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) Niebert M, Vogelgesang S, Koch UR, Bischoff AM, Kron M, Bock N, Manzke T
Expression and Function of Serotonin 2A and 2B Receptors in the Mammalian Respiratory Network.
PLoS One. 2011;6(7):e21395.
Neurons of the respiratory network in the lower brainstem express a variety of serotonin receptors (5-HTRs) that act primarily through adenylyl cyclase. However, there is one receptor family including 5-HT(2A), 5-HT(2B), and 5-HT(2C) receptors that are directed towards protein kinase C (PKC). In contrast to 5-HT(2A)Rs, expression and function of 5-HT(2B)Rs within the respiratory network are still unclear. 5-HT(2B)R utilizes a Gq-mediated signaling cascade involving calcium and leading to activation of phospholipase C and IP3/DAG pathways. Based on previous studies, this signal pathway appears to mediate excitatory actions on respiration. In the present study, we analyzed receptor expression in pontine and medullary regions of the respiratory network both at the transcriptional and translational level using quantitative RT-PCR and self-made as well as commercially available antibodies, respectively. In addition we measured effects of selective agonists and antagonists for 5-HT(2A)Rs and 5-HT(2B)Rs given intra-arterially on phrenic nerve discharges in juvenile rats using the perfused brainstem preparation. The drugs caused significant changes in discharge activity. Co-administration of both agonists revealed a dominance of the 5-HT(2B)R. Given the nature of the signaling pathways, we investigated whether intracellular calcium may explain effects observed in the respiratory network. Taken together, the results of this study suggest a significant role of both receptors in respiratory network modulation. [PubMed Citation] [Order full text from Infotrieve]

2) Nonogaki K, Suzuki M, Sanuki M, Wakameda M, Tamari T
The contribution of serotonin 5-HT2C and melanocortin-4 receptors to the satiety signaling of glucagon-like peptide 1 and liragultide, a glucagon-like peptide 1 receptor agonist, in mice.
Biochem Biophys Res Commun. 2011 Jul 2;
Glucagon-like peptide 1 (GLP-1), an insulinotropic gastrointestinal peptide produced mainly from intestinal endocrine L-cells, and liraglutide, a GLP-1 receptor (GLP-1R) agonist, induce satiety. The serotonin 5-HT2C receptor (5-HT2CR) and melanoroctin-4 receptor (MC4R) are involved in the regulation of food intake. Here we show that systemic administration of GLP-1 (50 and 200?g/kg)-induced anorexia was blunted in mice with a 5HT2CR null mutation, and was attenuated in mice with a heterozygous MC4R mutation. On the other hand, systemic administration of liraglutide (50 and 100?g/kg) suppressed food intake in mice lacking 5-HT2CR, mice with a heterozygous mutation of MC4R and wild-type mice matched for age. Moreover, once-daily consecutive intraperitoneal administration of liraglutide (100?g/kg) over 3days significantly suppressed daily food intake and body weight in mice with a heterozygous mutation of MC4R as well as wild-type mice. These findings suggest that GLP-1 and liraglutide induce anorexia via different central pathways. [PubMed Citation] [Order full text from Infotrieve]

3) Blier P, Briley M
The noradrenergic symptom cluster: clinical expression and neuropharmacology.
Neuropsychiatr Dis Treat. 2011;7(Suppl 1):15-20.
Signs and symptoms of depression can be linked to one or more monoaminergic systems, specifically the norepinephrine (NE), the dopamine (DA), and the serotonin (5-HT) systems. In particular, the modulation of energy, vigilance, and arousal can be directly linked to the NE system. There is, however, a great deal of overlap in the modulation of the symptoms of depression between these monoaminergic systems. There are considerable reciprocal interactions between the NE, DA, and the 5-HT systems. When using a selective serotonin reuptake inhibitor (SSRI), for example, 5-HT transmission is enhanced, but at the same time there is a dampening of the activity of NE and DA neurons through inhibitory 5-HT(2A) and 5-HT(2C) receptors, respectively. This could explain the residual symptoms of fatigue, lack of energy, and anhedonia, often seen after patients present an overall positive response to a SSRI. Using a dual 5-HT and NE reuptake inhibitor (SNRI), such as milnacipran, would result in an additional increase in NE activity. Futhermore, inhibiting NE reuptake increases DA availability in the frontal cortex since DA is mainly cleared by the NE transporters in several brain regions. A risk inherent in increased NE activity is that of provoking anxiety. This is avoided however by the attenuation of the phasic reactivity of the firing of NE neurons through prolonged administration of SSRI and SNRI. [PubMed Citation] [Order full text from Infotrieve]

