5-HT2C Receptor Research -- Neurotransmitter.net

(Updated 12/02)

Niswender CM, Sanders-Bush E, Emeson RB.
Identification and characterization of RNA editing events within the 5-HT2C receptor.
Ann N Y Acad Sci 1998 Dec 15;861:38-48
"Editing events at four major positions, termed A, B, C and D, as well as one minor site termed C', are predicted to alter amino acids within the second intracellular loop of the G-protein coupled 5-HT2C receptor. Editing is mediated by at least two members of a family of adenosine deaminases and is contingent upon the presence of an extensive RNA duplex structure formed by exonic and intronic sequences of 5-HT2C receptor precursor messenger RNA (pre-mRNA)." [Abstract]

Price, Raymond D., Sanders-Bush, Elaine
RNA Editing of the Human Serotonin 5-HT2C Receptor Delays Agonist-Stimulated Calcium Release
Mol Pharmacol 2000 58: 859-862
"The hVGV isoform shows a different pattern of calcium release compared with the hINI and hVSV isoforms, with a smaller peak height and longer latency." [Full Text]

Niswender CM, Herrick-Davis K, Dilley GE, Meltzer HY, Overholser JC, Stockmeier CA, Emeson RB, Sanders-Bush E.
RNA editing of the human serotonin 5-HT2C receptor. alterations in suicide and implications for serotonergic pharmacotherapy
Neuropsychopharmacology 2001 May;24(5):478-91 .
"An examination of the efficiencies of RNA editing of the 5-HT(2C)R in prefrontal cortex of control individuals vs. subjects diagnosed with schizophrenia or major depressive disorder revealed no significant differences in RNA editing among the three populations. However, subjects who had committed suicide (regardless of diagnosis) exhibited a statistically significant elevation of editing at the A-site, which is predicted to change the amino acid sequence in the second intracellular loop of the 5-HT(2C)R. These findings suggest that alterations in RNA editing may contribute to or complicate therapy in certain psychiatric disorders." [Abstract]

Bonaccorso S, Meltzer H, Li Z, Dai J, Alboszta A, Ichikawa J.
SR46349-B, a 5-HT(2A/2C) Receptor Antagonist, Potentiates Haloperidol-induced Dopamine Release in Rat Medial Prefrontal Cortex and Nucleus Accumbens.
Neuropsychopharmacology 2002 Sep;27(3):430
"The combination of M100907, a putative antipsychotic drug (APD) and serotonin (5-HT)(2A) antagonist, and the typical APD haloperidol, can enhance dopamine (DA) release in rat medial prefrontal cortex (mPFC), an effect which has been postulated to be of value to improve cognition and negative symptoms. The present study demonstrated that another putative APD and 5-HT(2A/2C) antagonist, SR46349-B (10 mg/kg, but not 1-3 mg/kg) alone, but not M100907 (0.1 and 3 mg/kg) alone, increased mPFC DA release, whereas neither drug alone affected nucleus accumbens (NAC) DA release. Neither SR46349-B nor M100907 alone affected nucleus accumbens (NAC) DA release. Neither SR46349-B nor M100907 alone affected nucleus accumbens (NAC) DA release. SR46349-B (3 mg/kg) potentiated haloperidol-induced DA release in both regions, whereas M100907 (0.1 mg/kg) potentiated haloperidol (0.1 mg/kg)-induced mPFC DA release and inhibited it in the NAC." [Abstract]

Stout, Brian D., Clarke, William P., Berg, Kelly A.
Rapid Desensitization of the Serotonin2C Receptor System: Effector Pathway and Agonist Dependence
J Pharmacol Exp Ther 2002 302: 957-962
"The serotonin2C (5-HT2C) receptor couples to multiple effector mechanisms, including phospholipase A2-mediated arachidonic acid (AA) release and phospholipase C-mediated production of inositol phosphates (IP). Agonist relative efficacy differs depending upon which response (AA release or IP accumulation) is measured. In this study, we investigated the characteristics and agonist dependence of rapid desensitization of 5-HT2C receptor-mediated AA release and IP accumulation measured simultaneously from the same cell population. Pretreatment with 5-HT reduced the ability of a maximal concentration of 5-HT to elicit AA release and IP accumulation by about 60%; however, the AA response desensitized more rapidly (t1/2 = 1.3 min) than the IP response (t1/2 = 6.9 min). In addition, desensitization of the IP response was more sensitive (occurred at lower receptor occupancy levels) than the AA response. Moreover, in response to submaximal 5-HT concentrations, after an initial transient desensitization, the AA response was enhanced by up to ~250%. After maximal desensitization, both responses recovered, but recovery of the AA response was complete and faster than that for IP. Desensitization of both responses was also agonist-dependent, and the capacity of agonists to elicit desensitization was not related to their efficacy to activate signaling. These data suggest that desensitization of the 5-HT2C receptor system is both agonist- and effector pathway-dependent and underscore the need to study multiple cellular responses to multiple agonists to understand receptor-mediated signaling systems." [Abstract]

Chen CX, Cho DS, Wang Q, Lai F, Carter KC, Nishikura K.
A third member of the RNA-specific adenosine deaminase gene family, ADAR3, contains both single- and double-stranded RNA binding domains.
RNA 2000 May;6(5):755-67
"The presence of this ssRNA-binding domain as well as its expression in restricted brain regions and postmitotic neurons make ADAR3 distinct from the other two ADAR gene family members, editing competent ADAR1 and ADAR2. ADAR3 inhibited in vitro the activities of RNA editing enzymes of the ADAR gene family, raising the possibility of a regulatory role in RNA editing." [Abstract]

Becamel, Carine, Alonso, Gerard, Galeotti, Nathalie, Demey, Emmanuelle, Jouin, Patrick, Ullmer, Christoph, Dumuis, Aline, Bockaert, Joel, Marin, Philippe
Synaptic multiprotein complexes associated with 5-HT2C receptors: a proteomic approach
EMBO J. 2002 21: 2332-2342 [Abstract]

Wang, Qingde, O'Brien, Peter J., Chen, Chun-Xia, Cho, Dan-Sung C., Murray, John M., Nishikura, Kazuko
Altered G Protein-Coupling Functions of RNA Editing Isoform and Splicing Variant Serotonin2C Receptors
J Neurochem 2000 74: 1290-1300
"Asp158 present in the IDV isoform may mimic a structure similar to phosphorylated Ser158, providing a possible mechanism for fine adjustment of the constitutive activity via RNA editing and consequent phosphorylation of the edited Ser158 by a casein kinase II-like activity." [Abstract]

Burns CM, Chu H, Rueter SM, Hutchinson LK, Canton H, Sanders-Bush E, Emeson RB.
Regulation of serotonin-2C receptor G-protein coupling by RNA editing.
Nature 1997 May 15;387(6630):303-8 [Abstract]

Carine Bécamel, Andrea Figge, Sebastian Poliak, Aline Dumuis, Elior Peles, Joël Bockaert, Hermann Lübbert, and Christoph Ullmer
Interaction of Serotonin 5-Hydroxytryptamine Type 2C Receptors with PDZ10 of the Multi-PDZ Domain Protein MUPP1
J. Biol. Chem. 276: 12974-12982, April 20, 2001. [Full Text]

Jon R. Backstrom, Raymond D. Price, Darcie T. Reasoner, and Elaine Sanders-Bush
Deletion of the Serotonin 5-HT2C Receptor PDZ Recognition Motif Prevents Receptor Phosphorylation and Delays Resensitization of Receptor Responses
J. Biol. Chem. 275: 23620-23626, August 4, 2000. [Full Text]

Li Q, Wichems CH, Ma L, Van de Kar LD, Garcia F, Murphy DL.
Brain region-specific alterations of 5-HT2A and 5-HT2C receptors in serotonin transporter knockout mice.
J Neurochem 2003 Mar;84(6):1256-65
"The aim of the present studies was to determine the effects of reduced or absent serotonin (5-HT) transporters (5-HTTs) on 5-HT2A and 5-HT2C receptors. The density of 5-HT2C receptors was significantly increased in the amygdala and choroid plexus of 5-HTT knockout mice. On the other hand, the density of 5-HT2A receptors was significantly increased in the hypothalamus and septum, but reduced in the striatum, of 5-HTT knockout mice. However, 5-HT2A mRNA was not changed in any brain region measured. 5-HT2C mRNA was significantly reduced in the choroid plexus and lateral habenula nucleus of these mice. The function of 5-HT2A receptors was evaluated by hormonal responses to (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI). Oxytocin, but not adrenocorticotrophic hormone or corticosterone, responses to DOI were significantly greater in 5-HTT knockout mice. In addition, Gq and G11 proteins were not significantly changed in any brain region measured. The present results suggest that the constitutive alteration in the function of 5-HTTs changes the density of 5-HT2A and 5-HT2C receptors in a brain region-specific manner. These changes may not be mediated by alterations in their gene expression or in the level of Gq/11 proteins. The alterations in these receptors may be related to the altered behaviors of 5-HTT knockout mice." [Abstract]

