Serotonin has been implicated in the etiology and pathophysiology of mental illness such as depression, schizophrenia, anxiety disorder, eating disorder, obsessive compulsive disorder, and panic disorder. Many current used treatments of these disorders are thought to act through the modulation of the serotonergic tone. To improve on the efficacy of antipsychotics that are potent D2 receptor blockers, much interest has evolved around complimenting or replacing D2 dopaminergic antagonism by the action on serotonergic transmission. 5-HT2A receptor blockade, under the condition of weaker D2 receptor antagonism, may contribute to the ability of atypical antipsychotics to increase dopamine release in the medical prefrontal cortex while having a smaller effect on mesolimbic dopamine release. These effects may contribute to their advantage for cognition, negative symptoms and psychotic activity. The use of 5-HT1A receptor agonists may substitute for 5-HT2A antagonism and achieve many of the same benefits in combination with weak D2 receptors blockade. Antagonism of 5-HT2C receptors may also useful for improving cortical function. Thus, 5-HT has joined dopamine as a critical target for developing effective antipsychotics in schizophrenia. In the development of new first-line pharmacological treatment for major depressive disorder, 5-HT system will most likely remain important especially if agents can be developed with improved tolerability, faster onset of response or greater efficacy. The promising area for development of serotonergic antidepressants are agents that target the specific 5-HT receptor subtypes, and agents that affect 5-HT plus one or more of the noradrenaline, CRF, dopamine and glucocorticoids systems. Selective targeting of serotonin receptors such as 5-HT1, 5-HT2, or 5-HT7 may have considerable potential in the treatment of depressive disorders. Trophic agents that increased neuroplasticity or neurogenesis via the activation of cyclic AMP-CREB pathway may be beneficial as a target for novel antidepressants.
Antidepressive Agents ; Antipsychotic Agents ; Anxiety Disorders ; Cognition ; Depression* ; Depressive Disorder ; Depressive Disorder, Major ; Dopamine ; Feeding and Eating Disorders ; Glucocorticoids ; Neurogenesis ; Neuronal Plasticity ; Norepinephrine ; Obsessive-Compulsive Disorder ; Panic Disorder ; Prefrontal Cortex ; Receptor, Serotonin, 5-HT1A ; Receptor, Serotonin, 5-HT2A ; Receptor, Serotonin, 5-HT2C ; Receptors, Serotonin ; Schizophrenia* ; Serotonin ; Serotonin Agents*

Serotonin (5-HT), the endogenous nonselective 5-HT receptor agonist, activates the inositol -1,4,5- triphosphate / calcium (InsP3/Ca2+) signaling pathway and exerts both stimulatory and inhibitory actions on cAMP production and neuromodulin secretion in rat hypothalamic neurons. Specific mRNA transcripts for 5-HT1A, 5-HT2C and 5-HT4 were identified in rat hypothalamic neurons. These experiments were supported by combined techniques such as cAMP and a Ca2+ assays in order to elucidate the associated receptors and signaling pathways. The cAMP production and neuromodulin release were profoundly inhibited during the activation of the Gi-coupled 5-HT1A receptor. Treatment with a selective agonist to activate the Gq-coupled 5-HT2C receptor stimulated InsP3 production and caused Ca2+ release from the sarcoplasmic reticulum. Selective activation of the Gs-coupled 5-HT4 receptor also stimulated cAMP production, and caused an increase in neuromodulin secretion. These findings demonstrate the ability of 5-HT receptor subtypes expressed in neurons to induce neuromodulin production. This leads to the activation of single or multiple G-proteins which regulate the InsP3/Ca2+/PLC-gamma and adenyl cyclase / cAMP signaling pathways.
Animals ; Calcium ; GAP-43 Protein* ; GTP-Binding Proteins ; Inositol ; Neurons* ; Rats* ; Receptor, Serotonin, 5-HT1A ; Receptor, Serotonin, 5-HT2C ; Receptors, Serotonin, 5-HT4 ; RNA, Messenger ; Sarcoplasmic Reticulum ; Serotonin* ; Adenylyl Cyclases