4) McKie S, Richardson P, Elliott R, V�llm BA, Dolan MC, Williams SR, Anderson IM, Deakin JF
Mirtazapine antagonises the subjective, hormonal and neuronal effects of m-chlorophenylpiperazine (mCPP) infusion: A pharmacological-challenge fMRI (phMRI) study.
Neuroimage. 2011 Jun 25;
Aberrant signalling through central 5-HT(2C) receptor pathways has been implicated in various psychiatric disorders but this has not been amenable to experimental investigation in the absence of a valid in-vivo biomarker of functional 5-HT(2C) neurotransmission. One approach is drug-challenge pharmaco-magnetic resonance imaging (phMRI). We have previously shown that intravenous administration of the 5-HT(2C) agonist m-chlorophenylpiperazine (mCPP) elicits increases in blood oxygenation dependent signal (BOLD) in regions consistent with the distribution of 5-HT(2C) receptors. In the current study we determined whether BOLD signal responses to mCPP could be blocked by pre-treatment with a 5-HT(2C) antagonist. Healthy male volunteers received oral mirtazapine, 5-HT(2)/5-HT(3) receptor antagonist, or placebo 90min prior to intravenous mCPP challenge phMRI. BOLD signal increases following mCPP infusion occurred in areas known to be rich in 5-HT(2C) receptors such as the substantia nigra, hypothalamus, pallidum and amygdala. These responses were attenuated by mirtazapine pre-treatment. The results suggest that mCPP-challenge phMRI produces reliable patterns of response that are mediated by 5-HT(2C) receptors; these responses may therefore be useful in-vivo measures of 5-HT(2C) function in psychiatric disorders. [PubMed Citation] [Order full text from Infotrieve]

5) Hui-Juan Z, Zi-Meng J
Anti-obesity Drugs: Status Quo and Recent Advances.
Zhongguo Yi Xue Ke Xue Yuan Xue Bao. 2011 Jul;33(3):243-7.
Obesity has become a major health problem worldwide. The prevalence and morbidity of obesity-related diseases including diabetes, hypertension, cerebro-cardiovascular diseases, and tumors also have remarkably increased. Treatment of obesity poses a challenge for clinicians. Anti-obesity treatment is helpful to improve and even reverse obesity-related complications. Diet control and physical exercises remain the predominant interventions for obese patients. Anti-obesity drugs can be considered in those who respond poorly to behavioral intervention or those who have developed obesity-related complications. The commonly used anti-obesity drugs include gastrointestinal lipase inhibitors and appetite suppressants. Glucagon-like peptide 1 has also been found to be effective in reducing body weight. Some more drugs are under development, which include selective 5-HT 2c agonist, ?3 receptor agonist, and melanocortin receptor 4 agonist, may also be promising. [PubMed Citation] [Order full text from Infotrieve]

6) Alam N, Haleem DJ, Najam R, Haider S, Ahmed SP
Hypophagic and hypolocomotive effects of metachloro phenyl piperazine in rats treated with theophylline and caffeine.
Pak J Pharm Sci. 2011 Jul;24(3):251-4.
Long term intake of coffee is known to produce anxiety and suppression of appetite. 5- hydroxytryptamine (5-HT) acting via 5-HT-2C receptors elicits anorexia and anxiety. The present study is design to monitor metachloro phenyl piperazine (m-CPP) at a dose of 3mg/ml/kg, induces hypophagia and hypolocomotion in rats taking a solution of caffeine (a component of coffee and tea) or theophylline (a component of tea) as a sole source of water. We found that hypophagic and hypolocomotive effects of m-CPP were attenuated in theophylline but not in caffeine treated animals suggesting that long term intake of theophylline may attenuate anorexiogenic and anxiogenic effects of 5-HT. A possible role of 5-HT-2C receptors in the modulation of anxiety and appetite in people drinking coffee or tea discussed. [PubMed Citation] [Order full text from Infotrieve]

