Progress in 5-HT2C receptor as a therapeutic target for treatment of schizophrenia / 上海交通大学学报（医学版）

With an increasing number of reports on side effects including antipsychotic induced weight gain and cardiovascular risks, interest of the researchers has been transferred to a new target for the treatment of schizophrenia-serotonin 2C receptor (5-HT2C receptor). On one hand, activation on 5-HT2C receptors can lead to decrease of dopamine in the nigrostriatum, which presents its potential antipsychotic effect; on the other hand, the secondgeneration of antipsychotics’ antagonism on the 5-HT2C receptors is an important factor of patients' weight gain. Conversely, agonism on the 5-HT2C receptors may result in weight loss efficacy. This paper introduced the potential therapeutical effect of 5-HT2C receptor on schizophrenia and the relation between the receptor and correlated weight gain.

Bioassay-guided isolation of saikosaponins with agonistic activity on 5-hydroxytryptamine 2C receptor from Bupleurum chinense and their potential use for the treatment of obesity / 中国天然药物

5-Hydroxytryptamine 2C (5-HT) receptor is one of the major targets of anti-obesity agents, due to its role in regulation of appetite. In the present study, the 70% EtOH extract of the roots of Bupleurum chinense was revealed to have agonistic activity on 5-HT receptor, and the subsequent bioassay-guided isolation led to identification of several saikosaponins as the active constituents with 5-HT receptor agonistic activity in vitro and anti-obesity activity in vivo. The new compound, 22-oxosaikosaponin d (1), was determined by extensive spectroscopic analyses (HR-ESI-MS, IR, and 1D and 2D NMR). The primary structure-activity relationship study suggested that the intramolecular ether bond between C-13 and C-28 and the number of sugars at C-3 position were closely related to the 5-HT receptor agonistic activity. Saikosaponin a (3), the main saponin in B. chinense, showed obviously agonistic activity on 5-HT receptor with an EC value of 21.08 ± 0.33 μmol·Lin vitro and could reduce food intake by 39.1% and 69.2%, and weight gain by 13.6% and 16.4%, respectively, at 3.0 and 6.0 mg·kgin vivo. This investigation provided valuable information for the potential use of B. chinense as anti-obesity agent.

Effects of social isolation on the cognition and expression of 5-HT2C receptor and ADAR1 in BALB/c mice / 中华行为医学与脑科学杂志

ObjectiveTo explore the effects of social isolation on the cognition and expression of 5-HT2C receptor(5-HT2CR) and adenosine deaminase that act on RNA 1(ADAR1) in BALB/c mice.MethodsThe healthy BALB/c mice were isolated for 2,4,and 8 weeks individually since postnatal 21 days respectively to set up isolation mice model,the same age mice without isolation were regarded as control group.The new object location and the new object recognition tests were used to measure the spatial and non-spatial cognitive function,and western blot was used to measure the protein expression of 5-HT2CR and ADAR1.ResultsThe new object location test showed that the spatial discrimination index (DI) of BALB/c mice isolated for 2 weeks was decreased significantly compared with the control group(control group was (0.075±0.340),isolation group was (-0.653±0.308),P<0.05),and no obvious difference was found for the group isolated for 4 and 8 weeks.The new object recognition test showed that the non-spatial DI of BALB/c mice isolated for 2 and 4 weeks were decreased significantly compared with the control group(control 2 weeks group was (0.088±0.210),isolation 2 weeks group was (-0.945±0.194),P<0.05;control 4 weeks group was (0.105±0.267),isolation 4 weeks group was (-0.506±0.215),P<0.05),and no obvious difference was found for the group isolated for 8 weeks.Compared with the control group the expression of 5-HT2CR and ADAR1 in the hippocampus were decreased significantly for the group isolated for 2 weeks.(5-HT2CR:control group was (1.025±0.144),isolation group was (0.891±0.026),P<0.05.ADAR1: control group was (0.839±0.120),isolation group was (0.629±0.094),P<0.05).ConclusionsTwo week social isolation results in the decrease of spatial and non-spatial cognitive function in BALB/c mice,in the meanwhile,social isolation stress results in the obvious decrease of 5-HT2C receptor and ADAR1 protein expression in the hippocampus of BALB/c mice.

Pharmacological activation of serotonin 5-HT2C receptor ameliorates naloxone-precipitated withdrawal in morphine-dependent mice / 中国药理学通报

Aim To explore the effect of pharmacolog-ical activation of serotonin 5-HT2C receptor (5-HT2C R) on naloxone-precipitated withdrawal in morphine-de-pendent mice. Method EthoVision Noldus video tracking system was used to record the effect of 5-HT2C R agonist WAY on locomotor activities and behavioral performances in mice.Results Selective 5-HT2C R ag-onist WAY (0.5,0.75 or 1 .0 mg·kg -1 ,i.p.)a-lone did not alter the locomotor activities as determined by distance traveled and velocity (all P values >0.05).Chronic morphine treatment induced depend-ence in mice as demonstrated by increases in distance traveled,velocity and jumping behavior.WAY (0.5, 0.75 or 1 .0 mg·kg -1 ,i.p.)and clonidine (0.2 mg ·kg -1 ,i.p.)significantly ameliorated naloxone-pre-cipitated withdrawal symptoms,including burrowing, jumping,body grooming,rearing,“wet dog”shakes, head shakes,face grooming,penile grooming,scratch (all P values <0.05).Conclusion Pharmacological activation of 5-HT2C R ameliorates naloxone-precipitated withdrawal symptoms in morphine-dependent mice.5-HT2C R may be a novel target to develop therapeutic ap-proach against morphine physical dependence,craving and relapsing.