Blonanserin is a newly developed agent which is approved for the treatment of schizophrenia in Japan and Korea. This agent has high affinity to dopamine D2 receptor and serotonin 5-HT2A receptor. Blonanserin was as effective as risperidone in the treatment of schizophrenia, and showed greater efficacy in negative symptoms than haloperidol. Blonanserin was well tolerated in both the short- and long-term studies, and the frequency and intensity of EPS is generally similar with risperidone. For other side effects, blonanserine seems to have better safety profiles compared with other atypicals, and showed less prolactin elevation than risperidone. These findings suggest that blonanserin is useful in the treatment of schizophrenia.
Haloperidol ; Japan ; Korea ; Piperazines ; Piperidines ; Prolactin ; Receptor, Serotonin, 5-HT2A ; Receptors, Dopamine D2 ; Risperidone ; Schizophrenia ; Serotonin

BACKGROUND: Spinal 5-hydroxytryptamine (5-HT) has been shown to display an antinociceptive effect, which is mediated by 5-HT receptors. Previous studies have revealed the presence of at least four types of 5-HT receptors in the spinal cord. The aim of this study was to assess the role of each spinal 5-HT receptor in the antinociception of intrathecal 5-HT using the formalin test. METHODS: Rats were implanted with lumbar intrathecal catheters. After the administration of 5-HT, formalin-induced nociceptive behavior (flinching response) was observed for 60 min. To further clarify the role of the 5-HT receptors in the antinociception of 5-HT, several antagonists of 5-HT receptors were administered intrathecally 10 min before 5-HT delivery, and formalin was injected 10 min later. RESULTS: Intrathecal 5-HT dose-dependently suppressed flinching during phase 1 and 2 in the formalin test. 5-HT1B (GR 55562), 5-HT2C (N-desmethylclozapine), 5-HT3 (LY-278,584) and 5-HT4 (SDZ-205,557) receptors antagonists reversed this antinociception by 5-HT during both phases in the formalin test. 5-HT1A receptor antagonist (WAY-100635) decreased antinociception by 5-HT in phase 2, but not in phase 1. A 5-HT1D receptor antagonist (BRL 15572) did not antagonize the antinociception of 5-HT in either phases. CONCLUSIONS: Spinal 5-HT1B, 5-HT2C, 5-HT3 and 5-HT4 receptors, but not the 5-HT1D receptor, are involved in the antinociception of serotonin in the facilitated state and in the acute pain evoked by a formalin stimulus. The 5-HT1A receptor seems to play a role in 5-HT-induced antinociception in the facilitated state.
Acute Pain ; Animals ; Catheters ; Formaldehyde ; Pain Measurement ; Rats* ; Receptor, Serotonin, 5-HT1A ; Receptor, Serotonin, 5-HT1D ; Receptors, Serotonin ; Receptors, Serotonin, 5-HT4 ; Serotonin* ; Spinal Cord*

OBJECTIVES: Recently, polymorphisms of several serotonin genes have been suggested to be associated with suicide, but the results are still unclear. We examined whether the T102C polymorphisms of the serotonin 2A receptor gene and the G861C polymorphisms of the serotonin 1B receptor gene were associated with suicidal behavior using drug intoxication. METHODS: The subjects were 52 patients who visited emergency room with suicidal behaviors. Fifty controls were selected from healthy volunteers matched for sex and age to the suicide subjects. The polymorphisms were analyzed with TaqMan(R) assay using primers based on previous studies. RESULTS: The T102C polymorphism of the serotonin 2A receptor gene showed no significant difference between the suicidal attempters and controls in both genotype and allele frequency analyses(p=0.179 and p=0.422, respectively). There was no statistically significant difference between the suicidal attempters and the controls in the G861C polymorphism of the serotonin 1B receptor gene and any significant effect of the genotype distributions or the allele frequencies was not observed(p=0.092 and p=0.987, respectively). CONCLUSION: These findings suggest that the T102C polymorphism in serotonin 2A receptor gene and the G861C polymorphism in serotonin 1B receptor gene are not related to the susceptibility to suicide attempts using drugs. To clarify the genetic influences of the serotonergic system on suicidal behavior, the polymorphisms of other candidate genes in the serotonergic system should be studied with larger numbers of subjects.
Emergency Service, Hospital ; Gene Frequency ; Genotype ; Healthy Volunteers ; Humans ; Receptor, Serotonin, 5-HT1B ; Receptor, Serotonin, 5-HT2A ; Serotonin* ; Suicide