7) Homberg JR
Serotonin and decision making processes.
Neurosci Biobehav Rev. 2011 Jun 12;
Serotonin (5-HT) is an important player in decision making. Serotonergic antidepressant, anxiolytic and antipsychotic drugs are extensively used in the treatment of neuropsychiatric disorders characterized by impaired decision making, and exert both beneficial and harmful effects in patients. Detailed insight into the serotonergic mechanisms underlying decision making is needed to strengthen the first and weaken the latter. Although much remains to be done to achieve this, accumulating studies begin to deliver a coherent view. Thus, high central 5-HT levels are generally associated with improved reversal learning, improved attentional set shifting, decreased delay discounting, and increased response inhibition, but a failure to use outcome representations. Based on 5-HT's evolutionary role, I hypothesize that 5-HT integrates expected, or changes in, relevant sensory and emotional internal/external information, leading to vigilance behaviour affecting various decision making processes. 5-HT receptor subtypes play distinctive roles in decision making. 5-HT(2A) agonists and 5-HT2c antagonists decrease compulsivity, whereas 5-HT(2A) antagonists and 5-HT(2C) agonists decrease impulsivity. 5-HT(6) antagonists univocally affect decision making processes. [PubMed Citation] [Order full text from Infotrieve]

8) Xu Y, Li S, Vernon MM, Pan J, Chen L, Barish PA, Zhang Y, Acharya AP, Yu J, Govindarajan SS, Boykin E, Pan X, O'Donnell JM, Ogle WO
Curcumin prevents corticosterone-induced neurotoxicity and abnormalities of neuroplasticity via 5-HT receptor pathway.
J Neurochem. 2011 Jun 20;
J. Neurochem. (2011) 10.1111/j.1471-4159.2011.07356.x ABSTRACT: Curcumin, a major active component of Curcuma longa, possesses antioxidant and neuroprotective activities. The present study explores the mechanisms underlying the neuroprotective effect of curcumin against corticosterone and its relation to 5-hydroxy tryptamine (5-HT) receptors. Exposure of cortical neurons to corticosterone results in decreased mRNA levels for three 5-HT receptor subtypes, 5-HT(1A) , 5-HT(2A) and 5-HT(4) , but 5-HT(1B,) 5-HT(2B) , 5-HT(2C) , 5-HT(6) and 5-HT(7) receptors remain unchanged. Pre-treatment with curcumin reversed this effect on mRNA for the 5-HT(1A) and 5-HT(4) receptors, but not for the 5-HT(2A) receptor. Moreover, curcumin exerted a neuroprotective effect against corticosterone-induced neuronal death. This observed effect of curcumin was partially blocked by either 5-HT(1A) receptor antagonist p-MPPI or 5-HT(4) receptor antagonist RS 39604 alone; whereas, the simultaneous application of both antagonists completely reversed the effect. Curcumin was also found to regulate corticosterone-induced morphological changes such as increases in soma size, dendritic branching and dendritic spine density, as well as elevate synaptophysin expression in cortical neurons. p-MPPI and RS 39604 reversed the effect of curcumin-induced change in neuronal morphology and synaptophysin expression of corticosterone-treated neurons. In addition, an increase in cyclic adenosine monophosphate (cAMP) level was observed after curcumin treatment, which was further prevented by RS 39604, but not by p-MPPI. However, curcumin-induced elevation in protein kinase A activity and phosphorylation of cAMP response element-binding protein levels were inhibited by both p-MPPI and RS 39604. These findings suggest that the neuroprotection and modulation of neuroplasticity exhibited by curcumin might be mediated, at least in part, via the 5-HT receptor-cAMP-PKA-CREB signal pathway. [PubMed Citation] [Order full text from Infotrieve]

