysis confirmed these results and also showed an antidyskinetic effect of 7.5 mg eltoprazine. Unified Parkinson's Disease Rating Scale part III scores did not differ between the placebo and eltoprazine treatments. The most frequent adverse effects after eltoprazine were nausea and dizziness. It can be concluded that a single dose, oral treatment with eltoprazine has beneficial antidyskinetic effects without altering normal motor responses to l-DOPA. All doses of eltoprazine were well tolerated, with no major adverse effects. Eltoprazine has a favourable risk-benefit and pharmacokinetic profile in patients with Parkinson's disease. The data support further clinical studies with chronic oral eltoprazine to treat l-DOPA-induced-dyskinesias.
© The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
Midbrain dopamine (DA) neurons are key players in motivation and reward processing. Increased DA release is thought to be central in the initiation of drug addiction. Whereas dopamine neurons are generally considered to be activated by drugs such as nicotine, we report here that nicotine not only induces excitation of ventral tegmental area (VTA) DA cells but also induces inhibition of a subset of VTA DA neurons that are anatomically segregated in the medial part of the VTA. These opposite responses do not correlate with the inhibition and excitation induced by noxious stimuli. We show that this inhibition requires D2 receptor (D2-R) activation, suggesting that a dopaminergic release is involved in the mechanism. Our findings suggest a principle of concurrent excitation and inhibition of VTA DA cells in response to nicotine. It promotes unexplored roles for DA release in addiction contrasting with the classical views of reinforcement and motivation, and give rise to a new interpretation of the mode of operation of the reward system. M idbrain dopamine (DA) neurons from the ventral tegmental area (VTA) are involved in several brain processes including reinforcement, associative learning, motivation, and are critically involved in the pathophysiology of addiction. Nicotine, the primary addictive component of tobacco, exerts its rein-forcing effects by modifying VTA DA neurons activity through its action on nicotinic acetylcholine receptors (nAChRs) 1–4 and through the subsequent DA release 5 in target areas such as the Nucleus Accumbens (NAc) and the prefrontal cortex (PFC). DA VTA cells can be segregated into different functional subpopulations, according to their spontaneous electrophysiological activity, protein expression, area of axonal projection 6,7
The 5-HT2C receptor agonist lorcaserin (Belviq®) has been Food and Drug Administration (FDA) approved for the treatment of obesity. The present study is a back translational investigation into the effect of 28-day lorcaserin treatment in a diet-induced obesity (DIO) model using male, Sprague–Dawley rats. An assessment of drug effect on efficacy and multiple safety endpoints including cardiac function was undertaken. Lorcaserin (1–2 mg/kg SC b.i.d.) significantly reduced percentage body weight gain compared to vehicle-treated controls (VEH: 10.6 ± 0.4%; LOR 1: 7.6 ± 1.2%; LOR 2: 5.4 ± 0.6%). Measurement of body composition using quantitative magnetic resonance (QMR) imaging indicated this change was due to the selective reduction in body fat mass. Modest effects on food intake were recorded. At the completion of the treatment phase, echocardiography revealed no evidence for valvulopathy, that is, no aortic or mitral valve regurgitation. The pharmacokinetics of the present treatment regimen was determined over a 7-day treatment period; plasma Cmin and Cmax were in the range 13–160 ng/mL (1 mg/kg b.i.d.) and 34–264 ng/mL (2 mg/kg b.i.d.) with no evidence for drug accumulation. In sum, these studies show an effect of lorcaserin in the DIO model, that in the context of the primary endpoint measure of % body weight change was similar to that reported clinically (i.e., 3.0–5.2% vs. 3.2%). The present studies highlight the translational value of obesity models such as DIO, and suggest that assuming consideration is paid to nonspecific drug effects such as malaise, the DIO model has reasonable forward translational value to help predict clinical outcomes of a new chemical entity.