Sedative-Hypnotic and Receptor Binding Studies of Fermented Marine Organisms

This study was performed to investigate the sedative-hypnotic activity of gamma-aminobutyric acid (GABA)-enriched fermented marine organisms (FMO), including sea tangle (FST) and oyster (FO) by Lactobacillus brevis BJ20 (L. brevis BJ20). FST and FO were tested for their binding activity of the GABA(A)-benzodiazepine and 5-HT(2C) receptors, which are well-known molecular targets for sleep aids. We also measured the sleep latency and sleep duration during pentobarbital-induced sleep in mice after oral administration of FST and FO. In GABA(A) and 5-HT(2C) receptor binding assays, FST displayed an effective concentration-dependent binding affinity to GABA(A) receptor, similar to the binding affinity to 5-HT(2C) receptor. FO exhibited higher affinity to 5-HT(2C) receptor, compared with the GABA(A) receptor. The oral administration of FST and FO produced a dose-dependent decrease in sleep latency and increase in sleep duration in pentobarbital-induced hypnosis. The data demonstrate that FST and FO possess sedative-hypnotic activity possibly by modulating GABA(A) and 5-HT(2C) receptors. We propose that FST and FO might be effective agents for treatment of insomnia.

Envolvimento de receptores 5-HT2C do hipocampo ventral em comportamentos de defesa de ratos no labirinto em cruz elevado / Involvement of ventral hippocampus 5-HT2C receptors on defensive behaviors of rats in the elevated plus-maze

A ativação farmacológica dos receptores 5-HT2C induz comportamentos de defesa em modelos animais. O estudo busca investigar se o bloqueio seletivo de receptores 5-HT2C no hipocampo ventral (HV) previne comportamentos defensivos induzidos por um agonista de receptor 5-HT2C administrado perifericamente em ratos expostos ao labirinto em cruz elevado (LCE). Quinze minutos após injeções intraperitoniais (IP, 1ml/kg) do agonista 5-HT2C WAY-161503, ratos foram microinjetados bilateralmente no HV com o antagonista seletivo de receptores 5-HT2C SB-242084 (0, 0,1, 0,5 ou 1.5μg). Dez minutos após, cada animal foi exposto ao LCE para o registro de categorias de ansiedade. Injeções sistêmicas do WAY-161503 reduziram seletivamente as explorações nos braços abertos e aumentaram padrões de avaliação de risco. Esse efeito foi atenuado de maneira dose-dependente pela microinjeção de SB-242084 no HV, confirmando a ação ansiogênica de agonistas 5-HT2C e sugerindo que esse perfil comportamental seja mediado, pelo menos em parte, por receptores 5-HT2C do HV.

Pharmacological 5-HT2C receptor activation induces defensive behaviors in several animal models of anxiety. The present study investigated whether the selective blockade of 5-HT2C receptors in the ventral hippocampus (VH) prevents defensive behaviors induced by a 5-HT2C agonist administered systemically in rats exposed to the elevated plus-maze (EPM). Fifteen minutes after intraperitonial (IP, 1ml/kg) injections of the selective 5-HT2C receptor agonist WAY-161503 (3 mg/kg), rats were bilaterally microinjected with the selective 5-HT2C antagonist SB-242084 (0, 0.1, 0.5 or 1.5μg) into the VH. Ten minutes after, each animal was exposed to the EPM for measuring classical and ethological anxiety measures. IP WAY-161503 injections selectively decreased open-arm exploration while increasing risk-assessment. This anxiogenic-like action was dose-dependently attenuated by intra-VH SB-242084 microinjections. These results not only further confirm the anxiogenic-like action of 5-HT2C agonists, but also suggest that this behavioral profile might be mediated at least in part by VH 5-HT2C receptors.

Antidepressant- and anxiogenic-like effects of acute 5-HT2C receptor activation in rats exposed to the forced swim test and elevated plus maze

This study investigated the behavioral effects in the forced swim test (FST) and the elevated plus-maze (EPM) of acute administration of WAY 161503 ([4aR]-8,9-dichloro-2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5[6 H]-one), a selective 5-HT2C receptor agonist with putative antidepressant-like properties. Fifteen minutes after intraperitoneal (i.p.) injections of either WAY 161503 (1, 3 and 10 mg/kg) or saline, naive male Wistar rats were exposed to the EPM for 5 min to assess classical and ethological anxiety-like measures. Immediately after EPM exposure, each animal was exposed to the FST, and the latency to the first episode of immobility was recorded (trial session). Twenty-four hours later, the rats were reexposed to a second EPM-FST exposure sequence (test session for FST) under the effect of the same pharmacological treatment. The two lowest WAY 161503 doses selectively reduced open-arm exploration and increased risk-assessment without affecting locomotor activity. This selective anxiogenic-like effect was observed in both the first and second EPM exposures. The highest WAY 161503 dose produced robust locomotor impairment. In the FST, the same WAY 161503 doses significantly increased the latency to the first immobility in the test session, a behavioral profile that suggests an antidepressant-like action. These results further support the involvement of 5-HT2C receptors in the mediation of anxiety and suggest an intricate relationship between anxiogenic- and antidepressant-like actions