9) Dagyte G, Luiten PG, De Jager T, Gabriel C, Moca�r E, Den Boer JA, Van der Zee EA
Chronic stress and antidepressant agomelatine induce region-specific changes in synapsin I expression in the rat brain.
J Neurosci Res. 2011 Jun 17;
The antidepressant agomelatine acts as a melatonergic receptor (MT(1) /MT(2) ) agonist and 5-HT(2C) receptor antagonist. Agomelatine has demonstrated efficacy in treating depression, but its neurobiological effects merit further investigation. Preclinical studies reported that agomelatine enhances adult hippocampal neurogenesis and increases expression of several neuroplasticity-associated molecules. Recently, we showed that agomelatine normalizes hippocampal neuronal activity and promotes neurogenesis in the stress-compromised brain. To characterize further the effects of this antidepressant in the stressed brain, here we investigated whether it induces changes in the expression of synapsin I (SynI), a regulator of synaptic transmission and plasticity. Adult male rats were subjected to daily footshock stress and agomelatine treatment for 3 weeks. Their brains were subsequently stained for total and phosphorylated SynI. Chronic footshock and agomelatine induced region-specific changes in SynI expression. Whereas chronic stress increased total SynI expression in all layers of the medial prefrontal cortex, agomelatine treatment abolished some of these effects. Furthermore, chronic agomelatine administration decreased total SynI expression in the hippocampal subregions of both stressed and nonstressed rats. Importantly, chronic stress decreased the fraction of phosphorylated SynI in all layers of the medial prefrontal cortex as well as selectively in the outer and middle molecular layers of the hippocampal dentate gyrus. These stress effects were at least partially abolished by agomelatine. Altogether, our data show that chronic stress and agomelatine treatment induce region-specific changes in SynI expression and its phosphorylation. Moreover, agomelatine partially counteracts the stress effects on SynI, suggesting a modulation of synaptic function by this antidepressant. � 2011 Wiley-Liss, Inc. [PubMed Citation] [Order full text from Infotrieve]

10) Bubar MJ, Stutz SJ, Cunningham KA
5-HT(2C) Receptors Localize to Dopamine and GABA Neurons in the Rat Mesoaccumbens Pathway.
PLoS One. 2011;6(6):e20508.
The serotonin 5-HT(2C) receptor (5-HT(2C)R) is localized to the limbic-corticostriatal circuit, which plays an integral role in mediating attention, motivation, cognition, and reward processes. The 5-HT(2C)R is linked to modulation of mesoaccumbens dopamine neurotransmission via an activation of ?-aminobutyric acid (GABA) neurons in the ventral tegmental area (VTA). However, we recently demonstrated the expression of the 5-HT(2C)R within dopamine VTA neurons suggesting the possibility of a direct influence of the 5-HT(2C)R upon mesoaccumbens dopamine output. Here, we employed double-label fluorescence immunochemistry with the synthetic enzymes for dopamine (tyrosine hydroxylase; TH) and GABA (glutamic acid decarboxylase isoform 67; GAD-67) and retrograde tract tracing with FluoroGold (FG) to uncover whether dopamine and GABA VTA neurons that possess 5-HT(2C)R innervate the nucleus accumbens (NAc). The highest numbers of FG-labeled cells were detected in the middle versus rostral and caudal levels of the VTA, and included a subset of TH- and GAD-67 immunoreactive cells, of which >50% also contained 5-HT(2C)R immunoreactivity. Thus, we demonstrate for the first time that the 5-HT(2C)R colocalizes in DA and GABA VTA neurons which project to the NAc, describe in detail the distribution of NAc-projecting GABA VTA neurons, and identify the colocalization of TH and GAD-67 in the same NAc-projecting VTA neurons. These data suggest that the 5-HT(2C)R may exert direct influence upon both dopamine and GABA VTA output to the NAc. Further, the indication that a proportion of NAc-projecting VTA neurons synthesize and potentially release both dopamine and GABA adds intriguing complexity to the framework of the VTA and its postulated neuroanatomical roles. [PubMed Citation] [Order full text from Infotrieve]