A major challenge of decision-making
research in recent years has been to develop models of poor decision-making to identify its neural bases. Toward this goal, we developed a Rat Gambling Task that discerns good and poor decision-makers in a complex and conflicting situation such as the human Iowa Gambling Task. Nothing is known about the role of the monoaminergic modulatory systems in shaping these phenotypes. Moreover, functional and temporal contributions of brain areas during poor compared to good decision-making remains elusive. Good and poor decision-makers were identified in the Rat Gambling Task. We investigated neurobiological correlates of decision-making capacities in (1) dopamine and serotonin turnovers using post-mortem tissue measurements, (2) the neural circuits differentially recruited during decision-making within the prefronto-subcortical network using cellular Fos immunodetection. Imbalance in monoamine metabolism was revealed in poor decision-makers, i.e. a higher infralimbic vs. lower amygdala serotonergic metabolism. Moreover, good decision-making recruited a wide prefronto-subcortical network but once good choices had been made, a disengagement of key prefrontal areas (insular and infralimbic cortices notably) and the amygdala was observed. By contrast, poor decision-making was associated with a strikingly low recruitment of the prefronto-subcortical network, together with sustained amygdala activity. Our results identify two complementary neurobiological substrates characterizing poor decision-makers: imbalanced monoaminergic systems at rest, congruent with their previously identified complex behavioral phenotype, and an aberrant low recruitment of key brain areas for executive functions and affective valence during the process of decision-making. These biomarkers could sustain vulnerability to developing poor decision-making related disorders.
Research of 5-HT2c receptors stretches back twenty-five years, and while much of it has been productive, the past decade of research has been extraordinary in terms of both amount produced and insights gained. It is hardly surprising that 5-HT2c receptor research has grown so fruitful, given that it is a prominent central serotonin receptor subtype widely expressed within the central and the peripheral nervous system and is thought to play a major role in the regulation of numerous behaviors. It has further been shown by experimental and clinical observation that it may represent a possible therapeutic target for the development of drugs for a range of central nervous system disorders. The time, therefore, is more than appropriate to offer the first ever overview of the research of 5-HT2c receptors. Part of the popular and important series, “The Receptors,” The 5-HT2c Receptor provides a thorough update of the functional status of the 5-HT2c receptor. It covers the molecular, cellular, anatomical, biochemical and behavioral aspects of this receptor so as to highlight its distinctive regulatory properties and the emerging functional significance of constitutive activity and RNA-editing in vivo. In addition, the book investigates the receptors’ therapeutic potential in a range of different diseases, treated individually in separate chapters, including depression, drug abuse, schizophrenia, eating disorders, Parkinson’s disease, Prader-Willi Syndrome, Alzheimer’s disease and epilepsy. While not exhaustive, this text is a vital tool in understanding the past and inspiring the future of interdisciplinary research on the 5-HT2c receptor.
The prefrontal cortex (PFC) is enriched in several serotonin receptors, including 5-HT1A-R, 5-HT2A-R, and 5-HT3-R. These receptors modulate PFC activity due to their expression in large neuronal populations (5-HT1A-R, 5-HT2A-R) or in selected GABAergic populations (5-HT3-R). They are also relevant for antidepressant and antipsychotic drug action. Less is known about the localization of 5-HT2C-R, for which atypical antipsychotics show high affinity. Here, we report on the cellular distribution of 5-HT2C-R in rat PFC and striatum, using double in situ hybridization histochemistry. In PFC, 5-HT2C-R are expressed in pyramidal (VGLUT1-positive) and GABAergic (GAD-positive) neurons, including parvalbumin-positive neurons.
There is a marked dorso-ventral gradient in the proportion of VGLUT1-positive cells expressing 5-HT2C-R (9% in the cingulate cortex, 61% in the tenia tecta and 66% in the piriform cortex), less marked for GABAergic neurons
(13–27%). There is also a laminar gradient, with more cells expressing 5-HT2C-R in deep (V–VI) than in intermediate (II–III) layers. In common with 5-HT3-R, layer I GABAergic cells express 5-HT2C-R. The proportion of 5-HT2C-R-expressing striatal neurons was 23% (dorsolateral caudate-putamen), 37% (ventromedial caudate-putamen), 53% (nucleus accumbens-core),
and 49% (nucleus accumbens-shell). These results help to better understand the serotonergic modulation of PFC-based networks,
including basal ganglia circuits, and atypical antipsychotic drug action.