Kuhn KU, Quednow BB, Bagli M, Meyer K, Feuchtl A, Westheide J, Frahnert C, Maier W, Rao ML.
Allelic Variants of the Serotonin2C Receptor and Neuroendocrinological Responses to the Serotonin2C Receptor Agonist m-Chlorophenylpiperazine in Healthy Male Volunteers.
Pharmacopsychiatry 2002 Nov;35(6):226-30
"The neurotransmitter serotonin (5-HT) possesses several receptors and their subtypes, some of which are polymorphic, such as the 5-HT 2C receptor. The latter has been implicated in the control of neuroendocrine function, and has been discussed in the pathophysiology and pharmacotherapy of psychiatric disorders such as obsessive-compulsive disorder, panic disorder and bipolar affective disorder. To investigate whether the 5-HT 2C receptor polymorphism contributes to the variation of neuroendocrinological responses elicited by activation of the hypothalamic-pituitary axis, we performed an m-chlorophenylpiperazine (m-CPP) challenge and monitored m-CPP and ACTH, cortisol and prolactin plasma levels in 16 healthy male volunteers carrying the common 5-HT 2C -cys-23 receptor gene and 16 healthy male volunteers carrying the less frequent 5-HT 2C -ser-23 receptor gene. The 5-HT 2C polymorphism contributed little to the variation of the scores regarding hormonal responses of ACTH, cortisol and prolactin to the m-CPP challenge. The group carrying the rare 5-HT 2C -ser-23 receptor gene showed a faster and stronger but not statistically significant ACTH response to the challenge. However, it is noteworthy that there is a 'medium' effect size of the ACTH response according to the conventions of Cohen, and thus comparable to other studies. Both groups show similar major scores in the Temperament and Character Inventory (TCI)." [Abstract]

Lerer B, Macciardi F, Segman RH, Adolfsson R, Blackwood D, Blairy S, Del Favero J, Dikeos DG, Kaneva R, Lilli R, Massat I, Milanova V, Muir W, Noethen M, Oruc L, Petrova T, Papadimitriou GN, Rietschel M, Serretti A, Souery D, Van Gestel S, Van Broeckhoven C, Mendlewicz J.
Variability of 5-HT2C receptor cys23ser polymorphism among European populations and vulnerability to affective disorder.
Mol Psychiatry 2001 Sep;6(5):579-85 [Full Text]

Lucas, Guillaume, Spampinato, Umberto
Role of Striatal Serotonin2A and Serotonin2C Receptor Subtypes in the Control of In Vivo Dopamine Outflow in the Rat Striatum
J Neurochem 2000 74: 693-701
"These results indicate that striatal 5-HT2A receptors, probably through activation of DA synthesis, positively modulate DA outflow only under activated conditions. In contrast, striatal 5-HT2C receptors exert a facilitatory control on basal DA efflux, which appears to be both tonic and phasic." [Abstract]

Virkkunen M, Goldman D, Linnoila M.
Serotonin in alcoholic violent offenders.
Ciba Found Symp 1996;194:168-77; discussion 177-82
"Thus far, polymorphisms of the tryptophan hydroxylase (TPH) and 5-HT2C receptor genes have been the most informative findings." [Abstract]

Evans J, Reeves B, Platt H, Leibenau A, Goldman D, Jefferson K, Nutt D.
Impulsiveness, serotonin genes and repetition of deliberate self-harm (DSH).
Psychol Med 2000 Nov;30(6):1327-34
"Males with the 5-HT2c serine variant were more impulsive than those with the cysteine variant (039 standardized units, P = 0.041, 95% CI 0.017 to 0.076)." [Abstract]

Canton, H, Emeson, RB, Barker, EL, Backstrom, JR, Lu, JT, Chang, MS, Sanders-Bush, E
Identification, molecular cloning, and distribution of a short variant of the 5-hydroxytryptamine2C receptor produced by alternative splicing
Mol Pharmacol 1996 50: 799-807 [Abstract]

Fitzgerald LW, Iyer G, Conklin DS, Krause CM, Marshall A, Patterson JP, Tran DP, Jonak GJ, Hartig PR.
Messenger RNA editing of the human serotonin 5-HT2C receptor.
Neuropsychopharmacology 1999 Aug;21(2 Suppl):82S-90S
"We observed that editing reduces both the binding affinity and functional potency of agonists for recombinant human 5-HT2C receptor isoforms. This effect on binding affinity was proportional to the agonist's intrinsic activity, with full agonists most affected, and antagonists showing no effect." [Abstract]

Berg, KA, Maayani, S, Clarke, WP
5-hydroxytryptamine2C receptor activation inhibits 5- hydroxytryptamine1B-like receptor function via arachidonic acid metabolism
Mol Pharmacol 1996 50: 1017-1023
"5-hydroxytryptamine2C receptor activation inhibits 5- hydroxytryptamine1B-like receptor function via arachidonic acid metabolism." [Abstract]

Herrick-Davis, Katharine, Grinde, Ellinor, Niswender, Colleen M.
Serotonin 5-HT2C Receptor RNA Editing Alters Receptor Basal Activity: Implications for Serotonergic Signal Transduction
J Neurochem 1999 73: 1711-1717 [Abstract]

Berg, Kelly A., Cropper, Jodie D., Niswender, Colleen M., Sanders-Bush, Elaine, Emeson, Ronald B., Clarke, William P.
RNA-editing of the 5-HT2C receptor alters agonist-receptor-effector coupling specificity
Br. J. Pharmacol. 2001 134: 386-392 [Abstract]

Berg, Kelly A., Maayani, Saul, Goldfarb, Joseph, Scaramellini, Clare, Leff, Paul, Clarke, William P.
Effector Pathway-Dependent Relative Efficacy at Serotonin Type 2A and 2C Receptors: Evidence for Agonist-Directed Trafficking of Receptor Stimulus
Mol Pharmacol 1998 54: 94-104 [Full Text]

LAPPALAINEN, J;ZHANG, L;DEAN, M;OZ, M;OZAKI, N;YU, DH;VIRKKUNEN, M;WEIGHT, F;LINNOILA, M;GOLDMAN, D
IDENTIFICATION, EXPRESSION, AND PHARMACOLOGY OF A CYS(23)-SER(23) SUBSTITUTION IN THE HUMAN 5-HT2C RECEPTOR GENE (HTR2C)
GENOMICS 27: (2) 274-279 MAY 20 1995
"Allele frequencies in unrelated Caucasians were 0.13 and 0.87 for 5-HT2Cser and 5-HT2Ccys, respectively." [Abstract]

Di Matteo V, Di Giovanni G, Di Mascio M, Esposito E.
SB 242084, a selective serotonin2C receptor antagonist, increases dopaminergic transmission in the mesolimbic system.
Neuropharmacology 1999 Aug;38(8):1195-205 [Abstract]

Pompeiano M, Palacios JM, Mengod G.
Distribution of the serotonin 5-HT2 receptor family mRNAs: comparison between 5-HT2A and 5-HT2C receptors.
Brain Res Mol Brain Res 1994 Apr;23(1-2):163-78 [Abstract]

De Deurwaerdere, Philippe, Chesselet, Marie-Francoise
Nigrostriatal Lesions Alter Oral Dyskinesia and c-Fos Expression Induced by the Serotonin Agonist 1-(m-Chlorophenyl)piperazine in Adult Rats
J. Neurosci. 2000 20: 5170-5178 [Full Text]

Meltzer HY.
The role of serotonin in antipsychotic drug action.
Neuropsychopharmacology 1999 Aug;21(2 Suppl):106S-115S
"Stimulation of the 5-HT1a receptor appears to produce many of the same effects as antagonism of the 5-HT2a receptor while antagonism of the 5-HT2c receptor appears to diminish some of the actions of 5-HT2a receptor antagonism." [Abstract]

Segman RH, Ebstein RP, Heresco-Levy U, Gorfine M, Avnon M, Gur E, Nemanov L, Lerer B.
Schizophrenia, chronic hospitalization and the 5-HT2C receptor gene.
Psychiatr Genet 1997 Summer;7(2):75-8
"However, proportion of time spent in hospital since the first admission was significantly greater in patients hemi- of homozygous for the 5-HT2Cser allele than in patients carrying other genotypes (p = 0.006). The 5-HT2Cser genotype conferred a 3.3-fold increased risk for lifetime hospitalization exceeding 10 years. Genetically determined variation in the 5-HT2C receptor may influence the clinical course and phenotypic expression of schizophrenia." [Abstract]

Roger M. Nitsch, Meihua Deng, John H. Growdon, and Richard J. Wurtman
Serotonin 5-HT2a and 5-HT2c Receptors Stimulate Amyloid Precursor Protein Ectodomain Secretion
J. Biol. Chem. 271: 4188-4194, February 23, 1996. [Full Text]

Cowen PJ, Clifford EM, Walsh AE, Williams C, Fairburn CG.
Moderate dieting causes 5-HT2C receptor supersensitivity.
Psychol Med 1996 Nov;26(6):1155-9 [Abstract]

HEISLER, L. K., CHU, H.-M, TECOTT, L. H.
Epilepsy and Obesity in Serotonin 5-HT2C Receptor Mutant Mice
Ann NY Acad Sci 1998 861: 74-78 [Abstract]

Benjamin J, Ebstein RP, Belmaker RH.
Personality genetics.
Isr J Psychiatry Relat Sci 1997;34(4):270-80
"In the Israeli sample we also found an interaction between the D4DR gene and the serotonin 2C receptor gene (5-HT2C) with a marked effect on the trait of reward dependence." [Abstract]

Segman RH, Heresco-Levy U, Finkel B, Inbar R, Neeman T, Schlafman M, Dorevitch A, Yakir A, Lerner A, Goltser T, Shelevoy A, Lerer B.
Association between the serotonin 2C receptor gene and tardive dyskinesia in chronic schizophrenia: additive contribution of 5-HT2Cser and DRD3gly alleles to susceptibility.
Psychopharmacology (Berl) 2000 Nov;152(4):408-13
"We found a significant excess of 5-HT2Cser alleles in schizophrenia patients with TD (27.2%) compared to patients without TD (14.6%) and normal controls (14.2%; chi2=6.4, df 2, P=0.03) which was due to the female patients (chi2=8.6, df 2, P=0.01). Among the female TD patients there was an excess of cys-ser and ser-ser genotypes (chi2= 11.9, df 4, P=0.02)." [Abstract]

