Serotonin 2C Research Articles

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.

Role of 5-Hydroxytryptamine2CReceptors in Ca2+-Dependent Ethanol Potentiation of GABA Release onto Ventral Tegmental Area Dopamine Neurons

Activation of ventral tegmental area (VTA)-dopaminergic (DA) neurons by ethanol has been implicated in the rewarding and reinforcing actions of ethanol. GABAergic transmission is thought to play an important role in regulating the activity of DA neurons. We have reported previously that ethanol enhances GABA release onto VTA-DA neurons in a brain slice preparation. Because intraterminal Ca(2+) levels regulate neurotransmitter release, we investigated the roles of Ca(2+)-dependent mechanisms in ethanol-induced enhancement of GABA release. Acute ethanol enhanced miniature inhibitory postsynaptic current (mIPSC) frequency in the presence of the nonspecific voltage-gated Ca(2+) channel inhibitor, cadmium chloride, even though basal mIPSC frequency was reduced by cadmium. Conversely, the inositol-1,4,5-triphosphate receptor inhibitor, 2-aminoethoxydiphenylborane, and the sarco/endoplasmic reticulum Ca(2+) ATPase pump inhibitor, cyclopiazonic acid, eliminated the ethanol enhancement of mIPSC frequency. Recent studies suggest that the G protein-coupled receptor, 5-hydroxytryptamine (5-HT)(2C), may modulate GABA release in the VTA. Thus, we also investigated the role of 5-HT(2C) receptors in ethanol enhancement of GABAergic transmission. Application of 5-HT and the 5-HT(2C) receptor agonist, Ro-60-0175 [(alphaS)-6-chloro-5-fluoro-alpha-methyl-1H-indole-1-ethanamine fumarate], alone enhanced mIPSC frequency of which the latter was abolished by the 5-HT(2C) receptor antagonist, SB200646 [N-(1-methyl-5-indoyl)-N-(3-pyridyl)urea hydrochloride], and substantially diminished by cyclopiazonic acid. Furthermore, SB200646 abolished the ethanol-induced increase in mIPSC frequency and had no effect on basal mIPSC frequency. These observations suggest that an increase in Ca(2+) release from intracellular stores via 5-HT(2C) receptor activation is involved in the ethanol-induced enhancement of GABA release onto VTA-DA neurons.

Genetik der Antipsychotika-assoziierten Gewichtszunahme

Weight gain is a serious adverse event during neuroleptic or antipsychotic treatment of schizophrenic disorders. The risk of weight gain varies among the class of neuroleptics, however no reliable predictors exist that adequately estimate individual risk. It is hoped that molecular genetic tests will help determine individual risk in the future. This article summarizes studies performed till now and concludes that gene variants of the serotonin 2C receptor and leptin significantly correlated with weight gain in several studies. Further interesting findings were obtained with variants of CYP2D6, the synaptosome-associated protein of 25 kDa (SNAP-25) as well as with the adrenergic alpha-2A genes. The group sizes were however small, and more studies are required for genetic tests to become available. Nonetheless the first steps towards genetic risk assessment have been performed, and its application in the near future has become likely.

RNA editing of the serotonin 2C receptor and expression of Galpha(q) protein: genetic mouse models do not support a role for regulation or compensation.

The serotonin 2C (5-HT(2C)) receptor undergoes RNA editing at five bases in a region of the pre-mRNA encoding the second intracellular loop, generating many unique 5-HT(2C) receptor isoforms. Mechanisms regulating in vivo expression of different edited 5-HT(2C) receptor isoforms are poorly understood, as are the adaptive consequences of variation in editing profiles. Recent findings suggest a putative relationship between expression levels of Galpha(q/11) protein and the degree of editing of 5-HT(2C) receptor transcripts. To elucidate the potential regulatory or adaptive role of Galpha(q/11) protein levels, we quantified editing of 5-HT(2C) receptor RNA transcripts in Galpha(q) null mice and protein levels of Galpha(q) and Galpha(11) in transgenic male mice solely expressing either the non-edited (INI) or the fully edited (VGV) isoforms of the 5-HT(2C) receptor. Pyrosequencing of RNA isolated from amygdaloid cortex in Galpha(q) null and wild-type mice revealed no significant differences in 5-HT(2C) receptor mRNA editing profiles. Cortical tissue from INI/y, VGV/y, and wild-type mice was assayed for expression of Galpha(q) and Galpha(11) subunits by Western blotting. No differences in signal density between wild-type and INI/y or VGV/y groups were found, indicating equivalent levels of Galpha(q) and Galpha(11) protein. Together, these data do not support a causal or compensatory relationship between 5-HT(2C) receptor RNA editing and G(q) protein levels.