Cariprazine (RCH-188, MP-214, Vroylor™) is a new dopa-mine receptor ligond developed for the treatment of sev-eral neuropsychiatric diseases including schizophrenia and bipolar disorders. Cariprazine displays higher affinity at dopamine D3 receptors and a similar affinity at D2 and 5-HT2b receptors. At variance with some atypical anti-psychotics, its affinity at 5-HT1A 5-HT2A and histamine Hi receptors is modest compared with its three main tar-gets. Cariprazine could correspond to a biased agonist at dopamine receptors; displaying either antagonist or par-tial agonist properties depending on the signaling path-ways linked to D2/D3 receptors. The compound crosses the blood-brain barrier; as revealed by positron emission tomography and pharmacokinetic studies in various spe-cies. Two main metabolites result mainly from the activity of CYP34A and display properties similar to those of the parent drug. Behavioral data report that cariprazine is efficacious in animal models addressing positivenegative and cognitive symptoms of schizophrenia with no extrapy-ramidal side effects. In September 2015, the FDA approved the use of cariprazine for the treatment of schizophrenia and type I bipolar disorder. The efficacy of cariprazine in other neuropsychiatric diseases is currently being evaluated in preclinical and clinical studies. Side effects have been observed in humans, including extrapyramidal side effects and akathisia of mild to moderate intensity. Copyright © 2016 prous science S.A.U. or its licensors. All right reserved.
Tardive dyskinesia (TD), a movement disorder produced by long-term treatment with a classical antipsychotic drug, is generally considered to be a disorder of dopamine (DA) systems, since classical antipsychotics are potent DA D-2 receptor blockers. Also, acute DA D-1 agonist treatment of rats is known to produce vacuous chewing movements (VCMs), a behavioral feature resembling the oral dyskinesia that is so prominent in most instances of TD. In this paper we outline a series of studies in a new animal model of TD in which DA D, receptor supersensitivity was produced by neonatal 6-hydroxydopamine (6-OHDA) -induced destruction of nigrostriatal DA fibers. In rats so-lesioned 5-HT receptor supersensitivity is additionally produced, and in fact 5-HT receptor antagonists attenuate enhanced DA D, induction of VCMs. Moreover, in 6-OHDA-lesioned rats treated with haloperidol for one year, there is a 2-fold increase in numbers of VCMs (versus intact rats treated with haloperidol); and this high frequency of VCMs persists for more than 6 months after discontinuing haloperidol treatment. During this stage, 5-HT2 receptor antagonists, but not DA D-1 receptor antagonists, attenuate the incidence of VCMs. This series of findings implicates the 5-HT neuronal phenotype in TD, and promotes 5-HT2 receptor antagonists, more specifically 5-HT2C receptor antagonists, as a rational treatment approach for TD in humans.
The anticonvulsant mood stabilizers valproic acid (250, 500 but not 50 mg/kg) and carbamazepine (6, 12.5 but not 3 mg/kg) were found to increase extracellular dopamine levels in rat medial prefrontal cortex, but not nucleus accumbens. Increased prefrontal dopamine was completely abolished by the selective 5-HT1A receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexa necarboxamide (WAY100635, 0.05 mg/kg). Anticonvulsants and clozapine may share a common mood stabilizing mechanism since clozapine is reported to have mood stabilizing effects and increase prefrontal dopamine by 5-HT1A receptor activation.