Gurevich I, Tamir H, Arango V, Dwork AJ, Mann JJ, Schmauss C.
Altered editing of serotonin 2C receptor pre-mRNA in the prefrontal cortex of depressed suicide victims.
Neuron. 2002 Apr 25;34(3):327-8.
"Five adenosines within the coding sequence of the serotonin 2C receptor (5-HT2C) pre-mRNA are converted to inosines by RNA editing (named A, B, C' (E), C, and D sites). In human prefrontal cortex (PFC), the most abundant 5-HT2C mRNA sequences result from editing at the A site, or from the editing combinations AC'C, ABCD, and ABD. In suicide victims with a history of major depression, C' site editing is significantly increased, D site editing is significantly decreased, and the C site shows a trend toward increased editing. Treatment of mice with the antidepressant drug fluoxetine (Prozac) causes changes in C', C, and D site editing that are exactly opposite to those seen in suicide victims. Thus, one outcome of fluoxetine treatment may be to reverse the abnormalities in 5-HT2C pre-mRNA editing seen in depressed suicide victims." [Abstract] [PDF]

Gurevich I, Englander MT, Adlersberg M, Siegal NB, Schmauss C.
Modulation of serotonin 2C receptor editing by sustained changes in serotonergic neurotransmission.
J Neurosci 2002 Dec 15;22(24):10529-32
"Serotonin 2C (5-HT2C) receptor pre-mRNA is a substrate for RNA editing enzymes that convert five adenosines (named A, B, C', C, and D editing sites) to inosines. Editing of two of these sites (C' and C) is crucial for decreasing the efficiency of the receptor to activate G-protein. Nucleotide sequence analysis of mouse forebrain neocortical 5-HT2C mRNA isoforms revealed that editing at these two sites is regulated in a serotonin-dependent manner. In serotonin-depleted mice, C'- and C-site editing is significantly decreased. This results in an increased expression of 5-HT2C mRNA isoforms encoding receptors with higher sensitivity to serotonin. In contrast, a 4 d treatment with the 5-HT2A/2C agonist (+/-)-1-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane significantly increases the editing frequency at the C' site and leads to increased expression of 5-HT2C mRNA isoforms encoding receptors that activate G-protein least efficiently. None of the drug treatments led to alterations in cytoplasmic 5-HT2C mRNA levels. These data indicate that editing of 5-HT2C pre-mRNA is a mechanism that retains basic response properties of 5-HT2C receptors in the face of changing synaptic input to keep receptor activation within an optimal range for information processing." [Abstract] [PDF]

Iwamoto K, Kato T.
RNA editing of serotonin 2C receptor in human postmortem brains of major mental disorders.
Neurosci Lett. 2003 Aug 7;346(3):169-72.
"The importance of serotonin 2C receptor (HTR2C) in mental disorders has been implicated by studies of HTR2C-deficient mice and linkage and association studies. Recent studies have revealed that RNA editing of HTR2C is involved in mental disorders. Here we examined RNA editing efficiencies of site A and D of HTR2C in the prefrontal cortex samples of patients with bipolar disorder, schizophrenia, and major depression as well as control subjects by using primer extension combined with denaturing high performance liquid chromatography. Postmortem samples were donated by the Stanley Foundation Brain Collection. We could not find significant alterations of RNA editing efficiencies of these sites in patients. However, we found trends for increased RNA editing efficiencies of site D in depressive patients (P=0.08) and site A in suicide victims (P=0.07). These findings are in accordance with the previous findings, and suggest that altered RNA editing of HTR2C may have some significance in major depression and suicide." [Abstract]

More RNA editing information is listed here.

Blackburn TP, Minabe Y, Middlemiss DN, Shirayama Y, Hashimoto K, Ashby CR Jr.
Effect of acute and chronic administration of the selective 5-HT2C receptor antagonist SB-243213 on midbrain dopamine neurons in the rat: An in vivo extracellular single cell study.
Synapse 2002 Dec 1;46(3):129-139
"Overall, our results indicate that antagonism of the 5-HT(2C) receptor alters the activity of midbrain DA neurons in anesthetized rats and suggest that SB-243213 has an atypical antipsychotic profile following chronic administration." [Abstract]

Becamel, Carine, Alonso, Gerard, Galeotti, Nathalie, Demey, Emmanuelle, Jouin, Patrick, Ullmer, Christoph, Dumuis, Aline, Bockaert, Joel, Marin, Philippe
Synaptic multiprotein complexes associated with 5-HT2C receptors: a proteomic approach
EMBO J. 2002 21: 2332-2342
"Using a proteomic approach based on peptide affinity chromatography followed by mass spectrometry and immunoblotting, we have identified 15 proteins that interact with the C- terminal tail of the 5-hydroxytryptamine 2C (5-HT2C) receptor, a GPCR. These proteins include several synaptic multidomain proteins containing one or several PDZ domains (PSD95 and the proteins of the tripartite complex Veli3–CASK–Mint1), proteins of the actin/spectrin cytoskeleton and signalling proteins. Coimmunoprecipitation experiments showed that 5-HT2C receptors interact with PSD95 and the Veli3–CASK–Mint1 complex in vivo. Electron microscopy also indicated a synaptic enrichment of Veli3 and 5-HT2C receptors and their colocalization in microvilli of choroidal cells. These results indicate that the 5-HT2C receptor is associated with protein networks that are important for its synaptic localization and its coupling to the signalling machinery." [Abstract]

Yong Liu, Ronald B. Emeson, and Charles E. Samuel
Serotonin-2C Receptor Pre-mRNA Editing in Rat Brain and in Vitro by Splice Site Variants of the Interferon-inducible Double-stranded RNA-specific Adenosine Deaminase ADAR1
J. Biol. Chem. 274: 18351-18358, 1999. [Full Text]

Mike Chang, Lianshan Zhang, James P. Tam, and Elaine Sanders-Bush
Dissecting G Protein-coupled Receptor Signaling Pathways with Membrane-permeable Blocking Peptides. ENDOGENOUS 5-HT2C RECEPTORS IN CHOROID PLEXUS EPITHELIAL CELLS
J. Biol. Chem. 275: 7021-7029, March 10, 2000. [Full Text]

Cussac, Didier, Newman-Tancredi, Adrian, Duqueyroix, Delphine, Pasteau, Valerie, Millan, Mark J.
Differential Activation of Gq/11 and Gi3 Proteins at 5-Hydroxytryptamine2C Receptors Revealed by Antibody Capture Assays: Influence of Receptor Reserve and Relationship to Agonist-Directed Trafficking
Mol Pharmacol 2002 62: 578-589 [Abstract]

Berg, Kelly A., Stout, Brian D., Cropper, Jodie D., Maayani, Saul, Clarke, William P.
Novel Actions of Inverse Agonists on 5-HT2C Receptor Systems
Mol Pharmacol 1999 55: 863-872 [Full Text]

Sallese, Michele, Mariggio, Stefania, D'Urbano, Etrusca, Iacovelli, Luisa, De Blasi, Antonio
Selective Regulation of Gq Signaling by G Protein-Coupled Receptor Kinase 2: Direct Interaction of Kinase N Terminus with Activated Galpha q
Mol Pharmacol 2000 57: 826-831 [Full Text]

Hurley, Joyce H., Bloem, Laura J., Pavalko, Fred, Liu, Jian, Tian, Mingting, Simon, Jay R., Yu, Lei
Structure--Function Studies of the Eighth Hydrophobic Domain of a Serotonin Receptor
J Neurochem 1999 72: 413-421 [Abstract]

Raymond D. Price, David M. Weiner, Mike S. S. Chang, and Elaine Sanders-Bush
RNA Editing of the Human Serotonin 5-HT2C Receptor Alters Receptor-mediated Activation of G13 Protein
J. Biol. Chem. 276: 44663-44668, November 30, 2001.
"Taken together, these data support the hypothesis that the INI isoform has the ability to activate Gq, G13, and G15, whereas the edited VSV and VGV receptor isoforms can efficiently activate only the Gq family of G-proteins." [Full Text]

Di Giovanni G, De Deurwaerdere P, Di Mascio M, Di Matteo V, Esposito E, Spampinato U.
Selective blockade of serotonin-2C/2B receptors enhances mesolimbic and mesostriatal dopaminergic function: a combined in vivo electrophysiological and microdialysis study.
Neuroscience 1999;91(2):587-97 [Abstract]

Heisler LK, Tecott LH.
A paradoxical locomotor response in serotonin 5-HT(2C) receptor mutant mice.
J Neurosci 2000 Apr 15;20(8):RC71
"We report that a single receptor gene mutation produces a paradoxical response to the nonspecific serotonin receptor agonist m-chlorophenylpiperazine (mCPP). Although this compound normally suppresses locomotion, it produces hyperactivity in mice bearing a targeted mutation of the 5-HT(2C) receptor gene. This effect was blocked by pretreatment with a 5-HT(1B) receptor antagonist, indicating that the behavioral consequences of mCPP-induced 5-HT(1B) receptor stimulation are unmasked in animals devoid of 5-HT(2C) receptor function." [Abstract]

Westphal, RS, Backstrom, JR, Sanders-Bush, E
Increased basal phosphorylation of the constitutively active serotonin 2C receptor accompanies agonist-mediated desensitization
Mol Pharmacol 1995 48: 200-205 [Abstract]

Westphal, RS, Sanders-Bush, E
Differences in agonist-independent and -dependent 5-hydroxytryptamine2C receptor-mediated cell division
Mol Pharmacol 1996 49: 474-480 [Abstract]

Laurence H. Tecott, Sheree F. Logue, Jeanne M. Wehner, and Julie A. Kauer
Perturbed dentate gyrus function in serotonin 5-HT2C receptor mutant mice
PNAS 95: 15026-15031, December 8, 1998. [Full Text]