An innovative real-time PCR method to measure changes in RNA editing of the serotonin 2C receptor (5-HT 2CR) in brain

The serotonin 2C receptor (5-HT 2CR) plays a significant role in psychiatric disorders (e.g., depression) and is a target for pharmacotherapy. The 5-HT 2CR is widely expressed in brain and spinal cord and is the only G-protein coupled receptor currently known to undergo mRNA editing, a post-transcriptional modification that results in translation of distinct, though closely related, protein isoforms. The 5-HT 2CR RNA can be edited at five sites to alter up to three amino acids resulting in modulation of receptor:G-protein coupling and constitutive activity. To rapidly quantify changes ex vivo in individual 5-HT 2CR isoform levels in response to treatment, we adapted quantitative (real-time) reverse transcription polymerase chain reaction (qRT-PCR) utilizing TaqMan ® probes modified with a minor groove binder (MGB). Probes were developed for four 5-HT 2CR RNA isoforms and their sensitivity and specificity were validated systematically using standard templates. Relative expression of the four isoforms was measured in cDNAs from whole brain extracted from 129S6 and C57BL/6J mice. Rank order derived from this qRT-PCR analysis matched that derived from DNA sequencing. In mutant mice solely expressing either non-edited or fully edited 5-HT 2CR transcripts, only expected transcripts were detected. These data suggest this qRT-PCR method is a precise and rapid means to detect closely related mRNA sequences ex vivo without the necessity of characterizing the entire 5-HT 2CR profile. Implementation of this technique will expand and expedite studies of specific brain 5-HT 2CR mRNA isoforms in response to pharmacological, behavioral and genetic manipulation, particularly in ex vivo studies which require rapid collection of data on large numbers of samples.

Pharmacological targeting of the serotonergic system for the treatment of obesity.

The attenuation of food intake as induced by an increase in serotonergic (5-hydroxytryptamine, 5-HT) efficacy has been a target of antiobesity pharmacotherapies. However, the induction of tolerance and/or side-effects limited the clinical utility of the earliest serotonin-related medications. With the global prevalence of obesity rising, there has been renewed interest in the manipulation of the serotonergic system as a point of pharmacological intervention. The serotonin(2C) receptor (5-HT(2C)R), serotonin(1B) (rodent)/serotonin(1Dbeta) (human) receptor (5-HT(1B/1Dbeta)R) and serotonin(6) receptor (5-HT(6)R) represent the most promising serotonin receptor therapeutic targets. Canonical serotonin receptor compounds have given way to a myriad of novel receptor-selective ligands, many of which have observable anorectic effects. Here we review serotonergic compounds reducing ingestive behaviour and discuss their clinical potential for the treatment of obesity.

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

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

Developmental Changes in Serotonin 2C Receptor mRNA Editing in the Rat Cerebral Cortex and Primary Cultured Cortical Neurons

Serotonin 2C receptor (5-HT2CR) mRNA has been reported to receive editing at 5 nucleotide positions (named sites A-E) which are located inconsecutively on the nucleotide sequence encoding the 2nd intracellular loop of the receptor protein. To clarify the physiological role of 5-HT2CR mRNA editing, we investigated developmental changes in editing frequencies at sites A-E in the rat cerebral cortex and primary cultured cortical neurons. The editing at sites A and B increased in parallel with the rat brain development and reached a plateau of 80-100% frequency at postnatal days 1-3. Although editing frequency at site C was low compared to those detected at other sites except site E during a developmental period, it reached the maximal value of 30% during a first 7-d period after birth and then decreased gradually to the negligible level at PN49. Site D exhibited almost constant susceptibility (about 60%) to editing, while no editing at site E was occurred during rat brain development. Similar changes during development in editing frequencies at these sites were observed in primary cultured cortical cells during the cultivation period. These findings indicated that editing sites A-D on 5-HT2CR mRNA have different susceptibility and that the frequencies at these sites are not always constant during development.

