5-HT2C Agonist Research Articles

The Activation of Peripheral 5-HT1A Receptors Can Inhibit Seminal Vesicle Contraction: An In Vivo Animal Study

To elucidate the differential effects of stimulating various peripheral 5-HT receptor subtypes on the contractile response of seminal vesicles (SVs) induced by electrical stimulation (ES). Male Wistar rats (aged 12-14 weeks) were prepared as our previously established model, which allows an intraarterial injection of test agents to directly act on SV. Four selective 5-HT agonists-8-OH-DPAT (5-HT1A), 5-nonyloxytryptamine (5-HT1B), BW723C86 (5-HT2B), and MK-212 (5-HT2C)-were injected at various concentrations (from 10(-8) to 10(-4) mmol/kg). After an injection, the SV contractile response was recorded after ES of lesser splanchnic nerve was applied. Relationships between the concentration of an agonist and its effect on SV contraction were plotted and analyzed. The peripheral injection of 5-HT1A agonist had a dose-dependent inhibitory effect on SV contraction and could achieve an inhibition of >50%; the IC50 was 3.16x10(-6) mmol/kg. No significant effects were observed with the peripheral injection of 5-HT1B, 5-HT2B, or 5-HT2C agonist. Our in vivo animal study shows that the activation of peripheral 5-HT1A receptors can inhibit ES-induced SV contraction, whereas the activation of peripheral 5-HT1B, 5-HT2B, or 5-HT2C receptors has no significant effect. The results suggest that the peripheral 5-HT pathway is a potential therapeutic target of the treatment for premature ejaculation.

Altered 5-HT2C receptor agonist-induced responses and 5-HT2C receptor RNA editing in the amygdala of serotonin transporter knockout mice

BackgroundThe serotonin 5-HT2C receptor (5-HT2CR) is expressed in amygdala, a region involved in anxiety and fear responses and implicated in the pathogenesis of several psychiatric disorders such as acute anxiety and post traumatic stress disorder. In humans and in rodent models, there is evidence of both anxiogenic and anxiolytic actions of 5-HT2C ligands. In this study, we determined the responsiveness of 5-HT2CR in serotonin transporter (SERT) knockout (-/-) mice, a model characterized by increased anxiety-like and stress-responsive behaviors.ResultsIn the three-chamber social interaction test, the 5-HT2B/2C agonist mCPP decreased sociability and sniffing in SERT wildtype (+/+) mice, both indicative of the well-documented anxiogenic effect of mCPP. This 5-HT2C-mediated response was absent in SERT -/- mice. Likewise, in the open field test, the selective 5-HT2C agonist RO 60-0175 induced an anxiogenic response in SERT +/+ mice, but not in SERT -/- mice. Since 5-HT2CR pre-mRNA is adenosine-to-inosine (A-to-I) edited, we also evaluated the 5-HT2CR RNA editing profiles of SERT +/+ and SERT -/- mice in amygdala. Compared to SERT +/+ mice, SERT-/- mice showed a decrease in less edited, highly functional 5-HT2C isoforms, and an increase in more edited isoforms with reduced signaling efficiency.ConclusionsThese results indicate that the 5-HT2CR in the amygdala of SERT -/- mice has increased RNA editing, which could explain, at least in part, the decreased behavioral responses to 5-HT2C agonists in SERT -/- mice. These alterations in 5-HT2CR in amygdala may be relevant to humans with SERT polymorphisms that alter SERT expression, function, and emotional behaviors.

The effects of the 5-HT2C agonist m-chlorophenylpiperazine on elite athletes with unexplained underperformance syndrome (overtraining)

The effects of the 5-HT2C agonist m-chlorophenylpiperazine on elite athletes with unexplained underperformance syndrome (overtraining)

Current and future drug targets in weight management.

Obesity will continue to be one of the leading causes of chronic disease unless the ongoing rise in the prevalence of this condition is reversed. Accumulating morbidity figures and a shortage of effective drugs have generated substantial research activity with several molecular targets being investigated. However, pharmacological modulation of body weight is extremely complex, since it is essentially a battle against one of the strongest human instincts and highly efficient mechanisms of energy uptake and storage. This review provides an overview of the different molecular strategies intended to lower body weight or adipose tissue mass. Weight-loss drugs in development include molecules intended to reduce the absorption of lipids from the GI tract, various ways to limit food intake, and compounds that increase energy expenditure or reduce adipose tissue size. A number of new preparations, including combinations of the existing drugs topiramate plus phentermine, bupropion plus naltrexone, and the selective 5-HT2C agonist lorcaserin have recently been filed for approval. Behind these leading candidates are several other potentially promising compounds and combinations currently undergoing phase II and III testing. Some interesting targets further on the horizon are also discussed.