11) Hsieh JT, Liu SP, Chang HC, Tsai VF, Chien CT, Yu HJ, Ho CH
The Activation of Peripheral 5-HT1A Receptors Can Inhibit Seminal Vesicle Contraction: An In Vivo Animal Study.
Urology. 2011 Jun 13;
OBJECTIVES: To elucidate the differential effects of stimulating various peripheral 5-HT receptor subtypes on the contractile response of seminal vesicles (SVs) induced by electrical stimulation (ES). METHODS: Male Wistar rats (aged 12-14 weeks) were prepared as our previously established model, which allows an intraarterial injection of test agents to directly act on SV. Four selective 5-HT agonists-8-OH-DPAT (5-HT1A), 5-nonyloxytryptamine (5-HT1B), BW723C86 (5-HT2B), and MK-212 (5-HT2C)-were injected at various concentrations (from 10(-8) to 10(-4) mmol/kg). After an injection, the SV contractile response was recorded after ES of lesser splanchnic nerve was applied. Relationships between the concentration of an agonist and its effect on SV contraction were plotted and analyzed. RESULTS: The peripheral injection of 5-HT1A agonist had a dose-dependent inhibitory effect on SV contraction and could achieve an inhibition of >50%; the IC50 was 3.16x10(-6) mmol/kg. No significant effects were observed with the peripheral injection of 5-HT1B, 5-HT2B, or 5-HT2C agonist. CONCLUSIONS: Our in vivo animal study shows that the activation of peripheral 5-HT1A receptors can inhibit ES-induced SV contraction, whereas the activation of peripheral 5-HT1B, 5-HT2B, or 5-HT2C receptors has no significant effect. The results suggest that the peripheral 5-HT pathway is a potential therapeutic target of the treatment for premature ejaculation. [PubMed Citation] [Order full text from Infotrieve]

12) Santini MA, Klein AB, El-Sayed M, Ratner C, Knudsen GM, Mikkelsen JD, Aznar S
Novelty-induced activity-regulated cytoskeletal-associated protein (Arc) expression in frontal cortex requires serotonin 2A receptor activation.
Neuroscience. 2011 Jun 2;
Many psychiatric disorders are characterized by cognitive and emotional alterations that are related to abnormal function of the frontal cortex (FC). FC is involved in working memory and decision making and is activated following exposure to a novel environment. The serotonin 2A receptor (5-HT(2A)R) is highly expressed in the FC where its activation induces hallucinations, while blockade of 5-HT(2A)Rs contributes to the therapeutic effects of atypical antipsychotic drugs. The purpose of the present study was to investigate the involvement of 5-HT(2A)R in FC activation following exposure to a novel environment. As an output of FC activation we measured expression of activity-regulated cytoskeletal-associated protein (Arc). Novelty-exposure (open-field arena) robustly up-regulated FC Arc mRNA expression (?160%) in mice compared to home-cage controls. This response was inhibited with the 5-HT(2A)R antagonists ketanserin and MDL100907, but not with the selective 5-HT(2C)R antagonist SB242084. Novelty-exposure also induced Arc mRNA expression in hippocampus (?150%), but not in cerebellum or brainstem. Pretreatment with 5-HT(2A)R antagonist ketanserin did not repress the Arc induction in hippocampus, indicating that the involvement of 5-HT(2A)R in this response is restricted to the FC. Similarly, the novelty-induced stress as determined by increasing levels of plasma corticosterone, was not influenced by 5-HT(2A)R antagonism suggesting that Arc mRNA and stress are activated via distinct mechanisms. Taken together, our results demonstrate that the induction of Arc in the FC following exposure to a novel environment is dependent on the 5-HT(2A)R, and that the simultaneous release of corticosterone is regulated via another system independent of 5-HT(2A)R activation. [PubMed Citation] [Order full text from Infotrieve]