Dual dopamine D2/5-HT2A receptor antagonists have potent activity and are referred to atypical antipsychotics due to their lower propensity to elicit EPS and their moderate efficacy toward negative symptoms. However, an on-going challenge in developing atypical antipsychotics drugs is to maintain the favorable profiles and avoid of cardiovascular risk. In this paper, comparative pharmacophore analysis of dual dopamine D2/5-HT2A receptor antagonists, hERG K+ channel blockers, and alA adrenoceptor antagonists is carried out, and the results could give some insight into multi-target drug design.
Adrenergic alpha-1 Receptor Antagonists ; Dopamine D2 Receptor Antagonists ; Drug Delivery Systems ; Drug Design ; ERG1 Potassium Channel ; Ether-A-Go-Go Potassium Channels ; antagonists & inhibitors ; chemistry ; Molecular Conformation ; Molecular Structure ; Receptor, Serotonin, 5-HT2A ; chemistry ; Receptors, Adrenergic, alpha-1 ; chemistry ; Receptors, Dopamine D2 ; chemistry ; Serotonin 5-HT2 Receptor Antagonists ; Structure-Activity Relationship

AIMTo study the correlation between 5-HT-induced pain response and the contribution by individual 5-HTR subtypes including 5-HT1R, 5-HT2R and 5-HT3R at the level of peripheral primary afferent.

METHODSThe experiments were done on acutely isolated trigeminal ganglion (TG) neurons using whole-cell patch clamp technique and the nociceptive effect was observed on behavior experiments by intraplantar injection of test drugs.

RESULTSThe majority of cells examined responded to 5-HT in a manner of concentration dependence (10(-6) - 10(-3) mol/) (61.4%, 54/88) and with a fast activating and rapid desensitizing inward current (I(5-HT)), which was thought to be mediated by the activation of 5-HT3R, since it could be blocked by 5-HT3R antagonist ICS 205930 and mimicked by 5-HT3R agonist 2-methyl-5-HT. It was found that I(5-HT) was potentiated by 5-HT2R agonist alpha-methyl-5-HT markedly, while 5-HT1R agonist R-(+)-UH 301 did not. In behavioral experiment performed on conscious rats, intraplantar injection of 5-HT(10(-5), 10(-4) and 10(-3) mol/L) induced an increment of cumulative lifting time first 20 min in a manner of concentration dependence. By dissociating 5-HTR subtypes using their corresponding antagonists (ICS and CYP) the potency order of hindpaw lifting time was identified as follows: 5-HT > 5-HT + ICS > 5-HT + CYP.

CONCLUSIONThe results suggest that in 5-HT-induced nociceptive response at the primary sensory level 5-HT3R may play a role of initiation, but 5-HT2R mediates maintaining and modulatory effect in the processes of nociceptive information convey.

Animals ; Male ; Membrane Potentials ; Pain ; physiopathology ; Patch-Clamp Techniques ; Rats ; Rats, Sprague-Dawley ; Receptors, Serotonin, 5-HT1 ; metabolism ; Receptors, Serotonin, 5-HT2 ; metabolism ; Receptors, Serotonin, 5-HT3 ; metabolism ; Sensory Receptor Cells ; metabolism ; physiology

OBJECTIVEDisruptive behavior disorder (DBD) is one of the main comorbidity of attention deficit hyperactivity disorder (ADHD). Previous studies showed significantly different serotonin function between ADHD children with and without the comorbidity of DBD. Therefore, it is needed to compare these two groups in terms of serotonin receptor gene polymorphisms, which may provide further evidence for the previous studies. The current study aimed to investigate the relationship between two serotonin receptor 2C (HTR2C) gene polymorphisms, that are C-759T and G-697C polymorphisms, and ADHD with or without concomitant DBD.