Investigation of the serotonin 2C receptor gene in attention deficit hyperactivity disorder in UK samples

BackgroundAttention deficit hyperactivity disorder (ADHD) is a common, childhood-onset neurodevelopmental disorder that is more frequent in males than females. Several genes on the X chromosome have been studied as candidate risk factors for ADHD including the 5-HT2C receptor (HTR2C) gene. Association between polymorphisms in HTR2C and ADHD were reported in a recent study.FindingsIn this study we investigated the association between ADHD and two polymorphisms C-759T (rs3813929) and G-697C (rs518147) in the promoter region of the HTR2C gene using a sample of 180 UK ADHD probands and their parents. We have shown that the -697G allele was significantly over-transmitted to affected ADHD probands (P = 0.017). No association was detected between the C-759T polymorphism and ADHD. Haplotype analysis of the two markers revealed no significantly increased transmission of any haplotype to ADHD.ConclusionThe findings provide evidence that the G-allele of the G-697C HTR2C polymorphism may be involved in the development of ADHD. The results replicate one of the findings published recently.

Targeting the serotonin 2C receptor for the treatment of obesity and type 2 diabetes

Targeting the serotonin 2C receptor for the treatment of obesity and type 2 diabetes

Dysregulated Editing of Serotonin 2C Receptor mRNAs Results in Energy Dissipation and Loss of Fat Mass

RNA editing that converts adenosine to inosine replaces the gene-encoded Ile, Asn, and Ile (INI) of serotonin [5-hydroxytryptamine (5-HT)] receptor 2C (5-HT(2C)R) with Val, Gly, and Val (VGV). Up to 24 different 5-HT(2C)R isoforms are detected in different brain regions (Burns et al., 1997; Fitzgerald et al., 1999; Wang et al., 2000). To elucidate the physiological significance of 5-HT(2C)R mRNA editing, we derived mutant mouse lines harboring a knock-in INI or VGV allele, resulting in sole expression of one of two extremely different editing isoforms 5-HT(2C)R-INI (editing blocked) or -VGV (fully edited). Although INI mice grew normally, VGV mice had a severely reduced fat mass, despite compensatory hyperphagia, as a result of constitutive activation of the sympathetic nervous system and increased energy expenditure. Furthermore, serotonergic neurotransmission was oversensitized in VGV mice, most likely because of the increased cell surface expression of VGV receptors. Melanocortin 4 receptor (MC4R) regulates energy homeostasis (Balthasar et al., 2005; Heisler et al., 2006; Lam et al., 2008), and Mc4r(-/-) mice are obese because of hyperphagia and reduced energy expenditure (Huszar et al., 1997). However, the elevated energy expenditure of VGV mice could not be rescued in the Mc4r(-/-) background, indicating the presence of a distinct signaling pathway mediated via 5-HT(2C)R-VGV that dominates the MC4R-dependent pathway in control of energy expenditure. Our results highlight the importance of regulated 5-HT(2C)R mRNA editing, because dysregulation could result in the pathological consequences such as growth retardation seen in VGV mice.

Effects of systemic and intra-nucleus accumbens 5-HT2C receptor compounds on ventral tegmental area self-stimulation thresholds in rats

Serotonin 2C (5-HT(2C)) receptors may play a role in regulating motivation and reward-related behaviours. To date, no studies have investigated the possible role of 5-HT(2C) receptors in ventral tegmental area (VTA) intracranial self-stimulation (ICSS). The current study investigated the hypotheses that 5-HT(2C) receptors play an inhibitory role in VTA ICSS, and that 5-HT(2C) receptors within the nucleus accumbens (NAc) shell may be involved. Male Sprague-Dawley rats were implanted with a VTA electrode and bilateral NAc shell cannulae for the experiment involving microinjections, and trained to respond for electrical self-stimulation. The systemic effects of the selective 5-HT(2C) receptor agonist WAY 161503 (0-1.0 mg/kg), the 5-HT(1A/1B/2C) receptor agonist TFMPP (0.3 mg/kg) and the selective 5-HT(2C) receptor antagonist SB 242084 (1.0 mg/kg) were compared using rate-frequency threshold analysis. Intra-NAc shell microinjections of WAY 161503 (0-1.5 microg/side) were investigated and compared to amphetamine (1.0 microg/side). WAY 161503 (1.0 mg/kg) and TFMPP (0.3 mg/kg) significantly increased rate-frequency thresholds (M50 values) without altering maximal response rates (RMAX values). SB 242084 attenuated the effects of TFMPP; SB 242084 had no affect on M50 or RMAX values. Intra-NAc shell WAY 161503 had no effect on M50 or RMAX values; intra-NAc amphetamine decreased M50 values. These results suggest that 5-HT(2C) receptors play an inhibitory role in regulating reward-related behaviour while 5-HT(2C) receptor activation in the NAc shell did not appear to influence VTA ICSS behaviour under the present experimental conditions.