13) de Oliveira Sergio T, de Bortoli VC, Zangrossi H
Serotonin-2A receptor regulation of panic-like behavior in the rat dorsal periaqueductal gray matter: the role of GABA.
Psychopharmacology (Berl). 2011 Jun 10;
RATIONALE: Electrical stimulation of the dorsal periaqueductal gray (dPAG) evokes escape, a defensive response associated with panic attacks. Stimulation of 5-HT1A or 5-HT2A receptors in this midbrain area equally inhibits escape performance, even though at the molecular level these receptors cause opposite effects, i.e., activation of the former hyperpolarizes the cell membrane, while the latter excites it. A proposal has been made that 5-HT2A receptor agonists exert their inhibitory effect on escape by activating GABAergic interneurons located in the dPAG. OBJECTIVES: In the present study, we evaluated this hypothesis by investigating whether previous intra-dPAG administration of the GABAA receptor antagonist bicuculline blocks the anti-escape effect caused by the local injection of different 5-HT2A/2C receptor agonists. RESULTS: Intra-dPAG administration of 5-HT, the preferential 5-HT2A receptor agonist DOI, the nonselective 5-HT2C receptor agonist mCPP or the 5-HT2C receptor agonist RO 60-0175 significantly inhibited the escape reaction induced by electrical stimulation of the same brain area. In all cases, this panicolytic-like effect was blocked by previous microinjection of bicuculline. This GABAA antagonist, however, failed to antagonize the anti-escape effect caused by the 5-HT1A receptor agonist 8-OH-DPAT. The inhibitory effect caused by DOI, RO 60-0175, and mCPP was also blocked by previous intra-dPAG injection of the preferential 5-HT2A receptor antagonist ketanserin. Pre-administration of the 5-HT2C receptor antagonist SB-242084 in the dPAG did not block the anti-escape effect of RO 60-0175. CONCLUSIONS: Stimulation of 5-HT2A but not 5-HT2C receptors in the dPAG causes a panicolytic-like effect that is mediated by facilitation of GABAergic neurotransmission. [PubMed Citation] [Order full text from Infotrieve]

14) Andrade AL, Abrahao KP, Goeldner FO, Souza-Formigoni ML
Administration of the 5-HT2C receptor antagonist SB-242084 into the nucleus accumbens blocks the expression of ethanol-induced behavioral sensitization in Albino Swiss mice.
Neuroscience. 2011 May 27;
Behavioral sensitization to the stimulating effect of ethanol (EtOH) or other drugs, which can be observed in mice as an increase in locomotor activity after repeated administration, has been associated with neuroadaptations within the dopaminergic mesolimbic pathway. In the nucleus accumbens (NAc), an afferent region of the mesolimbic pathway, dopamine (DA) release can be modulated by serotonergic 2C receptors (5-HT2C(R)). The aim of the present study was to evaluate the function of 5-HT2C(R) in the expression of EtOH-induced behavioral sensitization in Albino Swiss mice with various levels of sensitization to EtOH. In the four experiments that we performed, the mice were given saline or 2.2 g/kg EtOH daily for 21 days. Based on their locomotion on day 21, the EtOH-pretreated mice were assigned to one of two groups, highly sensitized or weakly sensitized to the stimulating effect of EtOH. In each experiment, 2 weeks after the 21-day treatment (withdrawal period), the mice were submitted to four pharmacological challenges of two drug treatments each. The mice in experiments 1 and 2 received two i.p. injections, whereas the mice in experiments 3 and 4 received an intra-NAc administration followed by an i.p. injection. The challenges were: saline+saline; saline+EtOH; SB-242084 (a 5-HT2C(R) antagonist; 0.5, 1.0 or 2.0 mg/kg i.p. or 1.0 or 2.0 ?g/side intra-NAc)+EtOH; and SB-242084 (0.5, 1.0 or 2.0 mg/kg i.p. or 1.0 or 2.0 ?g/side intra-NAc)+saline. At all tested doses, i.p. administration of SB-242084 did not affect the stimulating effect of EtOH in the highly sensitized mice. However, when delivered by intra-NAc administration, SB-242084 reduced (at 1.0 ?g/side) or completely blocked (at 2.0 ?g/side) the expression of EtOH-induced behavioral sensitization in the highly sensitized mice. These findings suggest that the expression of behavioral sensitization to the stimulating effect of EtOH depends on accumbal 5-HT2C(R) activity. [PubMed Citation] [Order full text from Infotrieve]