Selective activation of 5-HT1 receptors has been shown to produce near to full suppression of L-DOPA-induced dyskinesia (LID) in animal models of Parkinson's disease; however, a reduction of the therapeutic effect of L-DOPA has been reported in several studies. Conversely, we recently found that increasing the serotonergic tone with chronic administration of the serotonin precursor 5-hydroxy-tryptophan (5-HTP) can reduce LID in 6-OHDA-lesioned rats, without affecting L-DOPA efficacy. To directly compare the effects of selective versus non-selective serotonin receptor activation, here we first tested different acute doses of the 5-HT1A/1B receptor agonist eltoprazine and 5-HTP on LID in order to identify doses of the individual compounds showing similar anti-dyskinetic efficacy in L-DOPA-primed dyskinetic rats. About 50% reduction of LID was observed with 0.1mg/kg and 24mg/kg of eltoprazine and 5-HTP, respectively; we then compared the effect of the two drugs, individually and in combination, on L-DOPA-induced stepping test in L-DOPA-naïve parkinsonian animals and LID over three weeks of L-DOPA treatment. Results showed that eltoprazine induced significant worsening of L-DOPA-mediated performance in the stepping test, while 5-HTP did not. Interestingly, combination of 5-HTP with eltoprazine prevented the reduction in the forelimb use induced by eltoprazine. Moreover, 5-HTP and eltoprazine given individually showed similar efficacy also upon chronic treatment, and had additive effect in dampening the appearance of LID when given in combination. Finally, chronic administration of eltoprazine and/or 5-HTP did not affect striatal serotonin innervation, compared to L-DOPA alone, as measured by serotonin transporter expression.
Copyright © 2015. Published by Elsevier B.V.
Rewards are crucial objects that induce learning, approach behavior, choices, and emotions. Whereas emotions are difficult to investigate in animals, the learning function is mediated by neuronal reward prediction error signals which implement basic constructs of reinforcement learning theory. These signals are found in dopamine neurons, which emit a global reward signal to striatum and frontal cortex, and in specific neurons in striatum, amygdala, and frontal cortex projecting to select neuronal populations. The approach and choice functions involve subjective value, which is objectively assessed by behavioral choices eliciting internal, subjective reward preferences. Utility is the formal mathematical characterization of subjective value and a prime decision variable in economic choice theory. It is coded as utility prediction error by phasic dopamine responses. Utility can incorporate various influences, including risk, delay, effort, and social interaction. Appropriate for formal decision mechanisms, rewards are coded as object value, action value, difference value, and chosen value by specific neurons. Although all reward, reinforcement, and decision variables are theoretical constructs, their neuronal signals constitute measurable physical implementations and as such confirm the validity of these concepts. The neuronal reward signals provide guidance for behavior while constraining the free will to act.
Copyright © 2015 the American Physiological Society.
INCOMING serotonergic fibers are known to make direct synaptic contact with dopamine-containing neurones in the substantia nigra pars compacta (SNc). However, the effects of 5-HT (5-hydroxytryptamine) on these cells have not been thoroughly investigated. In the present study we show that application of 10-50-mu-M 5-HT increases the firing frequency of SNc neurones in-vitro, and produces inward rectification in a voltage region negative to -50mV. This effect is sensitive to extracellular Cs+, but not to Ba2+, and has similar properties as the intrinsic inward rectifier current, I(h). Antagonists of the 5-HT1A and 5-HT2 receptors were inefficacious. It is concluded that 5-HT excites SNc neurones via an enhancement of the conductance underlying I(h).
Agomelatine is a new antidepressant that is a potent agonist of melatonin receptors and an antagonist of the serotonin 5-HT2C receptor subtype. It is in late-phase trials for the treatment of major depressive disorder (MDD). Symptoms of depression significantly improved with agomelatine compared with placebo in large placebo-controlled trials, and agomelatine appears to be as efficacious in treating MDD as other antidepressants but with fewer adverse effects. Agomelatine appears to improve sleep quality and ease of falling asleep, as measured subjectively in depressed patients. Polysomnographic studies have shown that agomelatine decreases sleep latency, decreases wake after sleep onset (WASO), and improves sleep stability as measured by changes in the cyclic alternating pattern.
Agomelatine is generally well tolerated in patients with MDD; in clinical trials, adverse events were generally mild to moderate in nature, with an overall frequency close to that of placebo. Discontinuation of agomelatine because of adverse effects occurred at a similar rate to placebo.