Loss of cholecystokinin and glucagon-like peptide-1-induced satiation in mice lacking serotonin 2C receptors

To investigate the role of serotonin 2C receptors (2CR), which are expressed only in the central nervous system, in the satiating actions of the gut peptides CCK and glucagon-like peptide 1 (GLP-1), we examined 1) the effect of null mutations of serotonin 2CR (2CR KO) on the eating-inhibitory potencies of dark-onset intraperitoneal injections of 0.9, 1.7, or 3.5 nmol/kg (1, 2, or 4 microg/kg) CCK and 100, 200, and 400 nmol/kg (33, 66, or 132 microg/kg) GLP-1, and 2) the effects of intraperitoneal injections of 1.7 nmol//kg CCK and 100 nmol/kg GLP-1 on neuronal activation in the brain, as measured by c-Fos expression. All CCK and GLP-1 doses decreased 30-min food intake in wild-type (WT) mice, but none of them did in 2CR KO mice. CCK increased the number of cells expressing c-Fos in the nucleus tractus solitarii (NTS) of WT, but not 2CR KO mice. CCK induced similar degrees of c-Fos expression in the paraventricular (PVN) and arcuate (Arc) nuclei of the hypothalamus of both genotypes. GLP-1, on the other hand, increased c-Fos expression similarly in the NTS of both genotypes and increased c-Fos expression more in the PVN and Arc of 2CR KO mice, but not WT mice. These results indicate that serotonin signaling via serotonin 2CR is necessary for the full satiating effects of CCK and GLP-1. In addition, they suggest that the satiating effects of the two peptides are mediated by different neural mechanisms.

5-HT2CRs Expressed by Pro-Opiomelanocortin Neurons Regulate Energy Homeostasis

SummaryDrugs activating 5-hydroxytryptamine 2C receptors (5-HT2CRs) potently suppress appetite, but the underlying mechanisms for these effects are not fully understood. To tackle this issue, we generated mice with global 5-HT2CR deficiency (2C null) and mice with 5-HT2CRs re-expression only in pro-opiomelanocortin (POMC) neurons (2C/POMC mice). We show that 2C null mice predictably developed hyperphagia, hyperactivity, and obesity and showed attenuated responses to anorexigenic 5-HT drugs. Remarkably, all these deficiencies were normalized in 2C/POMC mice. These results demonstrate that 5-HT2CR expression solely in POMC neurons is sufficient to mediate effects of serotoninergic compounds on food intake. The findings also highlight the physiological relevance of the 5-HT2CR-melanocortin circuitry in the long-term regulation of energy balance.

Fluvoxamine exerts anorexic effect in 5-HT2C receptor mutant mice with heterozygous mutation of β-endorphin gene

Serotonin (5-hydroxytryptamine; 5-HT) 2C receptors and the downstream melanocortin pathway are suggested to mediate the anorexic effects of m-chlorophenylpiperazine (mCPP) and fenfluramine. We previously reported that fluvoxamine, a selective serotonin reuptake inhibitor, together with pharmacological inactivation of 5-HT2C receptors exert feeding suppression through activation of 5-HT1B receptors in mice. Here, we report that fluvoxamine exerted anorexic effects in 5-HT2C receptor mutant mice with heterozygous mutation of beta-endorphin gene (2CREnd mice), whereas fluvoxamine had no effect on food intake in age-matched wild-type mice and 5-HT2C receptor mutant mice, which are associated with decreases in hypothalamic proopiomelanocortin (POMC) expression. mCPP suppressed food intake in 5-HT2C receptor mutant mice, 2CREnd mice and age-matched wild-type mice. These results suggest that fluvoxamine-induced feeding suppression requires a perturbation of 5-HT2C receptor and beta-endorphin signalling plus functional hypothalamic POMC activity, whereas mCPP-induced feeding suppression does not always require functional 5-HT2C receptor, beta-endorphin, and POMC activity in mice.