15) Gaikwad U, Parle M
Combination of aripiprazole and ethanol attenuates marble-burying behavior in mice.
Acta Pol Pharm. 2011 May-Jun;68(3):435-40.
Obsessive-Compulsive Disorder (OCD) is characterized by absurd, recurrent thoughts (obsessions) followed by certain stereotyped actions (compulsions). 5-Hydroxytryptamine (5-HT) abnormalities may be involved in OCD, and further, cause changes in serotonergic transmission that may have direct or indirect effects on the neuronal firing of other neuromodulators affecting thoughts, feelings and behaviors. Serotonin-related genes that are found in OCD include those coding for the 5-HT transporter (5-HTT) and receptors (5-HT(2A), 5-HT(2B), 5-HT(2C) and 5-HT(1B)) as well the 5-HT enzyme tryptophan hydroxylase. OCD can impair all areas of brain functioning and produce devastating effects on patients and their families. Marble-burying behavior of mice has been employed to study anxiety disorders, including the OCD. The aim of this study was to test the efficacy of aripiprazole and alcohol per se and in combination on marble-burying behavior of mice. A total of 114 male Swiss mice divided in 19 groups were studied. Aripiprazole (0.1 mg/kg, i.p.) per se as well as ethanol (0.1% w/v) per se did not show any anti-compulsive activity. But the combination comprising of ineffective doses of aripiprazole (0.1 mg/kg, i.p.) and ethanol (0.1% w/v) showed significant anti-compulsive activity as reflected by inhibition of marble-burying behavior. [PubMed Citation] [Order full text from Infotrieve]

16) Chen G, Cuzon Carlson VC, Wang J, Beck A, Heinz A, Ron D, Lovinger DM, Buck KJ
Striatal Involvement in Human Alcoholism and Alcohol Consumption, and Withdrawal in Animal Models.
Alcohol Clin Exp Res. 2011 May 25;
Background:? Different regions of the striatum may have distinct roles in acute intoxication, alcohol seeking, dependence, and withdrawal. Methods:? The recent advances are reviewed and discussed in our understanding of the role of the dorsolateral striatum (DLS), dorsomedial striatum (DMS), and ventral striatum in behavioral responses to alcohol, including alcohol craving in abstinent alcoholics, and alcohol consumption and withdrawal in rat, mouse, and nonhuman primate models. Results:? Reduced neuronal activity as well as dysfunctional connectivity between the ventral striatum and the dorsolateral prefrontal cortex is associated with alcohol craving and impairment of new learning processes in abstinent alcoholics. Within the DLS of mice and nonhuman primates withdrawn from alcohol after chronic exposure, glutamatergic transmission in striatal projection neurons is increased, while GABAergic transmission is decreased. Glutamatergic transmission in DMS projection neurons is also increased in ethanol withdrawn rats. Ex vivo or in vivo ethanol exposure and withdrawal causes a long-lasting increase in NR2B subunit-containing NMDA receptor activity in the DMS, contributing to ethanol drinking. Analyses of neuronal activation associated with alcohol withdrawal and site-directed lesions in mice implicate the rostroventral caudate putamen, a ventrolateral segment of the DMS, in genetically determined differences in risk for alcohol withdrawal involved in physical association of the multi-PDZ domain protein, MPDZ, with 5-HT(2C) receptors and/or NR2B. Conclusions:? Alterations of dopaminergic, glutamatergic, and GABAergic signaling within different regions of the striatum by alcohol is critical for alcohol craving, consumption, dependence, and withdrawal in humans and animal models. [PubMed Citation] [Order full text from Infotrieve]

17) Hickie IB, Rogers NL
Novel melatonin-based therapies: potential advances in the treatment of major depression.
Lancet. 2011 May 17;
Major depression is one of the leading causes of premature death and disability. Although available drugs are effective, they also have substantial limitations. Recent advances in our understanding of the fundamental links between chronobiology and major mood disorders, as well as the development of new drugs that target the circadian system, have led to a renewed focus on this area. In this review, we summarise the associations between disrupted chronobiology and major depression and outline new antidepressant treatment strategies that target the circadian system. In particular, we highlight agomelatine, a melatonin-receptor agonist and selective serotonergic receptor subtype (ie, 5-HT(2C)) antagonist that has chronobiotic, antidepressant, and anxiolytic effects. In the short-term, agomelatine has similar antidepressant efficacy to venlafaxine, fluoxetine, and sertraline and, in the longer term, fewer patients on agomelatine relapse (23�9%) than do those receiving placebo (50�0%). Patients with depression treated with agomelatine report improved sleep quality and reduced waking after sleep onset. As agomelatine does not raise serotonin levels, it has less potential for the common gastrointestinal, sexual, or metabolic side-effects that characterise many other antidepressant compounds. [PubMed Citation] [Order full text from Infotrieve]