Polymorphisms and Serotonin Dopamine Antagonist-Induced Weight Gain in Patients with Schizophrenia / 대한정신약물학회지

OBJECTIVE: Several lines of pharmacological evidences including the data of animal studies indicate that serotonin 2C receptor (5HT2C) is involved in the pharmacodynamic process of serotonin dopamine antagonists (SDA)-induced weight gain. Controversial data have been reported on the association between the polymorphisms of 5HT2C receptor gene and antipsychotics-induced weight gain. This study aims at investigating the association between the polymorphisms of 5HT2C receptor gene and SDA-induced weight gain in korean schizophrenic patients. METHODS: Seventy-seven schizophrenia patients in their first episode or patients who did not take any antipsychotics for the previous two months were recruited. All the patients were administered with one of the SDAs (risperidone, olanzapine, quetiapine, clozapine) for 8weeks. Body mass index (BMI) were measured weekly during the 8weeks. The subjects were genotyped for the -759 C/T and -697 G/C polymorphism of the 5HT2C receptor gene. RESULTS: The degree of linkage disequilibrium between the two polymorphic loci genotyped are almost 100%. Significant association was not observed between polymorphisms of the 5HT2C receptor gene (-759 C/T and -697 G/C) and SDA-induced weight gain after 8 weeks of treatment. CONCLUSION: Our data do not support the involvement of the polymorphisms of 5HT2C receptor gene (-759 C/T and -697 G/C) in SDA- induced weight gain. Further studies with sufficient sample size are warranted to follow up on the trend of high weight gain in the male patients having -759 T (-697 C) allele.

Association between Clozapine-Induced Weight Gain and Serotonin 5-HT2C Receptor Gene Polymorphism in Patients with Schizophrenia / 대한정신약물학회지

OBJECTIVE: Weight gain is one of the troublesome adverse reaction to clozapine treatment. This problem can lead to poor adherence to treatment. Clozapine-induced weight gain may be associated with genetic predisposition. Recent studies have shown that a polymorphism of the promoter region of the serotonin 5-HT2C receptor gene is associated with antipsychotic-induced weight gain. This study is to investigate the association of clozapine-induced weight gain with -759C/T polymorphism of serotonin 5-HT2C receptor promoter gene in schizophrenic patients. METHODS: Fifty three patients with schizophrenia were included in this study. The subjects were divided into two groups according to body weight change between the start and 10 weeks of clozapine. The cutoff level of weight change is 5% increase of initial body weight. Genotypes of -759C/T polymorphism were identified from AciI-digested fragments of two-primer products amplified by polymerase chain reaction corresponding to -885 to -634 of the serotonin 5-HT2C receptor gene promoter region on chromosome X. RESULTS: There were no differences of baseline variables between patient groups with and without weight gain. 4 of 32 male patients and 6 of 21 female patients had -759T allele, respectively. The authors found that patients with -759T allele had tendency to show less weight gain than those without this allele. CONCLUSION: These findings suggest that clozapine- induced weight gain may be associated with genetic predisposition in schizophrenic patients.

Effect of 5-HT2c Receptor Modulation on the m-Chlorophenlpiperazine-Induced Hypoactivity / 대한정신약물학회지

It was aimed to investigate the effect of 5-HT2C receptor modulation on the rat behavioral responses induced by 1-(m-chlorophenyl) piperazine(mCPP), a major metabolite of trazodone. The animal activities(ambulation, stereotypy and total activity) were measured for 3 hours following mCPP administration, using an animal activity meter which accumulates the frequency of light beam interruption. mCPP(1-10 mg / kg, i.p.) induced dose-dependent decreases in ambulation and stereotypy, consequently leading to hypoactivity. The hypoactivity induced by mCPP(1mg / kg, i.p.) was significantly inhibited by pretreatment with mianserin(1mg / kg, i.p.), an antagonist with high affinity for 5-HT2C receptor, whereas pretreatment with 5-HT2 antagonists, ketanserin and ritanserin(1mg / kg, i.p., respectively) was without effect. Furthermore, long-term pretreatment with imipramine(10mg / kg, i.p., b.i.d. for 2 weeks) markedly attenuated the mCPP-induced hypoactivity. Mianserin and imipramine in the absence of mCPP did not increase the animal activity. Taken together, these results indicate that the mCPP-induced hypoactivity is mediated by 5-HT2C receptor, and that selective 5-HT2C antagonists and down regulation of 5-HT2C receptor might be useful for inhibiting the mCPP-induced hypoactivity.