Grottick, Andrew J., Fletcher, Paul J., Higgins, Guy A.
Studies to Investigate the Role of 5-HT2C Receptors on Cocaine- and Food-Maintained Behavior
J Pharmacol Exp Ther 2000 295: 1183-1191
"Taken together, these studies suggest that, in addition to reducing food intake, 5-HT2C receptor agonists reduce cocaine-reinforced behavior. This would be consistent with electrophysiological and biochemical evidence suggesting an important modulatory influence of 5-HT2C receptor activation on mesolimbic dopamine function." [Full Text]

McMahonLance R, LR McMahon, M Filip, KA Cunningham
Differential regulation of the mesoaccumbens circuit by serotonin 5-hydroxytryptamine (5-ht)2a and 5-ht2c receptors
JOURNAL OF NEUROSCIENCE: THE OFFICIAL JOURNAL OF THE SOCIETY FOR NEUROSCIENCE, THE , 21(19):7781-7787 2001
"These findings are the first to demonstrate that the behavioral effects of cocaine are generated in part by activation of 5-HT(2A)Rs in the VTA and by activation of 5-HT(2C)Rs in the NAc shell." [Abstract]

Herrick-Davis, Katharine, Grinde, Ellinor, Teitler, Milt
Inverse Agonist Activity of Atypical Antipsychotic Drugs at Human 5-Hydroxytryptamine2C Receptors
J Pharmacol Exp Ther 2000 295: 226-232 [Full Text]
-note that 5-HT2C agonism as an atypical antipsychotic mechanism of efficacy is purely conjectural

Berg, Kelly A., Stout, Brian D., Maayani, Saul, Clarke, William P.
Differences in Rapid Desensitization of 5-Hydroxytryptamine2A and 5-Hydroxytryptamine2C Receptor-Mediated Phospholipase C Activation
J Pharmacol Exp Ther 2001 299: 593-602 [Abstract]

Deurwaerdere, Philippe De, Spampinato, Umberto
Role of Serotonin2A and Serotonin2B/2C Receptor Subtypes in the Control of Accumbal and Striatal Dopamine Release Elicited In Vivo by Dorsal Raphe Nucleus Electrical Stimulation
J Neurochem 1999 73: 1033-1042 [Abstract]

Maura, Guido, Marcoli, Manuela, Pepicelli, Olimpia, Rosu, Christian, Viola, Concetta, Raiteri, Maurizio
Serotonin inhibition of the NMDA receptor/nitric oxide/cyclic GMP pathway in human neocortex slices: involvement of 5-HT2C and 5-HT1A receptors
Br. J. Pharmacol. 2000 130: 1853-1858 [Abstract]

VERBEKE, MARLEEN, VAN DE VOORDE, JOHAN, DE RIDDER, LEO, LAMEIRE, NORBERT
Beneficial Effect of Serotonin 5-HT2-Receptor Antagonism on Renal Blood Flow Autoregulation in Cyclosporin-Treated Rats
J Am Soc Nephrol 1999 10: 28-34 [Full Text]

Feng, Jian, Cai, Xiang, Zhao, Jinghui, Yan, Zhen
Serotonin Receptors Modulate GABAA Receptor Channels through Activation of Anchored Protein Kinase C in Prefrontal Cortical Neurons
J. Neurosci. 2001 21: 6502-6511
"Our single-cell mRNA profiling experiments have shown that 5-HT2A receptors are expressed in the majority of PFC pyramidal neurons (>80%), whereas 5-HT2C receptors are detected in only one-third of these cells, suggesting that the effects of DOI on GABAA currents found in most PFC pyramidal neurons can be primarily attributed to 5-HT2A receptors." [Full Text]

Komatsu, Yukio
GABAB Receptors, Monoamine Receptors, and Postsynaptic Inositol Trisphosphate-Induced Ca2+ Release Are Involved in the Induction of Long-Term Potentiation at Visual Cortical Inhibitory Synapses
J. Neurosci. 1996 16: 6342-6352
"Inhibitory responses of layer V cells evoked by layer IV stimulation were studied in developing rat visual cortex slices by using intracellular and whole-cell recording methods. LTP induction was prevented by the application of an antagonist for GABAB receptors but not for GABAA or metabotropic glutamate receptors. Inhibition of postsynaptic G-proteins, phospholipase C, inositol trisphosphate (IP3) receptors, or Ca2+ increase prevented the generation of LTP, as did the blockade of GABAB receptors." [Full text]

Reynolds GP, Zhang ZJ, Zhang XB.
Association of antipsychotic drug-induced weight gain with a 5-HT2C receptor gene polymorphism.
Lancet 2002 Jun 15;359(9323):2086-7
"We noted significantly less weight gain in patients with the -759T variant allele (p=0.0003) than in those without this allele, who were more likely to have substantial (>7%) weight gain (p=0.002). We have identified a genetic factor that is associated with antipsychotic drug-induced weight gain." [Abstract]

Lindberg N, Virkkunen M, Tani P, Appelberg B, Virkkala J, Rimon R, Porkka-Heiskanen T.
Effect of a single-dose of olanzapine on sleep in healthy females and males.
Int Clin Psychopharmacol 2002 Jul;17(4):177-84
"The difference between the sexes could not be explained by differences in body mass index. Olanzapine affects sleep probably through 5-HT2C receptors. The receptor gene is located on the X-chromosome, inducing an allelic difference between the females and males. This difference may contribute to the different effects of olanzapine on sleep." [Abstract]

Arjona A, Pooler A, Lee R, Wurtman R.
Effect of a 5-HT(2C) serotonin agonist, dexnorfenfluramine, on amyloid precursor protein metabolism in guinea pigs.
Brain Res 2002 Sep 27;951(1):135
"These data indicate that the pharmacological activation of 5-HT(2C) receptors can stimulate CSF APP(s) secretion and reduce Abeta production in vivo. Hence 5-HT(2C) receptors, which apparently are localized to the brain, may represent useful targets for the development of treatments for Alzheimer's disease." [Abstract]

Millan MJ, Girardon S, Dekeyne A.
5-HT2C receptors are involved in the discriminative stimulus effects of citalopram in rats.
Psychopharmacology (Berl) 1999 Mar;142(4):432-4
"The preferential, high efficacy agonist at 5-HT2C receptors, Ro60-0175, dose-dependently generalized to citalopram with an ED50 of 0.3 mg/kg, IP. Further, the selective 5-HT2C receptor antagonist, SB242,084, dose-dependently (ED50=0.1 mg/kg, IP) blocked the citalopram DS. These data suggest that 5-HT2C receptors are involved in the DS properties of the SSRI, citalopram, in rats. They do not, however, exclude a potential role of other 5-HT receptor types." [Abstract]

Palvimaki EP, Roth BL, Majasuo H, Laakso A, Kuoppamaki M, Syvalahti E, Hietala J.
Interactions of selective serotonin reuptake inhibitors with the serotonin 5-HT2c receptor.
Psychopharmacology (Berl) 1996 Aug;126(3):234-40
"The present data provide evidence that fluoxetine, norfluoxetine and citalopram, along with many other antidepressant compounds, interact directly with the 5-HT2C receptor." [Abstract]

Gommans J, Bouwknecht JA, Hijzen TH, Berendsen HH, Broekkamp CL, Maes RA, Olivier B.
Stimulus properties of fluvoxamine in a conditioned taste aversion procedure.
Psychopharmacology (Berl) 1998 Dec;140(4):496-502
"We conclude that 5-HT1A receptors are involved in the stimulus properties of both fluvoxamine and fluoxetine, that 5-HT2C receptors are involved in fluvoxamine and especially fluoxetine, and, based primarily on the cross-comparison tests, that the two SSRIs have somewhat different stimulus properties." [Abstract]

Lightowler S, Wood M, Brown T, Glen A, Blackburn T, Tulloch I, Kennett G.
An investigation of the mechanism responsible for fluoxetine-induced hypophagia in rats.
Eur J Pharmacol 1996 Jan 25;296(2):137-43
"In slices of piglet choroid plexus fluoxetine (1, 10 and 33 microM) caused a rightward shift in the dose-response curve produced by 5-HT with no effect on the maximal response, and a mean pKB of 5.94 +/- 0.09. Norfluoxetine (10 microM) also produced a rightward shift in the 5-HT dose-response curve with no effect on the maximal response, and a pKB of 6.20. Thus, both compounds acted as surmountable antagonists with no agonist efficacy at 5-HT2C receptors present in choroid plexus." [Abstract]

Olivier B, van Oorschot R, Waldinger MD.
Serotonin, serotonergic receptors, selective serotonin reuptake inhibitors and sexual behaviour.
Int Clin Psychopharmacol 1998 Jul;13 Suppl 6:S9-14
"It appeared that the discriminatory stimulus of fluvoxamine is primarily mediated via 5-hydroxytryptamine (HT)1A receptors, whilst that of fluoxetine is primarily mediated via 5-HT2C receptors. Both types of receptors have been implicated in depression and it is conceivable that different SSRIs have intrinsic activity at these receptors." [Abstract]

Ward RP, Dorsa DM.
Colocalization of serotonin receptor subtypes 5-HT2A, 5-HT2C, and 5-HT6 with neuropeptides in rat striatum.
J Comp Neurol 1996 Jul 1;370(3):405-14
"All the serotonin receptors colocalized extensively with all three of the neuropeptides examined. None of the serotonin receptors showed preferential colocalization in striatopallidal (enkephalin containing), or striatonigral (substance P or dynorphin containing) cells. The 5-HT2A and 5-HT2C mRNAs displayed a differential distribution with regard to the scattered islands of strongly dynorphin mRNA positive cells, which are thought to reside in the striatal patch compartment. Within these islands, 5-HT2C mRNA expression was much higher than in surrounding areas. 5-HT2A mRNA showed the opposite pattern with decreased expression over dynorphin rich cell clusters." [Abstract]