New horizons for selective 5-HT2C receptor ligands in psychiatric/neurological disorders.

The serotonin (5-HT) 5-HT2C receptor is a key contributor to obesity, autism, psychiatric (eg, depression, schizophrenia), and neurological diseases (eg, Parkinson's disease). The diversity and regulation of the 5-HT2C receptor signaling pathways are complex and provocatively suggest the importance of this receptor in an array of functions and indications. Therapeutic opportunities for both agonist and antagonist compounds that engage this receptor continue to emerge. The most advanced 5-HT2C receptor agonist in development is lorcaserin, which has completed phase III clinical trials and has submitted an NDA for the treatment of obesity (Pauli and Abdelghany, 2010). In a 12-week obesity trial, approximately 30% of patients at 10 mg b.i.d. showed >5% weight loss with lorcaserin with minimal adverse events. Earlier in development is another 5-HT2C receptor agonist vabicaserin for the treatment of psychiatric indications. Vabicaserin is a highly selective 5-HT2C agonist (Dunlop et al, 2010) with a strong preclinical profile supporting multiple indications. Despite initial concerns regarding potential cardiovascular liabilities, selective 5-HT2C agonists are proving to be devoid of these concerning side effects (Pauli and Abdelghany, 2010). Many different genetically modified animals have been created to improve understanding of the 5-HT2C receptor. Much of the early work focused on the 5-HT2C receptor knockout mouse that showed a hyperphagic obesity phenotype. However, the 5-HT2C receptor is subject to RNA editing leading to different forms of the receptor that are more (unedited) or less (fully edited) sensitive to the functional effects of 5-HT2C agonists. Therefore, more recently, transgenic animals have been developed that lock the 5-HT2C receptor into a fully edited (VGV) or an unedited (INI) isoform. Interestingly, animals locked into the fully edited VGV form of the receptor show failure to thrive, neonatal muscular hypotonia, decreased somatic growth, and reduced fat mass despite hyperphagia, characteristics consistent with Prader–Willi syndrome (Kawahara et al, 2008; Morabito et al, 2010). The link between Prader–Willi syndrome and the 5-HT2C receptor has also been made through regulation of the splicing of the 5-HT2C receptor by HBII-52, a small nucleolar RNA that affects 5-HT2C receptor function (Kishore and Stam, 2006). Patients with Prader–Willi syndrome do not express HBII-52 that regulates alternative splicing of the 5-HT2C receptor by binding to a silencing element in exon Vb (Kishore and Stam, 2006). Moreover, these VGV mice have reduced G-protein-coupling efficiency and agonist binding but show enhanced behavioral sensitivity and serotonergic neurotransmission due to increased cell-surface expression of the 5-HT2C receptor (Kawahara et al, 2008; Olaghere da Silva et al, 2010). Interestingly, both the nonedited INI mice and the fully edited VGV mice show anxiety-like phenotypes with the INI mice showing a depressant-like phenotype and the VGV mice showing an antidepressant-like phenotype (Mombereau et al, 2010). Taken together, these transgenic models continue to show the complexity of the regulation of this receptor and the corresponding complexity of phenotypes. The multitude of ways that the 5-HT2C receptor is regulated through different signaling pathways, RNA editing, and changes in receptor expression coupled with its involvement in multiple psychiatric and neurological illness place this receptor as a critical player in the understanding of CNS disorders.

Novel 6,7,8,9-tetrahydro-5H-1,4,7,10a-tetraaza-cyclohepta[f]indene analogues as potent and selective 5-HT2C agonists for the treatment of metabolic disorders

The discovery of a novel series of 5-HT2C agonists based on a tricyclic pyrazolopyrimidine scaffold is described. Compounds with good levels of in vitro potency and moderate to good levels of selectivity with respect to the 5-HT2A and 5-HT2B receptors were identified. One of the analogues (7g) was found to be efficacious in a sub-chronic weight loss model. A key limitation of the series of compounds was that they were found to be potent inhibitors of the hERG ion channel. Some compounds, bearing polar side chains were identified which showed a much reduced hERG liability however these compounds were sub-optimal in terms of their in vitro potency or selectivity.