METHODBlood samples were taken from 237 trios with probands of ADHD with DBD comorbidity and 251 trios with probands of ADHD without comorbidity of DBD. All the subjects were from the ADHD clinic of Peking University Sixth Hospital. DNA was extracted and PCR was performed to amplify the fragments containing both C-759T and G-697C polymorphisms. AciI was used to detect different alleles of the two polymorphisms. Both allele-based and haplotype-based TDT analyses were used to test the association of the two polymorphisms of HTR2C gene and ADHD with or without comorbidity of DBD.

RESULTSThe haplotypes -759C (chi(2) = 4.25, P = 0.04), -697G(chi(2) = 3.21, P = 0.07), as well as -759C/-697G were over-transmitted (chi(2) = 4.31, P = 0.04) to the probands of ADHD without DBD. No biased transmission of any allele and haplotype were found in families with probands of ADHD with DBD.

CONCLUSIONADHD with or without the comorbidity DBD was different at the level of HTR2C gene polymorphisms of C-759T and G-697C. HTR2C is related to ADHD without DBD, while not related to ADHD with DBD. The results suggested that the two groups may have different genetic background, at least in HTR2C.

Alleles ; Attention Deficit Disorder with Hyperactivity ; complications ; genetics ; Attention Deficit and Disruptive Behavior Disorders ; complications ; genetics ; Child ; Comorbidity ; Gene Frequency ; Genetic Predisposition to Disease ; Genetic Testing ; Genotype ; Haplotypes ; Humans ; Linkage Disequilibrium ; Polymorphism, Genetic ; Receptor, Serotonin, 5-HT2C ; genetics ; Receptors, Serotonin ; Serotonin ; genetics

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.
Administration, Oral ; Animals ; Aquatic Organisms* ; gamma-Aminobutyric Acid ; Hypnosis ; Lactobacillus brevis ; Mice ; Ostreidae ; Receptor, Serotonin, 5-HT2C ; Receptors, GABA-A ; Sleep Initiation and Maintenance Disorders

OBJECTIVETo assess whether HTR1A and HTR1B polymorphisms are associated with the predisposition, gender, PUMC Classification and/or severity of adolescent idiopathic scoliosis (AIS).

METHODSRs6294 (HTR1A) and rs6296 (HTR1B) were genotyped in 103 AIS patients treated from January 2006 to March 2007, and 108 controls with matched gender and age. The data were analyzed by the allelic and genotypic association analysis, and the genotype-phenotype (gender, PUMC Classification, and Cobb angle) association analysis.

RESULTSThe distributions of the alleles of all the 2 SNPs met Hardy-Weinberg equilibrium in the controls (goodness-of-fit chi(2) test, P > 0.05). The allele A of rs6294 was related with the occurrence of AIS (P = 0.041), but differences of the allele frequencies of rs6296 and the genotype frequencies of both SNPs between 2 groups had no statistical significance (P > 0.05). The genotype A/A + A/G of rs6294 was associated with AIS PUMC type III, and there was no other positive results in genotype-phenotype association analysis.

CONCLUSIONThese results suggest that HTR1A may be a predisposition gene of AIS PUMC type III, and PUMC Classification may has its genetic basis.

Adolescent ; Gene Frequency ; Genetic Association Studies ; Genotype ; Humans ; Polymorphism, Genetic ; Polymorphism, Single Nucleotide ; Receptor, Serotonin, 5-HT1A ; genetics ; Receptor, Serotonin, 5-HT1B ; genetics ; Scoliosis ; genetics