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Recent 5-HT2A Receptor Research
1) Schulz SB, Heidmann KE, Mike A, Klaft ZJ, Heinemann U, Gerevich Z
First and second generation antipsychotics influence hippocampal gamma oscillations by interactions with 5-HT(3) and D(3) receptors.
Br J Pharmacol. 2012 Jul 20;
BACKGROUND AND PURPOSE:? Disturbed cortical gamma band oscillations (30-80 Hz) have been observed in schizophrenia: positive symptoms of the disease correlate with an increase in gamma oscillation power, whereas negative symptoms are associated with a decrease. EXPERIMENTAL APPROACH:? Here we investigated the effects of first and second generation antipsychotics (FGAs and SGAs) on gamma oscillations. The FGAs haloperidol, flupenthixol, chlorpromazine, chlorprothixene and the SGAs clozapine, risperidone, ziprasidone and amisulpride were applied on gamma oscillations induced by acetylcholine and physostigmine in the CA3 region of rat hippocampal slices. KEY RESULTS: Antipsychotics inhibited the power of gamma oscillations and increased the bandwidth of the gamma band. Haloperidol and clozapine had the highest inhibitory effects. To shed light on which receptor is responsible for the alterations of gamma oscillations, the effects of the antipsychotics were plotted against their pK(i) values for 19 receptors and analyzed for correlation. We found that serotonin 5-HT(3) receptors may have an enhancing effect on gamma oscillations whereas dopamine D(3) receptors may inhibit them. To test this prediction, m-Chlorophenylbiguanide (mCPBG), PD 128907 and CP 809101, selective agonists at 5-HT(3) , D(3) and 5-HT(2C) receptors, were applied and revealed that 5-HT(3) receptors indeed enhanced the gamma power whereas D(3) receptors reduced it. As predicted, 5-HT(2C) receptors had no effects on gamma oscillations. CONCLUSIONS AND IMPLICATIONS:? Our data suggest that antipsychotics alter hippocampal gamma oscillations by interacting with serotonin 5-HT(3) and dopamine D(3) receptors. Moreover, correlation of receptor affinities with the biological effects can be used to predict targets for the pharmacological effects of multi-target drugs. � 2012 The Authors. British Journal of Pharmacology � 2012 The British Pharmacological Society. [PubMed Citation] [Order full text from Infotrieve]

2) Baptista D, Nunes-de-Souza RL, Canto-de-Souza A
Activation of 5-HT(2C) receptors in the dorsal periaqueductal gray increases antinociception in mice exposed to the elevated plus-maze.
Behav Brain Res. 2012 Jul 16;
Several findings have pointed to the role of the dorsal periaqueductal gray (dPAG) serotonin 5-HT(1A) and 5-HT(2A-C) receptor subtypes in the modulation of defensive behavior in animals exposed to the elevated plus-maze (EPM). Besides displaying anxiety-like behavior, rodents also exhibit antinociception in the EPM. This study investigated the effects of intra-dPAG injections of 5-HT(1A) and 5-HT(2B/2C) receptor ligands on EPM-induced antinociception in mice. Male Swiss mice received 0.1?l intra-dPAG injections of vehicle, 5.6 and 10nmol of 8-OHDPAT, a 5-HT(1A) receptor agonist (Experiment 1), or 0.01, 0.03 and 0.1nmol of mCPP, a 5-HT(2B/2C) receptor agonist (Experiment 2). Five minutes later, each mouse received an intraperitoneal injection of 0.6% acetic acid (0.1ml/10g body weight; nociceptive stimulus) and was individually confined in the open (OA) or enclosed (EA) arms of the EPM for 5min, during which the number of abdominal writhes induced by the acetic acid was recorded. While intra-dPAG injection of 8-OHDPAT did not change open-arm antinociception (OAA), mCPP (0.01nmol) enhanced it. Combined injections of ketanserin (10nmol/0.1?l), a 5-HT(2A/2C) receptor antagonist, and 0.01nmol of mCPP (Experiment 3), selectively and completely blocked the OAA enhancement induced by mCPP. Although intra-dPAG injection of mCPP (0.01nmol) also produced antinociception in EA-confined mice (Experiment 2), this effect was not confirmed in Experiment 3. Moreover, no other compound changed the nociceptive response in EA-confined animals. These results suggest that the 5-HT(2C) receptors located within the PAG play a role in this type of environmentally induced pain inhibition in mice. [PubMed Citation] [Order full text from Infotrieve]

3) Chen G, Cho SJ, Huang XP, Jensen NH, Svennebring A, Sassano MF, Roth BL, Kozikowski AP
Rational Drug Design Leading to the Identification of a Potent 5-HT(2C) Agonist Lacking 5-HT(2B) Activity.
ACS Med Chem Lett. 2011 Dec 8;2(12):929-932.
The 5-HT(2C) receptor is an attractive drug target in the quest for new therapeutics to treat a variety of human disorders. We have previously undertaken a structural optimization campaign that has led to some potent and moderately selective 5-HT(2C) receptor agonists. After expanding our structure-function library, we were able to combine our datasets so as to allow the design of compounds of improved selectivity and potency. We disclose herein the structural optimization of our previously reported 5-HT(2B)/5-HT(2C) agonists, which has led to the identification of a highly selective 5-HT(2C) agonist, (+)-trans-[2-(2-cyclopropylmethoxyphenyl)cyclopropyl]methylamine hydrochloride, with an EC(50) of 55 nM and no detectable agonism at the 5-HT(2B) receptor. [PubMed Citation] [Order full text from Infotrieve]

4) Martins LC, Rocha NP, Torres KC, Dos Santos RR, Fran�a GS, de Moraes EN, Mukhamedyarov MA, Zefirov AL, Rizvanov AA, Kiyasov AP, Vieira LB, Guimar�es MM, Yalva� ME, Teixeira AL, Bicalho MA, Janka Z, Romano-Silva MA, Palot�s A, Reis HJ
Disease-specific expression of the serotonin-receptor 5-HT(2C) in natural killer cells in Alzheimer's dementia.
J Neuroimmunol. 2012 Jul 3;
Alzheimer's dementia (AD) is a degenerative brain disorder characterized mainly by cholinergic failure, but other neuro-transmitters are also deficient especially at late stages of the disease. Misfolded ?-amyloid peptide has been identified as a causative agent, however inflammatory changes also play a pivotal role. Even though the most prominent pathology is seen in the cognitive functions, specific abnormalities of the central nervous system (CNS) are also reflected in the periphery, particularly in the immune responses of the body. The aim of this study was to characterize the dopaminergic and serotonergic systems in AD, which are also markedly disrupted along with the hallmark acetyl-choline dysfunction. Peripheral blood mono-nuclear cells (PBMCs) from demented patients were judged against comparison groups including individuals with late-onset depression (LOD), as well as non-demented and non-depressed subjects. Cellular sub-populations were evaluated by mono-clonal antibodies against various cell surface receptors: CD4/CD8 (T-lymphocytes), CD19 (B-lymphocytes), CD14 (monocytes), and CD56 (natural-killer (NK)-cells). The expressions of dopamine D(3) and D(4), as well as serotonin 5-HT(1A), 5-HT(2A), 5-HT(2B) and 5-HT(2C) were also assessed. There were no significant differences among the study groups with respect to the frequency of the cellular sub-types, however a unique profound increase in 5-HT(2C) receptor exclusively in NK-cells was observed in AD. The disease-specific expression of 5-HT(2C), as well as the NK-cell cyto-toxicity, has been linked with cognitive derangement in dementia. These changes not only corroborate the existence of bi-directional communication between the immune system and the CNS, but also elucidate the role of inflammatory activity in AD pathology, and may serve as potential biomarkers for less invasive and early diagnostic purposes as well. [PubMed Citation] [Order full text from Infotrieve]

5) Mickey BJ, Sanford BJ, Love TM, Shen PH, Hodgkinson CA, Stohler CS, Goldman D, Zubieta JK
Striatal Dopamine Release and Genetic Variation of the Serotonin 2C Receptor in Humans.
J Neurosci. 2012 Jul 4;32(27):9344-50.
Mesoaccumbal and nigrostriatal projections are sensitive to stress, and heightened stress sensitivity is thought to confer risk for neuropsychiatric disorders. Serotonin 2C (5-HT(2C)) receptors mediate the inhibitory effects of serotonin on dopaminergic circuitry in experimental animals, and preclinical findings have implicated 5-HT(2C) receptors in motivated behaviors and psychotropic drug mechanisms. In humans, a common missense single-nucleotide change (rs6318, Cys23Ser) in the 5-HT(2C) receptor gene (HTR2C) has been associated with altered activity in vitro and with clinical mood disorders. We hypothesized that dopaminergic circuitry would be more sensitive to stress in humans carrying the Ser23 variant. To test this hypothesis, we studied 54 healthy humans using positron emission tomography and the displaceable D(2)/D(3) receptor radiotracer [(11)C]raclopride. Binding potential (BP(ND)) was quantified before and after a standardized stress challenge consisting of 20 min of moderate deep muscular pain, and reduction in BP(ND) served as an index of dopamine release. The Cys23Ser variant was genotyped on a custom array, and ancestry informative markers were used to control for population stratification. We found greater dopamine release in the nucleus accumbens, caudate nucleus, and putamen among Ser23 carriers, after controlling for sex, age, and ancestry. Genotype accounted for 12% of the variance in dopamine release in the nucleus accumbens. There was no association of Cys23Ser with baseline BP(ND). These findings indicate that a putatively functional HTR2C variant (Ser23) is associated with greater striatal dopamine release during pain in healthy humans. Mesoaccumbal stress sensitivity may mediate the effects of HTR2C variation on risk of neuropsychiatric disorders. [PubMed Citation] [Order full text from Infotrieve]