Evidence that the reward attenuating effect of the D1-like antagonist, SCH-23390, is not mediated by its agonist action at the 5-HT2c receptors

This study investigated the effect of the 5-HT2c receptor antagonist, SB-242,084, on the attenuation of brain stimulation reward by SCH-23390. An additional experiment determined the effectiveness of SB-242,084 at blocking the reward attenuating effect of 5-HT2c agonist, CP-809,101. Results show that SB-242,084 blocked the reward attenuating effect of CP-809,101 but failed to alter that of SCH-23390. These findings provide evidence that the agonist action of SCH-23390 at the 5-HT2c receptors does not contribute to its attenuating effect on reward.

Progressos recentes e novas perspectivas em farmacoterapia da obesidade

Obesity prevalence has risen dramatically over the past decades, which poses a great number of patients at risk of metabolic and cardiovascular complications. Long-term efficacy of lifestyle modification isolated has shown to be modest which, therefore, urges the need of more aggressive interventions such as adjuvant pharmacotherapy or the more radical surgical approach. Bariatric surgery has proven to date to be the most effective treatment, although it may be associated with nutritional and metabolic complications not yet completely recognized. By contrast, there is limited availability of antiobesity agents currently in the market, as well as historical facts involving the suspension of previously existing medications due to safety concerns. This article aims to present recent data on clinical trials of novel weight-loss drugs with short perspective to enter the market, if approved by the regulatory agencies. This review will discuss the efficacy and safety of these compounds, which include lorcaserin (selective serotonin 5-HT2c agonist), tesofensine (triple monoamine reuptake inhibitor), liraglutide (GLP-1 analogue) and cetilistat (gastrointestinal lipase inhibitor), as well as the combination therapies of bupropion/naltrexone, bupropion/zonisamide, phentermine/topiramate and pramlintide/metreleptin.

HTS and rational drug design to generate a class of 5-HT(2C)-selective ligands for possible use in schizophrenia.

Treating neurological conditions: Optimization of a previously identified lead 5-HT2C agonist (left) led to the discovery of a highly selective 5-HT2C agonist (right). Importantly, this compound is a 5-HT2B receptor antagonist. Because of its selective 5-HT2C receptor activity, the compound was further evaluated in the phencyclidine model of disrupted prepulse inhibition, and found to exhibit normalizing effects comparable to those shown by the 5-HT2C agonist vabicaserin, a drug currently in phase II clinical studies for schizophrenia.

Effect of agomelatine and its interaction with the daily corticosterone rhythm on progenitor cell proliferation in the dentate gyrus of the adult rat

Agomelatine, a novel melatonin analogue and anti-depressant that acts as an agonist on melatonin receptors 1 and 2 and as an antagonist at the 5HT2C receptor, was tested for its effects on cell proliferation in the dentate gyrus of the adult rat hippocampus under intact and flattened corticosterone rhythm conditions. Agomelatine stimulated mitosis rates in the intact male rat. Flattening the daily corticosterone rhythm by inserting a subcutaneous pellet of this steroid prevented the action of agomelatine. However, adding a daily injection of corticosterone at CT1200 to rats with implanted corticosterone pellets failed to restore agomelatine’s efficacy on cell proliferation. The 5HT2C receptor antagonist SB242084 stimulated progenitor cell proliferation in the dentate gyrus, while a 5HT2C agonist (RO600175) had no effect on cell proliferation alone, but counteracted that of agomelatine. These results suggest that agomelatine, a new anti-depressant, can stimulate progenitor cell mitosis in the dentate gyrus. Its action requires an intact diurnal corticosterone rhythm. The action of agomelatine on neurogenesis is likely to reside in its antagonism of the 5HT2C receptor, and suggests a mechanism distinct from that of fluoxetine, another anti-depressant, which, as previous work shows, acts through the 5HT1A receptor, but whose action is also blocked by a flattened corticosterone rhythm.