The prefrontal cortex plays a key role in the control of higher brain functions and is involved in the pathophysiology and treatment of schizophrenia. Here we report that ∼60% of the neurons in rat and mouse prefrontal cortex express 5-HT1A and/or 5-HT2A receptor mRNAs, which are highly co-localized (∼80%). The electrical stimulation of the dorsal and median raphe nuclei elicited 5-HT1A-mediated inhibitions and 5-HT2A-mediated excitations in identified pyramidal neurons recorded extracellularly in rat medial prefrontal cortex (mPFC). Opposite responses in the same pyramidal neuron could be evoked by stimulating the raphe nuclei at different coordinates, suggesting a precise connectivity between 5-HT neuronal subgroups and 5-HT1A and 5-HT2A receptors in pyramidal neurons. Microdialysis experiments showed that the increase in local 5-HT release evoked by the activation of 5-HT2A receptors in mPFC by DOI (5-HT2A/2C receptor agonist) was reversed by co-perfusion of 5-HT1A agonists. This inhibitory effect was antagonized by WAY-100635 and the prior inactivation of 5-HT1A receptors in rats and was absent in mice lacking 5-HT1A receptors. These observations help to clarify the interactions between the mPFC and the raphe nuclei, two key areas in psychiatric illnesses and improve our understanding of the action of atypical antipsychotics, acting through these 5-HT receptors.
This study was designed to investigate the therapeutic approaches and prognosis for cervical cancer associated with pregnancy. Clinical information, therapeutic strategies, and follow-up results of 20 patients with cervical cancer associated with pregnancy from Jan. 2000 to June 2009 in the Zhejiang Cancer Hospital were retrospectively analyzed. The International Federation of Gynecology and Obstetrics (FIGO) stages were: in situ n=1), stage IA1 n=1), stage IB1 n=5), stage IB2 n=1), stage IIA n=8), stage IIB n=3), and stage IIIB n=1). Eight patients were in the first trimester of pregnancy, four in the second, two in the third, and six at postpartum when diagnosed. The therapeutic strategies were either single or combined modalities, including surgery, radiotherapy, and chemotherapy. Fourteen patients survived, five patients died (four of remote metastasis and one of uremia), and one patient was lost to follow-up. One newborn from a patient at stage IIA carcinoma in the third trimester with postponed therapy six weeks after diagnosis survived. Retarded fetal growth was observed in one patient receiving neoadjuvant chemotherapy and cesarean section. Out of the six postpartum patients, three underwent cesarean section and survived, whereas only one out of the three who underwent vaginal delivery survived. The remaining two died of remote metastasis. Therefore, personalized treatment is necessary for cervical cancer associated with pregnancy. Cervical cancer patients in the third trimester of pregnancy can continue the pregnancy for a short period of time. There may be potential risk for the fetus by chemotherapy during pregnancy. Cesarean section is the preferred mode of delivery for pregnant cervical cancer patients.
概要
目的 探讨妊娠相关性宫颈癌合适的治疗方式, 包括维持妊娠、针对肿瘤的治疗、分娩方式, 以及预后。 创新点 在发展中国家对妊娠相关性宫颈癌治疗和分娩方式的选择, 以及相关预后。 方法 回顾性分析2000 年到2009 年浙江省肿瘤医院收治的20 例妊娠相关性宫颈癌患者的临床资料、治疗方案及随访结果。 结论 妊娠中晚期患者可选择在短期内继续妊娠; 新辅助化疗对胎儿可能有影响; 对合并宫颈癌的患者, 剖宫产术是较阴道分娩更合适的方式。
The neurotransmitter 5-hydroxytryptamine (5-HT; serotonin) has long been associated with the control of a variety of motivated behaviors, including feeding. Much of the evidence linking 5-HT and feeding behavior was obtained from studies of the effects of the 5-HT releaser (dex)fenfluramine in laboratory animals and humans. Recently, the selective 5-HT2C receptor agonist lorcaserin received FDA approval for the treatment of obesity. This review examines evidence to support the use of selective 5-HT2C receptor agonists as treatments for conditions beyond obesity, including substance abuse (particularly nicotine, psychostimulant, and alcohol dependence), obsessive compulsive, and excessive gambling disorder. Following a brief survey of the early literature supporting a role for 5-HT in modulating food and drug reinforcement, we propose that intrinsic differences between SSRI and serotonin releasers may have underestimated the value of serotonin-based pharmacotherapeutics to treat clinical forms of addictive behavior beyond obesity. We then highlight the critical involvement of the 5-HT2C receptor in mediating the effect of (dex)fenfluramine on feeding and body weight gain and the evidence that 5-HT2C receptor agonists reduce measures of drug reward and impulsivity. A recent report of lorcaserin efficacy in a smoking cessation trial further strengthens the idea that 5-HT2C receptor agonists may have potential as a treatment for addiction. This review was prepared as a contribution to the proceedings of the 11th International Society for Serotonin Research Meeting held in Hermanus, South Africa, July 9-12, 2014.