6) Pelloux Y, Dilleen R, Economidou D, Theobald D, Everitt BJ
Reduced Forebrain Serotonin Transmission is Causally Involved in the Development of Compulsive Cocaine Seeking in Rats.
Neuropsychopharmacology. 2012 Jul 4;
Whereas the majority of cocaine users quit as they experience the negative consequences of drug use, some lose control over their drug taking and compulsively seek drugs. We report that 20% of rats compulsively seek cocaine despite intermittent negative outcomes after escalating their cocaine self-administration. This compulsive subgroup showed marked reductions in forebrain serotonin utilization; increasing serotonin transmission reduced their compulsive cocaine seeking. Depleting forebrain serotonin induced compulsive cocaine seeking in rats with a limited cocaine taking history; this was reversed by systemic treatment with a 5-hydroxytryptamine (5-HT2C) receptor agonist and mimicked by systemic treatment with a 5-HT2C receptor antagonist in intact animals. These results indicate the causal involvement of reduced serotoninergic transmission in the emergence of compulsive drug seeking after a long cocaine-taking history.Neuropsychopharmacology advance online publication, 4 July 2012; doi:10.1038/npp.2012.111. [PubMed Citation] [Order full text from Infotrieve]

7) Stefano GB, Kr�l�čkov� M, Ptacek R, Kuzelova H, Esch T, Kream RM
Low dose morphine adjuvant therapy for enhanced efficacy of antipsychotic drug action: Potential involvement of endogenous morphine in the pathophysiology of schizophrenia.
Med Sci Monit. 2012 Jun 28;18(7):HY23-26.
Major thematic threads linking extensive preclinical and clinical efforts have established a working mechanistic scheme whereby atypical antipsychotic drugs ameliorate negative DSM IV diagnostic criteria by effecting relatively potent blockade of serotonin (5-HT)(2A) receptors coupled with weaker antagonism of dopamine D(2) receptors in frontal cortical areas. These contentions are more or less supported by in vitro binding experiments employing cloned receptors on cultured cells, although significant functional involvement of 5-HT(2C) receptors has also been proposed. It is interesting that a key statistical analysis indicates a major shift in usage back to typical antipsychotic agents for management of schizophrenia from 1995-2008, whereas off-label usage of atypical antipsychotic agents was markedly increased or expanded for bipolar affective disorder. Importantly, meta-analyses generally did not support efficacy differences between the other atypical antipsychotics compared with the older typical agents. A critical examination of putative functional linkages of morphine and its type-selective mu opioid receptor to higher order cortical regulation of cognitive processes may provide novel insights into human behavioral processes that are severely impaired in schizophrenia spectrum disorders.
[PubMed Citation] [Order full text from Infotrieve]

8) Zendehdel M, Taati M, Jonaidi H, Amini E
The role of central 5-HT(2C) and NMDA receptors on LPS-induced feeding behavior in chickens.
J Physiol Sci. 2012 Jun 27;
In mammals, LPS regulate feeding primarily through the 5-HT(1A) and 5-HT(2c) receptors within the brain. However, the central effect of 5-HT(1A) and 5-HT(2c) on LPS-induced feeding behavior has not been studied in non-mammalian species. Also, the role of glutamatergic system in LPS-induced anorexia has never been examined in either mammalian or non-mammalian species. Therefore, in this study, we examined the role of serotonergic and glutamatergic systems on LPS-induced anorexia in chickens. Food intake was measured in chickens after centrally administered lipopolysaccharide (LPS) (20�ng) (0�h), followed by intracerebroventricular (ICV) injection of the 5-HT(1A) autoreceptor agonist (8-OH-DPAT, 61�nmol), 5-HT(2c) receptor antagonist (SB 242084, 30�nm), and NMDA receptor antagonist (DL-AP5, 5�nm) at the onset of anorexia (4�h). In the following experiments, we used DL-AP5 before 5-HT (10�?g) and SB242084 before glutamate (300�nm) for evaluation of the interaction between 5-HTergic and glutamatergic systems on food intake. The results of this study showed that SB 242084 and DL-AP5 significantly attenuated food intake reduction caused by LPS (P�<�0.05) but 8-OH-DPAT had no effect. In addition, 5-HT-induced anorexia was significantly attenuated by DL-AP5 pretreatment (P�<�0.05), while SB 242084 had no effect on glutamate-induced hypophagia. These results indicated that 5-HT and glutamate (via 5-HT(2c) and NMDA receptor, respectively) dependently regulate LPS-induced hypophagia in chickens. [PubMed Citation] [Order full text from Infotrieve]

9) Xu Y, Jin JH, Wang Y, Wang RR, Li Z, Chen J
[Facilitation of synaptic transmission and connections of entorhinal-hippocampal pathway by 5-HT2C receptor subtype: multi-electrode array recordings].
Sheng Li Xue Bao. 2012 Jun 25;64(3):259-68.
Using 64-channels (8 � 8) multi-electrode array technique (MED-64 system), the modulatory actions of 5-hydroxytryptamine (5-HT) 2C receptor subtype on the entorhinal (EC)-hippocampal synaptic transmission and connections were studied. One of freshly dissociated acute hippocampal slices of rats which was placed on the MED-64 probe, was subject to constant perfusion with oxygenated artificial cerebrospinal fluid (ACSF, 95% O2 and 5% CO2). Two hours after ACSF incubation, simultaneous multi-site electrophysiological recordings were performed. One electrode was selected to be used for perforant path (PP) stimulation, and the remaining 63 electrodes were used for recordings of network field excitatory postsynaptic potentials (fEPSPs) within both CA1 and dentate gyrus (DG) that have been previously proved to be mediated by glutamate non-NMDA receptors. After stability of network fEPSPs was achieved, (�)-1(2, 5-Dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI, an agonist of 5-HT2C receptor subtype), or SB242084 (6-Chloro-2,3-dihydro-5-methyl-N-[6-[(2-methyl-3-pyridinyl)oxy]-3-pyridinyl]-1H-indole-1-carboxyamide dihydrochloride hydrate) (a selective antagonist of 5-HT2C receptor subtype) was applied for 10 min perfusion, respectively. Two-dimensional current source density (2D-CSD) analysis was also transformed by bilinear interpolation at each point of the 64 electrodes for spatial imaging of the fEPSP network responses. Based upon the polarities of fEPSP and 2D-CSD imaging, it was clearly shown that synaptic activations were evoked to occur within the molecular layer of DG and pyramidal cell layer of CA1 by the PP stimulation in which negative-going field potentials and current sink (blue) could be recorded. While, positive-going field potentials and current source (yellow) were mainly localized within the granule cell layer and hilus of DG and alveus of CA1, reflecting spread of electrical signals derived from depolarized region toward CA3 area or subiculum and fimbria along the axons. Perfusion of the hippocampal slices with DOI resulted in a significant enlargement of synaptic connection size at network level and enhancement of synaptic efficacy. However, on the contrary, perfusion with SB242084 produced reversal effect with either reduction in synaptic network size or decreased magnitude of fEPSPs (amplitude and slope) in the CA1 and DG. These results suggest that endogenous 5-HT causes facilitation of EC-CA1 and EC-DG synaptic transmission and connections via acting on 5-HT2C receptor subtype, leading to gain in synaptic transmission and enlargement of synaptic connections. [PubMed Citation] [Order full text from Infotrieve]

10) Navailles S, Lagi�re M, Roumegous A, Polito M, Boujema MB, Cador M, Dunlop J, Chesselet MF, Millan MJ, De Deurwaerd�re P
Serotonin2C ligands exhibiting full negative and positive intrinsic activity elicit purposeless oral movements in rats: distinct effects of agonists and inverse agonists in a rat model of Parkinson's disease.
Int J Neuropsychopharmacol. 2012 May 3;:1-14.
This study examined in naive or hemiparkinsonian rats the effect of various serotonin 2C (5-HT2C) receptor ligands differing in their intrinsic activity at 5-HT2C receptors on purposeless oral movements, a motor response integrated in the basal ganglia. Intraperitoneal administration of a non-selective [meta-chlorophenylpiperazine (m-CPP) 0.1-3 mg/kg], preferential [S-2-(6-chloro-5-fluoroindol-1-yl)-1-methylethylamine, Ro60-0175, 0.1-3 mg/kg] or selective [(7bR,10aR)-1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta-[b][1,4]diazepino[6,7,1hi]indole, WAY163909, 0.3-10 mg/kg] 5-HT2C agonists enhanced oral bouts in naive rats. The 5-HT2C inverse agonists SB206553 [1-20 mg/kg; 5-methyl-1-(3-pyridylcarbamoyl)-1,2,3,5-tetrahydropyrrolo[2,3-f]indole] and S32006 [1-20 mg/kg; N-pyridin-3-yl-1,2-dihydro-3H-benzo[e]indole-3-carboxamide], but not the 5-HT2C antagonist SB243213 [1-10 mg/kg; 5-methyl-1-[[2-[(2-methyl-3-pyridyl)oxy]-5-pyridyl]carbamoyl]-6-trifluoromethylindoline], likewise dose-dependently enhanced oral movements. The effects induced by preferential 5-HT2C agonists and inverse agonists, but not by the cholinomimetic drug pilocarpine (5 mg/kg), were abolished by SB243213 underpinning its specificity. S32006-induced oral bouts was unaffected by the 5,7-dihydroxytryptamine lesions of 5-HT neurons. Nigrostriatal dopaminergic lesions potentiated oral effects induced by the agonists Ro60-0175 (3 mg/kg) and WAY163909 (1 mg/kg), but not by the inverse agonist SB206553 (10 mg/kg). The effect of Ro60-0175 in dopamine-lesioned rats was suppressed by SB243213. These data show that 5-HT2C agonists and full inverse agonists (but not neutral antagonists) perturb oral activity in rodents, paralleling studies of common antidepressant, anxiolytic and antipsychotic properties. The differential sensitivity of their actions to depletion of dopamine suggests recruitment of different contrasting neural mechanisms in the basal ganglia. [PubMed Citation] [Order full text from Infotrieve]