Sizing Up Pharmacotherapy for Obesity

Obesity has increased over the last 20 years, from a condition affecting only a small portion of populations in developed countries, into a global pandemic.1 The impact of obesity can be appreciated in the context of the populations at risk, and it is estimated that >1 billion adults worldwide are overweight (BMI >25 kg/m2), 300 million of whom are clinically obese (BMI >30 kg/m2).2 In the United States, 65% of adults are overweight, and 32.2% of them are obese, a prevalence that has doubled over 20 years.3 In industrialized countries, obesity rates have tripled, coinciding with adoption of a Western lifestyle.4 Further, the growing worldwide rates of childhood obesity have reached epidemic values in developed countries.5 This global obesity pandemic reflects genetic susceptibility, availability of high-energy foods, and decreased physical activity. Accelerating rates of obesity have profound health and economic consequences. Obesity is associated with a myriad of co-morbidities, including type II diabetes, coronary artery disease, obstructive sleep apnea, stroke, cancer, hypertension, osteoarthritis, and liver and biliary disease which collectively increase mortality.6 Indeed, the health care impact of chronic obesity exceeds that of smoking or alcohol abuse.7 National health care costs of obesity are $70–100 billion, and if this trend continues, in 15 years 20% of health care costs in the United States will be attributed to the chronic diseases associated with obesity.8 Collectively, these considerations underscore the health and economic imperative to develop novel therapeutic approaches to combat obesity and its co-morbidities. In that context, overweight and obese individuals who receive assistance from their health care providers to lose weight are three times more likely to attempt weight loss.9 The most common approach to medical weight management is counseling and lifestyle modification. However, while patients enrolled in these programs initially lose weight, they usually regain 30–35% of their lost weight within one year following treatment, and >50% of patients return to their baseline weight by five years.10, 11 At present, only two drugs, orlistat and sibutramine, are approved for the long-term treatment of obesity. However, due to their inherent cardiovascular and gastrointestinal adverse effects, respectively, these drugs are often only utilized as rescue therapy for patients who fail diet and exercise. The scope of the obesity problem and the absence of available long-term solutions highlights the unmet clinical need for safe and effective pharmacotherapeutics to induce and maintain weight loss.

5-HT2C receptor agonists attenuate pain-related behaviour in a rat model of trigeminal neuropathic pain

Peripheral branches of the trigeminal nerve may be damaged during maxillofacial injury or surgical procedures and trigeminal trauma may induce severe pain that is very challenging to treat. Chronic constriction injury to the infraorbital nerve (ION-CCI) by loose ligatures has proven a useful model for some types of trigeminal neuropathic pain disorder. Using ION-CCI rats, we examined the antiallodynic effects of intrathecally administered agents which are selective for 5-HT2C receptors. Allodynia was evaluated by applying von Frey filaments to skin innervated by the injured ION. Dose-dependent antiallodynic effects followed administration of three 5-HT2C receptor agonists, 6-chloro-2-(1-piperazinyl)-pyrazine (MK212: 10, 30, and 100μg); (S)-2-(chloro-5-fluoro-indol-l-yl)-1-methyamine fumarate (RO 60-0175: 10, 30, and 100μg); (AaR)-8,9-dichloro-2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one (WAY-161503: 10, 30, and 100μg). ED50 values for antiallodynic effects of MK212, RO 60-0175, and WAY-161503 were 39.62, 46.67, and 51.22μg, respectively. Intrathecal administration of the 5-HT2C receptor antagonist, 8-[5-2,4-dimethoxy-5-(4-trifluoromethylphenylsulphonamido)phenyl-5-oxopentyl]-1,3,8-triazaspiro[4,5]decane-2,4-dione (RS-102221: 30μg) did not alter the mechanical threshold. Intrathecal pretreatment with RS-102221 (10 and 30μg) reduced the antiallodynic effects of the highest dose of 5-HT2C agonists. These results indicated that, in this rat model, the 5-HT2C receptor plays a role in spinal inhibition of trigeminal neuropathic pain.