The serotonin-6 (5-HT6) receptor is the most recently discovered serotonin receptor, and it represents an increasingly promising target for improving cognition in both normal and disease states. Recently, a new selective 5-HT6 receptor agonist, 2-(5 chloro-2-methyl-1H-indol-3-yl)-N,N-dimethylethanamine (ST1936), with nanomolar affinity for 5-HT6 receptors was described. We performed in-vivo electrophysiological studies to investigate the physiological role of 5-HT6 receptors in the control of the function of the substantia nigra pars compacta (SNc) and ventral tegmental area (VTA). Extracellular single-unit recordings were performed from putative dopamine-containing neurons in the SNc and VTA of anesthetised rats. In the SNc, acute systemic administration of ST1936 had no effects on basal firing activity of these dopamine neurons; however, in the VTA, ST1936 induced either dose-related increases (45% of cells) or decreases in basal activity of these dopaminergic neurons. Local application of ST1936 into the VTA caused excitation in all of the dopamine neurons, but had no effects on non-dopamine VTA neurons. Both effects of systemic and microiontophoretic ST1936 were completely reversed by the potent and selective 5-HT6 receptor antagonist 5-chloro-N-(4-methoxy-3-piperazin-1-ylphenyl)-3-methyl-2- benzothiophene-sulfonamide (SB271046). Systemic application of another 5-HT6 agonist, 2-(1-{6-chloroimidazo[2,1-b] [1,3]thiazole-5-sulfonyl}-1H-indol-3-yl)ethan-1-amine (WAY-181187), induced dose-dependent inhibition of these VTA dopaminergic neurons. ST1936 and WAY-181187 appear to have different effects on these VTA dopaminergic neurons, potentially due to different mechanisms of action or to the complexity of 5-HT6 receptor functions. Our data demonstrate the need for further investigations into the use of 5-HT6 receptor agonists to control cognitive disfunction, such as in schizophrenia and depression.
© The Author(s) 2015.
Objective:
To investigate the frequency of major depression (MD) and the severity of depressive symptoms among patients with Parkinson's disease (PD).Design:
The PD population was derived from a community-based prevalence study. Total case ascertainment and a high diagnostic accuracy of PD were attempted through a detailed community study and the use of a new clinical diagnostic classification. Major depression was diagnosed according to the criteria in the Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition. The severity of depression in the prevalence population was scored with the Montgomery and Åsberg Depression Rating Scale. The occurrence of depressive symptoms among patients with PD was compared with the occurrence among age-matched groups of patients with diabetes mellitus and of healthy elderly. In addition, the patients with PD and the control groups completed the Beck Depression Inventory.Setting:
Depression among patients with PD derived from a prevalence study in the county of Rogaland, Norway.Patients:
Two hundred forty-five patients with PD. Two age-matched control groups (each including 100 patients); one group included patients with diabetes mellitus and the other, healthy elderly.Results:
Of the 245 patients with PD, 7.7% met the criteria for MD. Based on their Montgomery and Åsberg Depression Rating score, 5.1% of the patients were moderately to severely depressed whereas another 45.5% had mild depressive symptoms. Among the patients who scored 20 or more on the Mini-Mental State Examination, 3.6% had MD compared with 25.6% of the patients with a score below 20. The frequency of patients with a Beck Depression Inventory score of 18 or more was higher in the PD group (24.1%) than among patients with diabetes mellitus (11%) and the healthy elderly controls (4%).Conclusion:
This study suggests that the prevalence of MD in PD is lower than previously assumed, but a substantial proportion of patients with PD have less severe depressive symptoms.