Serotonin 2C receptors in the medial prefrontal cortex facilitate cocaine-induced dopamine release in the rat nucleus accumbens

A functional balance between excitatory and inhibitory control over dopamine (DA)-dependent behavioral and neurochemical effects of cocaine is afforded by the serotonin 2C receptor (5-HT 2CR) located within the ventral tegmental area and the nucleus accumbens (NAc). The 5-HT 2CR located in the medial prefrontal cortex (mPFC) has also been shown to inhibit cocaine-induced behaviors perhaps through inhibition of DA function in the NAc. Using in vivo microdialysis in halothane-anesthetized rats, we tested this hypothesis by assessing the influence of mPFC 5-HT 2CRs on cocaine-induced DA outflow in the NAc shell. Intra-mPFC injection of the 5-HT 2CR agonist Ro 60-0175 at 5 μg/0.2 μl, but not 1 μg/0.2 μl, potentiated the increase in accumbal DA outflow induced by the intraperitoneal administration of 10 mg/kg of cocaine. Conversely, cocaine-induced accumbal DA outflow was significantly reduced by the intra-mPFC injection of the selective 5-HT 2CR antagonist SB 242084 (0.5 μg/0.2 μl) or SB 243213 (0.5 and 1 μg/0.2 μl). These results show that mPFC 5-HT 2CRs exert a positive control over cocaine-induced accumbal DA outflow. Observations further support the idea that the overall action of central 5-HT 2CRs on accumbal DA output is dependent on the functional balance among different 5-HT 2CR populations located within the mesocorticoaccumbens system, and that 5-HT 2CRs can modulate DA-dependent behaviors independently of changes of accumbal DA release itself.

Approaching the Molecular Pathology of Suicide

uicide risk and personality traits associated with suicidal behavior are often related to childhood maltreatment and other “environmental” stressors (1). Therefore, the pathohysiology of suicide is likely to involve molecular mechanisms hat are not necessarily related to genetic factors (defined here as hanges in DNA sequence), albeit this hypothesis is difficult to est conclusively. Somatic cells (including neurons) employ a wide array of olecular mechanisms to alter and regulate gene expression nd function without changing the sequence of the genomic NA itself. These include (but are not limited to) “epigenetic” echanisms, which are commonly defined by a chemical odification of the DNA and/or the histone proteins associted with it. For example, the methylation of DNA cytosine esidues at the sites of CpG dinucleotides within gene prooters is an epigenetic mark typically associated with represion or downregulation of RNA transcription (2). In addition, ene expression is also regulated by a rich set of postranslational modifications of specific histone residues; these nclude lysine acetylation, methylation, SUMOylation and biquitinylation, arginine methylation, serine phosphorylaion, and proline isomerization (2). Now, two provocative articles, one by Poulter et al. in this ournal (3) and the other one by McGowan et al. in PLoS ONE 4), provide evidence for DNA methylation changes in the frontal ortex (3) and hippocampus of suicide victims (4). Poulter et al. (3) focused on the promoter of the ionotropic -aminobutyric acid (GABA)-A a1 receptor subunit, which acording to their previous work is expressed at decreased levels in he anterior prefrontal cortex of suicide victims (5). However, it hould be noted that another study, conducted in anterior ingulate—which is in close proximity to the prefrontal cortex— eported a consistent increase in GABA-A a1 expression in ompleted suicides (6). The clinical cohorts in both studies were efined by an underlying diagnosis of mood disorder, and herefore the discrepancy remains to be resolved. If not exlained by demographic differences, medication history, postortem variables, and other confounds, one interesting hypothsis would be that levels of GABA-A a1 transcript show opposing lterations in different subdivisions of the frontal lobe of suicidal ubjects. In any case, Poulter et al. (3) now report that a small ubset of CpG dinucleotides at the proximal GABA-A a1 prooter are hypermethylated in prefrontal cortex of 10 male uicide victims diagnosed with major depression, compared with on-psychiatric control subjects who died from other causes. The ethylation levels in control subjects ranged from 6% to 10% but ere as high as 38% in suicide victims. When taken together with heir previous finding of decreased GABA-A a1 messenger RNA

Physical Interaction of Calmodulin with the 5-Hydroxytryptamine2C Receptor C-Terminus Is Essential for G Protein-independent, Arrestin-dependent Receptor Signaling