M‐chlorophenylpiperazine (mCPP) attenuates the behavioral‐stimulant effects of cocaine via activation of the 5‐HT2C receptor in nonhuman primates

Serotonin (5‐HT) indirect agonists have been shown to modulate the behavioral and neurochemical effects of cocaine in rodents and nonhuman primates, yet the specific receptors mediating these effects have not been fully elucidated. Recent evidence suggests that these actions may be partially mediated by the 5‐HT2C receptor in rodents, but this has not been systematically tested in nonhuman primates. In the present study, squirrel monkeys (n=3) were trained to lever‐press according to a fixed‐interval 300‐sec schedule of stimulus termination. Administration of cocaine (0.3 – 3.0 mg/kg) resulted in a typical inverted U‐shape dose‐response function with response rate as the dependent measure. Pretreatment with the preferential 5‐HT2C agonist mCPP (0.1 – 0.3 mg/kg) dose‐dependently and insurmountably attenuated the behavioral‐stimulant effects of cocaine, inducing a downward‐shift of the cocaine dose‐response curve. Moreover, the effects of mCPP were dose‐dependently reversed following pretreatment with the selective 5‐HT2C antagonist SB 242084 (0.01 – 0.3 mg/kg). These data are the first to demonstrate a modulatory effect of 5‐HT2C receptor activation on the behavioral effects of cocaine in nonhuman primates and warrant further investigation into the capacity of more selective compounds to alter cocaine's neurochemical and reinforcing effects. Support: F31DA026262, DA12514, DA00517 and RR00165.

Orally active and brain permeable proline amides as highly selective 5HT2c agonists for the treatment of obesity

Brain-penetrable proline amides were developed as 5HT2c agonists with more than 1000-fold binding selectivity against 5HT2b receptor. After medicinal chemistry optimization and SAR studies, orally active proline amides with robust efficacy in a rodent food intake inhibition model were uncovered.

S01-04 - 5-HT2C receptor activation inhibits stress-induced increase in 5-HT transmission: relevance to the effects of antidepressant drugs

Objectives5-HT2C receptors are well known to be involved in anxiety, but their implication in stress-induced changes of 5-HT transmission remained to be investigated. We thus assess the behavioral and neurochemical effects of 5-HT2C receptor activation in naïve and stressed mice, and after chronic paroxetine known to exert anxiolytic effects in humans.Methods and resultsThe effects of the preferential 5-HT2C agonists m-chlorophenylpiperazine (mCPP) and RO60-0175, the selective 5-HT2C receptor antagonist SB242,084 and restraint-stress on anxiety-like behavior in mice were assessed using the social interaction test, while the neurochemical effects of these treatments on 5-HT turnover (5-HIAA/5-HT ratio) and extracellular 5-HT were determined using HPLC and microdialysis. Both mCPP and restraint-stress increased anxiety-like behavior in the social interaction test, and these effects were blocked by pretreatment with SB242,084. Restraint-stress increased 5-HT turnover in various brain areas, and this effect could be prevented by the 5-HT2C receptor agonist RO60-0175. Acute administration of SB242,084 potentiated the stress-induced increase in 5-HT turnover and blocked the inhibitory effect of RO60-0175. Microdialysis studies in frontal cortex revealed that RO60-0175 has an inhibitory effect on the stress-induced increase in extracellular 5-HT levels, but not on basal 5-HT levels. Chronic paroxetine prevented the anxiogenic effect of mCPP and prevented the inhibitory effect of RO60-0175 on restraint-stress-induced increase in 5-HT turnover.ConclusionsThese data strongly suggest that 5-HT2C receptor activation mediates the anxiogenic effect of stress. In addition, the anxiolytic action of long term treatment with SSRIs might be causally related to a clear-cut 5-HT2C receptor desensitization.

Design and synthesis of orally-active and selective azaindane 5HT2c agonist for the treatment of obesity

Based on our original pyrazine hit, CP-0809101, novel conformationally-restricted 5HT2c receptor agonists with 2-piperazin-azaindane scaffold were designed. Synthesis and structure-activity relationship (SAR) studies are described with emphasis on optimization of the selectivity against 5HT2a and 5HT2b receptors with excellent 2c potency. Orally-active and selective compounds were identified with dose-responsive in vivo efficacy in our pre-clinical food intake model.