11) Ikram H, Choudhry AM, Haleem DJ
Regional neurochemical profile following development of apomorphine-induced reinforcement.
Pak J Pharm Sci. 2012 Jul;25(3):513-9.
Dopamine is primary neurotransmitter which mediates the reinforcing effects of abused drugs, serotonin (5-Hydroxytryptamine; 5-HT) also has a crucial role in the pathophysiology of addiction. The binding sites of various drugs of abuse are different from each other, their final rewarding effects are mediated by an increase in the dopamine level in the Nucleus Accumbens. The present study used conditioned place preference (CPP) test to monitor apomorphine's reinforcing effects. Associated alterations in 5-HT and dopamine metabolism were also monitored in various brain regions by HPLC-EC. Withdrawal from apomorphine administration (at a dose of 1.0 mg/kg on six alternate days) induced reinforcement as monitored in the conditioned place preference (CPP) paradigm. Serotonin and dopamine metabolism was also changed particularly in the ventral and dorsal striatum. Results therefore suggest desensitization of dopamine receptors in the presynaptic site is involved in apomorphine-induced reinforcement. Desensitization of somatodendritic 5-HT(1A) receptors resulting in increased availability of 5-HT at 5-HT(2C) receptors could attenuate apomorphine-induced reinforcement. Therefore, further investigations in this area should focus on attempts to attenuate apomorphine-induced reinforcement by desensitizing somatodendritic 5-HT(1A) receptors. [PubMed Citation] [Order full text from Infotrieve]

12) Li B, Dong L, Wang B, Cai L, Jiang N, Peng L
Cell Type-Specific Gene Expression and Editing Responses to Chronic Fluoxetine Treatment in the In Vivo Mouse Brain and Their Relevance for Stress-Induced Anhedonia.
Neurochem Res. 2012 Jun 19;
Recently developed methods for fluorescence-activated cell sorting (FACS) of freshly-isolated brain cells from transgenic mice combining fluorescent signals with cell type-specific markers allow cell-type separation. Based upon previous observations in primary cultures of mouse astrocytes we treated transgenic mice tagged with a neuron-specific or an astrocyte-specific marker with fluoxetine, either acute (10�mg/kg for 2�h) or chronic (10�mg/kg daily for 2�weeks). Acute treatment upregulated cfos and fosB mRNA expression in astrocytes and neurons. Chronic effects on astrocytes replicated those demonstrated in cultures, i.e., upregulation of mRNA and/or protein expression of 5-HT(2B) receptors (5-HT(2B)R), and GluK2 receptors, and of cPLA(2a) and ADAR2, together with increased GluK2 and 5-HT(2B)R editing. Neurons showed increased GluK4 and 5-HT(2C) receptor expression. To further correlate these findings with major depression we compared the changes in gene expression with those in a mouse model of anhedonia. Three out of 4 genes up-regulated in astrocytes by fluoxetine were down-regulated, whereas the neuronally upregulated 5-HT(2C) receptor gene showed no change. References are made to recent review papers discussing potential relations between observed fluoxetine effects and clinical effects of SSRIs, emphasizing that all 5 clinically used SSRIs have identical and virtually equipotent effects on cultured astrocytes. [PubMed Citation] [Order full text from Infotrieve]

13) Harvey ML, Swallows CL, Cooper MA
A double dissociation in the effects of 5-HT2A and 5-HT2C receptors on the acquisition and expression of conditioned defeat in Syrian hamsters.
Behav Neurosci. 2012 Aug;126(4):530-7.
Previous research indicates that serotonin enhances the development of stress-induced changes in behavior, although it is unclear which serotonin receptors mediate this effect. 5-HT2 receptors are potential candidates because activation at these receptors is associated with increased fear and anxiety. In this study, we investigated whether pharmacological treatments targeting 5-HT2 receptors would alter the acquisition and expression of conditioned defeat. Conditioned defeat is a social defeat model in Syrian hamsters in which individuals display increased submissive and defensive behavior and a loss of territorial aggression when tested with a novel intruder 24 hours after an acute social defeat. The nonselective 5-HT2 receptor agonist mCPP (0.0, 0.3, 1.0, or 3.0 mg/kg) was injected either prior to social defeat training or prior to conditioned defeat testing. Also, the 5-HT2A receptor antagonist MDL 11,939 (0.0, 0.5, or 2.0 mg/kg) was injected either prior to social defeat training or prior to conditioned defeat testing. Injection of mCPP prior to testing increased the expression of conditioned defeat, but injection of mCPP prior to training did not alter the acquisition of conditioned defeat. Conversely, injection of MDL 11,939 prior to training reduced the acquisition of conditioned defeat, but injection of MDL 11,939 prior to testing did not alter the expression of conditioned defeat. Our data suggest that mCPP activates 5-HT2C receptors during testing to enhance the display of submissive and defensive behavior, whereas MDL 11,939 blocks 5-HT2A receptors during social defeat to disrupt the development of the conditioned defeat response. In sum, these results suggest that serotonin acts at separate 5-HT2 receptors to facilitate the acquisition and expression of defeat-induced changes in social behavior. (PsycINFO Database Record (c) 2012 APA, all rights reserved). [PubMed Citation] [Order full text from Infotrieve]

14) Graves SM, Napier TC
SB 206553, a putative 5-HT2C inverse agonist, attenuates methamphetamine-seeking in rats.
BMC Neurosci. 2012 Jun 14;13(1):65.
ABSTRACT: BACKGROUND: Methamphetamine (meth) dependence presents a substantial socioeconomic burden. Despite the need, there is no FDA-approved pharmacotherapy for psychostimulant dependence. We consider 5-HT2C receptors as viable therapeutic targets. We recently revealed that the atypical antidepressant, mirtazapine, attenuates meth-seeking in a rodent model of human substance abuse. Mirtazapine historically has been considered to be an antagonist at 5-HT2C receptors, but more recently shown to exhibit inverse agonism at constitutively active 5-HT2C receptors. To help distinguish the roles for antagonism vs. inverse agonism, here we explored the ability of a more selective 5-HT2C inverse agonist, SB 206553 to attenuate meth-seeking behavior, and compared its effects to those obtained with 5-HT2C antagonists, SDZ Ser 082 and SB 242084. To do so, rats were trained to self-administer meth and tested for seeking-like behavior in cue reactivity sessions consisting of contingently presenting meth-associated cues without meth reinforcement. We also explored motor function to determine the influence of SB 206553 and SDZ Ser 082 on motor activity in the presence and absence of meth. RESULTS: Like mirtazapine, pretreatment with SB 206553 (1.0, 5.0, and 10.0 mg/kg), attenuated methseeking. In contrast, the antagonists, SDZ Ser 082 (0.1, 0.3, and 1.0 mg/kg) and SB 242084 (3.0 mg/kg) had no effect on cue reactivity (CR). SB 242084 (3.0 mg/kg) failed to attenuate the effects of 5.0 and 10 mg/kg SB 206553 on CR. Motor function was largely unaltered by the 5-HT2C ligands; however, SB 206553, at the highest dose tested (10.0 mg/kg), attenuated meth-induced rearing behavior. CONCLUSIONS: The lack of effect by 5-HT2C antagonists suggests that meth-seeking and meth-evoked motor activity are independent of endogenous 5-HT acting at 5-HT2C receptors. While SB 206553 dramatically impacted meth-evoked behaviors it is unclear whether the observed effects were 5-HT2C receptor mediated. Thus, SB 206553 deserves further attention in the study of psychostimulant abuse disorders. [PubMed Citation] [Order full text from Infotrieve]

15) Lin X, Huang XP, Chen G, Whaley R, Peng S, Wang Y, Zhang G, Wang SX, Wang S, Roth BL, Huang N
Life Beyond Kinases: Structure-Based Discovery of Sorafenib as Nanomolar Antagonist of 5-HT Receptors.
J Med Chem. 2012 Jun 28;55(12):5749-59.
Of great interest in recent years has been computationally predicting the novel polypharmacology of drug molecules. Here, we applied an "induced-fit" protocol to improve the homology models of 5-HT(2A) receptor, and we assessed the quality of these models in retrospective virtual screening. Subsequently, we computationally screened the FDA approved drug molecules against the best induced-fit 5-HT(2A) models and chose six top scoring hits for experimental assays. Surprisingly, one well-known kinase inhibitor, sorafenib, has shown unexpected promiscuous 5-HTRs binding affinities, K(i) = 1959, 56, and 417 nM against 5-HT(2A), 5-HT(2B), and 5-HT(2C), respectively. Our preliminary SAR exploration supports the predicted binding mode and further suggests sorafenib to be a novel lead compound for 5HTR ligand discovery. Although it has been well-known that sorafenib produces anticancer effects through targeting multiple kinases, carefully designed experimental studies are desirable to fully understand whether its "off-target" 5-HTR binding activities contribute to its therapeutic efficacy or otherwise undesirable side effects. [PubMed Citation] [Order full text from Infotrieve]