G protein-coupled receptors (GPCR) are a prominent class of plasma membrane proteins that regulate physiological responses to a wide variety of stimuli and therapeutic agents. While GPCR oligomerization has been studied extensively in recombinant cells, it remains uncertain whether native receptors expressed in their natural cellular environment are monomers, dimers or oligomers. The goal of this study was to determine the monomer/oligomer status of a native GPCR endogenously expressed in its natural cellular environment. Native 5-HT2C receptors in choroid plexus epithelial cells were evaluated using fluorescence correlation spectroscopy (FCS) with photon counting histogram (PCH). An anti-5HT2C fragment antigen binding protein was used to label native 5-HT2C receptors. A known monomeric receptor (CD-86) served as a control for decoding the oligomer status of native 5-HT2C receptors by molecular brightness analysis. FCS with PCH revealed molecular brightness values for native 5-HT2C receptors equivalent to the molecular brightness of a homodimer. 5-HT2C receptors displayed a diffusion coefficient of 5 x 10(-9) cm(2)/s and were expressed at 32 receptors/um(2) on the apical surface of choroid plexus epithelial cells. The functional significance and signaling capabilities of the homodimer were investigated in HEK293 cells using agonists that bind in a wash-resistant manner to one or both protomers of the homodimer. While agonist binding to one protomer resulted in G-protein activation, maximal stimulation required occupancy of both protomers. This study demonstrates, for the first time, the homodimeric structure of 5-HT2C receptors endogenously expressed in their native cellular environment and identifies the homodimer as a functional signaling unit.
The American Society for Pharmacology and Experimental Therapeutics.
Cocaine exhibits prominent abuse liability, and chronic abuse can result in cocaine use disorder with significant morbidity. Major advances have been made in delineating neurobiological mechanisms of cocaine abuse; however, effective medications to treat cocaine use disorder remain to be discovered. The present review will focus on the role of serotonin (5-HT; 5-hydroxytryptamine) neurotransmission in the neuropharmacology of cocaine and related abused stimulants. Extensive research suggests that the primary contribution of 5-HT to cocaine addiction is a consequence of interactions with dopamine (DA) neurotransmission. The literature on the neurobiological and behavioral effects of cocaine is well developed, so the focus of the review will be on cocaine with inferences made about other monoamine uptake inhibitors and releasers based on mechanistic considerations. 5-HT receptors are widely expressed throughout the brain, and several different 5-HT receptor subtypes have been implicated in mediating the effects of endogenous 5-HT on DA. However, the 5-HT2A and 5-HT2C receptors in particular have been implicated as likely candidates for mediating the influence of 5-HT in cocaine abuse as well as to traits (e.g., impulsivity) that contribute to the development of cocaine use disorder and relapse in humans. Lastly, new approaches are proposed to guide targeted development of serotonergic ligands for the treatment of cocaine use disorder.
Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.
The serotonin2C receptor (5-HT2CR) is known to control dopamine (DA) neuron function by modulating DA neuronal firing and DA exocytosis at terminals. Recent studies assessing the influence of 5-HT2CRs on cocaine-induced neurochemical and behavioral responses have shown that 5-HT2CRs can also modulate mesoaccumbens DA pathway activity at post-synaptic level, by controlling DA transmission in the nucleus accumbens (NAc), independently of DA release itself. A similar mechanism has been proposed to occur at the level of the nigrostriatal DA system. Here, using in vivo microdialysis in freely moving rats and molecular approaches, we assessed this hypothesis by studying the influence of the 5-HT2CR agonist Ro 60-0175 on cocaine-induced responses in the striatum. The intraperitoneal (i.p.) administration of 1 mg/kg Ro 60-0175 had no effect on the increase in striatal DA outflow induced by cocaine (15 mg/kg, i.p.). Conversely, Ro 60-0175 inhibited cocaine-induced Fos immunoreactivity and phosphorylation of the DA and c-AMP regulated phosphoprotein of Mr 32 kDa (DARPP-32) at threonine 75 residue in the striatum. Finally, the suppressant effect of Ro 60-0175 on cocaine-induced DARPP-32 phosphorylation was reversed by the selective 5-HT2CR antagonist SB 242084 (0.5 mg/kg, i.p.). In keeping with the key role of DARPP-32 in DA neurotransmission, our results demonstrate that 5-HT2CRs are capable of modulating nigrostriatal DA pathway activity at post-synaptic level, by specifically controlling DA signaling in the striatum.