Design, Synthesis, and Pharmacology of Fluorescently Labeled Analogs of Serotonin: Application to Screening of the 5-HT2C Receptor

Novel fluorescent derivatives of serotonin have been synthesized and used as tracers for the development of a 5-HT2C fluorescence polarization assay. Serotonin analogs that feature a fluorescent probe attached through an ether linkage at the tryptamine 5-position have high affinity for the 5-HT2C receptor, and affinity is dependent on both linker length and pendent dye. These variables have been optimized to generate Cy3B derivative 5a, which has 10-fold higher 5-HT2C affinity relative to serotonin (Kd=0.23 nM). In receptor activation experiments, 5a acts as a full agonist of 5-HT2C. Upon binding to 5-HT2C cell membranes, 5a shows a robust increase in fluorescence polarization (FP) signal. In an FP binding assay using 5a as a tracer ligand, Ki values for known 5-HT2C agonists and antagonists showed excellent agreement with Ki values from radioligand binding (r2=0.93). The FP ligand assay is suitable for high-throughput drug screening applications with respect to speed of analysis, displaceable signal, precision, and sensitivity to various reagents. A 384-well-based high-throughput assay that is rapid, economical, and predictive of test compounds' ability to bind to the 5-HT2C receptor has been compiled and validated.

Selective 5-Hydroxytryptamine 2C Receptor Agonists Derived from the Lead Compound Tranylcypromine: Identification of Drugs with Antidepressant-Like Action

We report here the design, synthesis, and pharmacological properties of a series of compounds related to tranylcypromine (9), which itself was discovered as a lead compound in a high-throughput screening campaign. Starting from 9, which shows modest activity as a 5-HT(2C) agonist, a series of 1-aminomethyl-2-phenylcyclopropanes was investigated as 5-HT(2C) agonists through iterative structural modifications. Key pharmacophore feature of this new class of ligands is a 2-aminomethyl-trans-cyclopropyl side chain attached to a substituted benzene ring. Among the tested compounds, several were potent and efficacious 5-HT(2C) receptor agonists with selectivity over both 5-HT(2A) and 5-HT(2B) receptors in functional assays. The most promising compound is 37, with 120- and 14-fold selectivity over 5-HT(2A) and 5-HT(2B), respectively (EC(50) = 585, 65, and 4.8 nM at the 2A, 2B, and 2C subtypes, respectively). In animal studies, compound 37 (10-60 mg/kg) decreased immobility time in the mouse forced swim test.

Distinct mechanisms involved in serotonin2C agonist- and inverse agonist-induced purposeless oral movements in hemiparkinsonian rats

Event Abstract Back to Event Distinct mechanisms involved in serotonin2C agonist- and inverse agonist-induced purposeless oral movements in hemiparkinsonian rats Philippe D. Deurwaerdere1*, Sylvia Navailles1, Audrey Roumegous1 and Christian Gross1 1 Universite Victor Segalen Bordeaux 2, Laboratoire Mouvement Adaptation Cognition – CNRS UMR5227, France Serotonin2C (5-HT2C) receptors would exert phasic, tonic and constitutive controls in basal ganglia, a group of subcortical structures involved in motor control. The noxious motor responses to 5-HT2C agonists (phasic) are thought to be potentiated in a rat model of Parkinson’s disease whereas no data are available concerning tonic and constitutive controls. Here, we evaluated the different facets of the 5-HT2C transmission (phasic, tonic and constitutive) on purposeless oral movements using the 5-HT2C agonist Ro-60-0175 (0.1-3 mg/kg), the 5-HT2C inverse agonist SB-206553 (1-20 mg/kg) and the antagonist SB 243213 (1-10 mg/kg) in naive rats or in rats bearing a unilateral lesion of dopaminergic neurons with 6-hydroxydopamine (6-OHDA). In naïve rats, SB-206553 and Ro-60-0175 induce a dose-dependent increase in oral bouts. The 5-HT2C antagonist SB 243213 (1-10 mg/kg) without effect per se blocks abnormal oral movements induced by SB-206553 and Ro-60-0175. The DA lesion, without modifying oral bouts induced by SB-206553 (10 mg/kg), potentiated those induced by Ro-60-0175 (3 mg/kg), an effect fully reversed by SB-243213. The effect of the agonist is in part related to 5-HT2C receptors present in the EPN because the intra-EPN injection of Ro-60-0175 (0.3-1 µg/0.1µl) elicited oral bouts in 6-OHDA rats only. These results suggest that the mechanisms involved in oral bouts induced by 5-HT2C agonists are different from those induced by 5-HT2C inverse agonists and involve in part alteration in 5-HT2C transmission in the EPN of hemiparkinsonian rats. These data further support the use of 5-HT2C neutral antagonists as antidyskinetic drugs in Parkinson’s disease. Conference: 3rd Mediterranean Conference of Neuroscience , Alexandria, Egypt, 13 Dec - 16 Dec, 2009. Presentation Type: Poster Presentation Topic: Aging & Environment Citation: Deurwaerdere PD, Navailles S, Roumegous A and Gross C (2009). Distinct mechanisms involved in serotonin2C agonist- and inverse agonist-induced purposeless oral movements in hemiparkinsonian rats. Front. Neurosci. Conference Abstract: 3rd Mediterranean Conference of Neuroscience . doi: 10.3389/conf.neuro.01.2009.16.183 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 29 Nov 2009; Published Online: 29 Nov 2009. * Correspondence: Philippe D Deurwaerdere, Universite Victor Segalen Bordeaux 2, Laboratoire Mouvement Adaptation Cognition – CNRS UMR5227, Bordeaux, France, philippe.de-deurwaerdere@lnpb.u-bordeaux2.fr Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Philippe D Deurwaerdere Sylvia Navailles Audrey Roumegous Christian Gross Google Philippe D Deurwaerdere Sylvia Navailles Audrey Roumegous Christian Gross Google Scholar Philippe D Deurwaerdere Sylvia Navailles Audrey Roumegous Christian Gross PubMed Philippe D Deurwaerdere Sylvia Navailles Audrey Roumegous Christian Gross Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Stimulation of 5-HT2A and 5-HT2C receptors blocks the reward-facilitating effect of cocaine in the rat