16) Manvich DF, Kimmel HL, Cooper DA, Howell LL
The Serotonin 2C Receptor Antagonist SB 242084 Exhibits Abuse-Related Effects Typical of Stimulants in Squirrel Monkeys.
J Pharmacol Exp Ther. 2012 Jun 8;
Antagonists of the serotonin 5-HT(2C) receptor (5-HT(2C)R) are being considered as potential pharmacotherapeutics for various affective disorders, but evidence suggests that these compounds enhance the effects of cocaine and related psychostimulants in rodents. However, the effects of selective 5-HT(2C)R antagonists have not been evaluated in nonhuman primates. The present studies utilized operant-behavioral and in vivo microdialysis techniques to assess the impact of 5-HT(2C)R antagonism upon the behavioral and neurochemical effects of cocaine in squirrel monkeys. In subjects trained to lever-press on a fixed-interval schedule of stimulus termination, pretreatment with the highly selective 5-HT(2C)R antagonist 6-chloro-2,3-dihydro-5-methyl-N-[6-[(2-methyl-3-pyridinyl)oxy]-3-pyridinyl]-1H-indole-1-carboxyamide dihydrochloride (SB 242084) (veh, 0.01-0.1 mg/kg) produced modest behavioral-stimulant effects alone and interacted with cocaine in an apparently additive manner. In monkeys trained to self-administer intravenous cocaine according to a second-order schedule of drug delivery, SB 242084 (veh, 0.03-0.1 mg/kg) modulated cocaine-induced reinstatement of previously-extinguished responding and maintained self-administration behavior when substituted for cocaine availability. These studies are the first to assess the direct reinforcing effects of a 5-HT(2C)R-selective antagonist in any species. Finally, in vivo microdialysis studies revealed that pretreatment with SB 242084 (0.1 mg/kg) modulated cocaine-induced dopamine increases within the nucleus accumbens, but not the caudate nucleus, of awake subjects. Taken together, the results suggest that SB 242084 exhibits a behavioral profile similar to other psychostimulants, although its maximal effects are modest compared to cocaine. The observed interactions with cocaine and the substitution for cocaine self-administration may be indicative of abuse potential in humans. [PubMed Citation] [Order full text from Infotrieve]

17) Aguiar CC, Almeida AB, Ara�jo PV, Vasconcelos GS, Chaves EM, do Vale OC, Mac�do DS, de Sousa FC, Viana GS, Vasconcelos SM
Anticonvulsant effects of agomelatine in mice.
Epilepsy Behav. 2012 Jul;24(3):324-8.
Agomelatine is a potent MT1 and MT2 melatonin receptor agonist and a 5-HT2C serotonin receptor antagonist. We analyzed whether agomelatine has anticonvulsant properties. The anticonvulsant activity of agomelatine (25, 50 or 75mg/kg, i.p.) was evaluated in mouse models of pentylenetetrazole (PTZ-85mg/kg, i.p.), pilocarpine (400mg/kg, i.p.), picrotoxin (7mg/kg, i.p.), strychnine (75mg/kg, i.p.) or electroshock-induced convulsions. In the PTZ-induced seizure model, agomelatine (at 25 or 50mg/kg) showed a significant increase in latency to convulsion, and agomelatine (at 50 or 75mg/kg) also increased significantly time until death. In the pilocarpine-induced seizure model, only agomelatine in high doses (75mg/kg) showed a significant increase in latency to convulsions and in time until death. In the strychnine-, electroshock- and picrotoxin-induced seizure models, agomelatine caused no significant alterations in latency to convulsions and in time until death when compared to controls. Our results suggest that agomelatine has anticonvulsant activity shown in PTZ- or pilocarpine-induced seizure models. [PubMed Citation] [Order full text from Infotrieve]

18) Nilsson SR, Ripley TL, Somerville EM, Clifton PG
Reduced activity at the 5-HT(2C) receptor enhances reversal learning by decreasing the influence of previously non-rewarded associations.
Psychopharmacology (Berl). 2012 May 29;
RATIONALE: Reversal learning deficits are a feature of many human psychopathologies and their associated animal models and have recently been shown to involve the 5-HT(2C) receptor (5-HT(2C)R). Successful reversal learning can be reduced to two dissociable cognitive mechanisms, to dissipate associations of previous positive (opposed by perseverance) and negative (opposed by learned non-reward) valence. OBJECTIVES: This study aims to explore the effect of reducing activity at the 5-HT(2C)R on the cognitive mechanisms underlying spatial reversal learning in the mouse. METHODS: Experiment 1 used the 5-HT(2C)R antagonist SB242084 (0.5�mg/kg) in a between-groups serial design, experiment 2 used 5-HT(2C)R KO mice in a repeated measures design. Animals initially learned to discriminate between two lit nosepoke holes. This was followed by three conditions; (1) full reversal, where contingencies reversed; (2) perseverance, where the previous CS+ became CS- and the previous CS- was replaced by a novel CS+; (3) learned non-reward, where the previous CS- became CS+ and the previous CS+ was replaced by a novel CS-. RESULTS: SB242084 treated and 5-HT(2C)R KO mice showed enhanced reversal learning seen as a decrease in trials, correct responses, and omissions to criterion in the full reversal condition. Similar effects were observed in the learned non-reward condition but SB242084 treated and 5-HT(2C)R KO mice did not differ from controls in the perseverance condition. SB242084 treated, but not 5-HT(2C)R KO mice, showed decreases in all latency indices in every condition. CONCLUSION: Reducing activity at the 5-HT(2C)R facilitates reversal learning in the mouse by reducing the influence of previously non-rewarded associations. [PubMed Citation] [Order full text from Infotrieve]

19) Kadiri N, Lagi�re M, Le Moine C, Millan MJ, De Deurwaerd�re P, Navailles S
Diverse effects of 5-HT(2C) receptor blocking agents on c-Fos expression in the rat basal ganglia.
Eur J Pharmacol. 2012 Aug 15;689(1-3):8-16.
Serotonin(2C) receptors (5-HT(2)C) exert continuous control on the activity of specific populations of neurons in the basal ganglia. While antagonists block the effect of endogenous 5-HT at 5-HT(2C) receptors, the actions of inverse agonists may also involve interruption of activity at constitutively active populations of 5-HT(2C) receptors. We have evaluated the regional impact of these controls by studying, in rats, the expression of the product of the proto-oncogene c-Fos in rat basal ganglia after peripheral doses of the 5-HT(2C) antagonist SB 243213 (5-methyl-1-[[2-[(2-methyl-3-pyridyl)oxy]-5-pyridyl]carbamoyl]-6-trifluoromethylindoline) and the 5-HT(2B/2C) inverse agonists SB 206553 (5-methyl-1-(3-pyridylcarbamoyl)-1,2,3,5-tetrahydropyrrolo[2,3-f]indole.hydrochloride) and S32006 (N-pyridin-3-yl-1,2-dihydro-3H-benzo[e]indole-3-carboxamide). The results show that 1 and 10mg/kg SB 243213 enhanced equally c-Fos expression in the subthalamic nucleus (STN) and dose-dependently in the striatum and nucleus accumbens core (NAcc). SB 206553 (1-10mg/kg), at 10mg/kg only, enhanced c-Fos expression in STN, striatum (except the dorsomedial part), NAcc, entopeduncular nucleus, substantia nigra pars reticulata (SNr) and compacta (SNc) and ventral tegmental area. S32006 induced a similar increase in c-Fos expression in the medial parts of the striatum and NAcc at doses of 1-10mg/kg while it dose-dependently enhanced c-Fos expression in medial parts of the STN and SNr. None of these drugs induced c-Fos expression in the globus pallidus. The distinct pattern of c-Fos expression elicited by the 5-HT(2C) antagonist and inverse agonists suggests the existence of cellular and functional heterogeneity in the response of the basal ganglia to drugs inhibiting 5-HT(2C) receptors. [PubMed Citation] [Order full text from Infotrieve]

20) Nonogaki K
Serotonin conflict in sleep-feeding.
Vitam Horm. 2012;89:223-39.
Short sleep duration has been suggested to be a risk factor for weight gain and adiposity. Serotonin (5-HT) substantially contributes to the regulation of sleep and feeding behavior. Although 5-HT predominately promotes waking and satiety, the effects of 5-HT depend on 5-HT receptor function. The 5-HT1A, 5-HT1B, 5-HT2A, 5-HT2C, 5-HT6, and 5-HT7 receptors reportedly contribute to sleep-waking regulation, whereas the 5-HT1B and 5-HT2C receptors contribute to the regulation of satiety. The 5-HT1B and 2C receptors may therefore be involved in the regulation of sleep-feeding. In genetic studies, 5-HT1B receptor mutant mice display greater amounts of rapid eye movement sleep (REMS) than wild-type mice, while displaying no effects on waking or slow wave sleep (SWS). On the other hand, 5-HT2C receptor mutant mice exhibit increased wakefulness and decreased SWS, without any effect on REMS. Moreover, the 5-HT2C receptor mutants display leptin-independent hyperphagia, leading to a middle-aged onset of obesity, whereas 5-HT1B receptor mutants do not display any effect on food intake. Thus, the genetic deletion of 5-HT2C receptors results in sleep loss-associated hyperphagia, leading to the late onset of obesity. This is a quite different pattern of sleep-feeding behavior than is observed in disturbed leptin signaling, which displays an increase in sleep-associated hyperphagia. In pharmacologic studies, 5-HT1B and 5-HT2C receptors upregulate wakefulness and downregulate SWS, REMS, and food intake. These findings suggest that 5-HT1B/2C receptor stimulation induces sleep loss-associated anorexia. Thus, the central 5-HT regulation of sleep-feeding can be dissociated. Functional hypothalamic proopiomelanocortin and orexin activities may contribute to the dissociated 5-HT regulation. [PubMed Citation] [Order full text from Infotrieve]