Copyright © 2014 Elsevier Ltd. All rights reserved.
Levodopa replacement therapy has long provided the most effective treatment for Parkinson's disease (PD). We review how this dopamine (DA) precursor enhances dopaminergic transmission by providing a greater sphere of neurotransmitter influence as a result of the confluence of increased quantal size and decreased DA reuptake, as well as loading DA as a false transmitter into surviving serotonin neuron synaptic vesicles. We further review literature on how presynaptic dysregulation of DA release after l-dopa might trigger dyskinesias in PD patients. © 2014 International Parkinson and Movement Disorder Society
L-dopa is the precursor to dopamine and has become the mainstay therapeutic treatment for Parkinson's disease (PD). Chronic L-dopa is administered to recover motor function in PD patients. However, drug efficacy decreases over time and debilitating side effects such as dyskinesia and mood disturbances occur. The therapeutic effect and some of the side effects of L-dopa have been credited to its effect on serotonin (5-HT) neurons. Given these findings, it was hypothesized that chronic L-dopa treatment decreases 5-HT neurons in the dorsal raphe nucleus (DRN) and the content of 5-HT in forebrain regions in a manner that is mediated by oxidative stress. Rats were treated chronically with L-dopa (6 mg/kg; twice daily) for 10 days. Results indicated that the number of 5-HT neurons was significantly decreased in the DRN after L-dopa treatment compared to vehicle. This effect was more pronounced in the caudal-extent of the dorsal DRN, a sub-region found to have a significantly higher increase in DOPAC/DA ratio in response to acute L-dopa treatment. Furthermore, pretreatment with ascorbic acid (400 mg/kg) or deprenyl (2 mg/kg), prevented the L-dopa induced decreases in 5-HT neurons. In addition, 5-HT content was decreased significantly in the DRN and prefrontal cortex by L-dopa treatment, effects that were prevented by ascorbic acid pretreatment. Taken together, these data illustrate that chronic L-dopa causes a 5-HT neuron loss and the depletion of 5-HT content in a sub-region of the DRN and as well as the frontal cortex through an oxidative-stress mechanism.
Serotonin is a neuromodulator that is involved extensively in behavioral, affective, and cognitive functions in the brain. Previous recording studies of the midbrain dorsal raphe nucleus (DRN) revealed that the activation of putative serotonin neurons correlates with the levels of behavioral arousal [1], rhythmic motor outputs [2], salient sensory stimuli [3-6], reward, and conditioned cues [5-8]. The classic theory on serotonin states that it opposes dopamine and inhibits behaviors when aversive events are predicted [9-14]. However, the therapeutic effects of serotonin signal-enhancing medications have been difficult to reconcile with this theory [15, 16]. In contrast, a more recent theory states that serotonin facilitates long-term optimal behaviors and suppresses impulsive behaviors [17-21]. To test these theories, we developed optogenetic mice that selectively express channelrhodopsin in serotonin neurons and tested how the activation of serotonergic neurons in the DRN affects animal behavior during a delayed reward task. The activation of serotonin neurons reduced the premature cessation of waiting for conditioned cues and food rewards. In reward omission trials, serotonin neuron stimulation prolonged the time animals spent waiting. This effect was observed specifically when the animal was engaged in deciding whether to keep waiting and was not due to motor inhibition. Control experiments showed that the prolonged waiting times observed with optogenetic stimulation were not due to behavioral inhibition or the reinforcing effects of serotonergic activation. These results show, for the first time, that the timed activation of serotonin neurons during waiting promotes animals' patience to wait for a delayed reward.