Event Abstract Back to Event Stimulation of 5-HT2A and 5-HT2C receptors blocks the reward-facilitating effect of cocaine in the rat Vicky Katsidoni1* and George Panagis1 1 University of Crete, Greece Serotonin (5-HT) appears to play a modulatory role in the behavioral effects of cocaine, although the impact of specific 5-HT receptors in this control has not been fully established. In the present study, the efficacy of selective ligands for the 5-HT2A and 5-HT2C receptors in altering the reward-facilitating effect of cocaine was examined in rats. Male Sprague-Dawley rats were implanted with a monopolar stimulating electrode into the medial forebrain bundle at the level of the lateral hypothalamus. Rate-frequency functions were determined by logarithmically decreasing the number of cathodal pulses in a stimulation train from a value that sustained maximal responding to one that did not sustain responding. After brain reward threshold stabilized rats received systemic injections with the selective 5-HT2A agonist TCB-2 (0.3mg/kg), the selective 5-HT2A antagonist R-96544 (0.3mg/kg), the selective 5-HT2C agonist WAY-161503 (0.3mg/kg) and the selective 5-HT2C antagonist SB-242084 (0.5mg/kg), followed by acute administration of cocaine (5mg/kg). Systemic injections of the 5-HT2A and 5-HT2C agonists blocked the reward-facilitating effect of cocaine. These effects were reversed by pretreatment with selective 5-HT2A and 5-HT2C antagonists, respectively. Interestingly, the 5-HT2C antagonist appeared to act synergistically with cocaine increasing further its reward-facilitating effect. To the contrary, the 5-HT2A antagonist did not have an effect. The present data support the hypothesis that serotonin through 5-HT2A and 5-HT2C receptors exerts an inhibitory influence on the reward-facilitating effect of cocaine. Intracranial microinjections of these drugs into specific brain regions of the mesocorticolimbic dopaminergic system expressing high levels of 5-HT2A and 5-HT2C receptors could reveal the specific neuroanatomical substrate of the present actions. Supported by a grant from the Research Committee of the University of Crete (KA 2581) Conference: 41st European Brain and Behaviour Society Meeting, Rhodes Island, Greece, 13 Sep - 18 Sep, 2009. Presentation Type: Poster Presentation Topic: Poster presentations Citation: Katsidoni V and Panagis G (2009). Stimulation of 5-HT2A and 5-HT2C receptors blocks the reward-facilitating effect of cocaine in the rat. Conference Abstract: 41st European Brain and Behaviour Society Meeting. doi: 10.3389/conf.neuro.08.2009.09.187 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 10 Jun 2009; Published Online: 10 Jun 2009. * Correspondence: Vicky Katsidoni, University of Crete, Crete, Greece, panagis@uoc.gr Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Vicky Katsidoni George Panagis Google Vicky Katsidoni George Panagis Google Scholar Vicky Katsidoni George Panagis PubMed Vicky Katsidoni George Panagis Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.