The serotonin (5-hydroxytryptamine; 5-HT)(2C) receptor is a G protein-coupled receptor (GPCR) exclusively expressed in CNS that has been implicated in numerous brain disorders, including anxio-depressive states. Like many GPCRs, 5-HT(2C) receptors physically interact with a variety of intracellular proteins in addition to G proteins. Here, we show that calmodulin (CaM) binds to a prototypic Ca(2+)-dependent "1-10" CaM-binding motif located in the proximal region of the 5-HT(2C) receptor C-terminus upon receptor activation by 5-HT. Mutation of this motif inhibited both beta-arrestin recruitment by 5-HT(2C) receptor and receptor-operated extracellular signal-regulated kinase (ERK) 1,2 signaling in human embryonic kidney-293 cells, which was independent of G proteins and dependent on beta-arrestins. A similar inhibition was observed in cells expressing a dominant-negative CaM or depleted of CaM by RNA interference. Expression of the CaM mutant also prevented receptor-mediated ERK1,2 phosphorylation in cultured cortical neurons and choroid plexus epithelial cells that endogenously express 5-HT(2C) receptors. Collectively, these findings demonstrate that physical interaction of CaM with recombinant and native 5-HT(2C) receptors is critical for G protein-independent, arrestin-dependent receptor signaling. This signaling pathway might be involved in neurogenesis induced by chronic treatment with 5-HT(2C) receptor agonists and their antidepressant-like activity.

Differential effects of 5-HT 2C receptor activation by WAY 161503 on nicotine-induced place conditioning and locomotor activity in rats

Rationale Numerous studies indicate a role for both the serotonin 2C receptor (5-HT 2C) and the nicotinic acetylcholine receptor in locomotion, reinforcement and motivated behaviours. Nicotine, a potent nicotinic acetylcholine receptor agonist, interacts with the dopaminergic and serotonergic systems and is known to positively affect reward-related behaviours. Objectives The current study examined the effects of 5-HT 2C receptor activation on nicotine-induced (0.6 mg/kg) place conditioning and spontaneous locomotion. Methods Using Sprague–Dawley rats, the effects of the selective 5-HT 2C receptor agonist WAY 161503 (0–1.0 mg/kg) and the selective 5-HT 2C receptor antagonist SB 242084 (1.0 mg/kg) alone, in combination, and on nicotine-induced (0.6 mg/kg) spontaneous locomotor activity were assessed. The effects of WAY 161503 (1.0, 3.0 mg/kg) were also investigated in nicotine-induced place conditioning using a two-compartment biased design; amphetamine (1.0 mg/kg) served as a positive control. As differential effects were observed between place conditioning and locomotor activity, the subjects used in the place conditioning experiments were also tested for effects on locomotor activity. Results WAY 161503 decreased baseline and nicotine-induced locomotor activity at the highest dose tested (1.0 mg/kg) and these effects were attenuated by SB 242084. Amphetamine and nicotine both induced robust place preferences and WAY 161503 did not have any effects in the context of place conditioning. In contrast, WAY 161503 (1.0 mg/kg) blocked nicotine-induced locomotor activity. Conclusions These results suggest that 5-HT 2C receptors may play an inhibitory role in nicotine-induced locomotor activity, but do not appear to influence place conditioning under the current conditions.

Drugs in the pipeline for the obesity market.

Obesity is a major public health problem. For many obese patients, diet and exercise are an inadequate treatment and bariatric surgery may be too extreme of a treatment. As with many other chronic diseases, pharmacologic treatment may be an attractive option for selected obese patients. Antiobesity drugs may potentially work through one of three mechanisms: (1) appetite suppression, (2) interference with absorption of nutrients, and (3) increased metabolism of nutrients. The three most widely prescribed drugs approved to treat obesity are phentermine, sibutramine, and orlistat. Drugs approved for treating obesity usually result in an additional weight loss of approximately 2-5 kg in addition to placebo. For pharmacologic therapy in obesity to be widely utilized, greater effectiveness and safety will be needed. Four types of single-agent drugs are in late stage development, including (1) selective central cannabinoid-1 receptor blockers, (2) selective central 5-hydroxytryptamine 2C serotonin receptor agonists, (3) an intestinal lipase blocker, and (4) central-acting incretin mimetic drugs. Four combination agent compounds in late stage development include (1) Contrave, which combines long-acting versions of naltrexone and bupropion; (2) Empatic, which combines long-acting bupropion and long-acting zonisamide; (3) Qnexa, which combines phentermine with controlled release topiramate; and (4) an injectable combination of leptin and pramlintide. Peptide YY and melanin-concentrating hormone receptor-1 antagonists are centrally acting agents in early stage development. It is expected that several new drug products for obesity will become available over the next few years. Their role in managing this disease remains to be determined.