18) Redman LM, Ravussin E
Lorcaserin for the treatment of obesity.
Drugs Today (Barc). 2010 Dec;46(12):901-10.
Obesity is a worldwide epidemic and there is an urgent need for the development of effective pharmacological therapies that target the metabolic and behavioral factors of body weight regulation. Serotonin (5-HT) has been implicated as a critical factor in the short-term (meal-by-meal) regulation of food intake and pharmaceutical companies have invested millions of dollars to discover and develop drug targets for the serotonergic pathway. Lorcaserin is a novel selective agonist of the 5-HT(2C) receptor for weight loss therapy. Preclinical and clinical studies indicate lorcaserin is well tolerated and not associated with cardiac valvulopathy or pulmonary hypertension suggesting that lorcaserin is a selective 5-HT(2C) receptor agonist and has little or no activation of the 5-HT(2B) and 5-HT(2A) receptors, respectively. Lorcaserin acts to alter energy balance through a reduction in energy intake and without an increase in energy expenditure and achieved the U.S. Food and Drug Administration guidelines for weight loss efficacy. It remains to be determined whether or not lorcaserin will be approved for the long-term management of obesity. [PubMed Citation] [Order full text from Infotrieve]

19) Guo L, Zhang J, Yan Q, Yin M
Establishment and characterization of RNA-edited serotonin 2C receptor isoform cell models and alteration of amyloid precursor protein ectodomain secretion in HEK293 APPSwe cells.
Hum Cell. 2011 Jun;24(2):104-11.
RNA editing is a mechanism for generating molecular diversity by altering the genetic code at the level of RNA. The 5-HT(2C) receptor is the only G protein-coupled receptor known to be edited. It has been reported that the non-edited 5-HT(2C) receptor stimulates secretion of the APP metabolite APP ectodomain (APPs). However, it remains unknown whether RNA-edited 5-HT(2C) receptors can also affect APPs secretion. In this study, cDNAs of five non-edited or partially/fully edited 5-HT(2C) receptor isoforms (INI, VNI, VNV, VSV and VGV) were stably transfected into HEK293APPSwe cells to detect the cell proliferation and APPs secretion. The results demonstrated that the overexpression of INI and VNI caused increased proliferation of host cells while VNV, VSV and VGV caused inverse effects (P�<�0.01). Compared with both control and non-edited isoform INI, APPs levels were significantly increased in the four edited 5-HT(2C) receptor isoforms, VNI (P�<�0.05), VNV (P�<�0.05), VSV (P�<�0.05) and VGV (P�<�0.01). These results suggest that the RNA editing of the 5-HT(2C) receptor may affect APPs secretion through different signaling pathways related to cell growth and protein processing, and that these cell models will provide appropriate useful information to study the association between the RNA editing of the serotonin 5-HT(2C) receptor and APP metabolism. [PubMed Citation] [Order full text from Infotrieve]

20) Cunningham KA, Fox RG, Anastasio NC, Bubar MJ, Stutz SJ, Moeller FG, Gilbertson SR, Rosenzweig-Lipson S
Selective serotonin 5-HT(2C) receptor activation suppresses the reinforcing efficacy of cocaine and sucrose but differentially affects the incentive-salience value of cocaine- vs. sucrose-associated cues.
Neuropharmacology. 2011 Sep;61(3):513-23.
Serotonin (5-HT) controls affective and motivational aspects of palatable food and drug reward and the 5-HT(2C) receptor (5-HT(2C)R) has emerged as a key regulator in this regard. We have evaluated the efficacy of a selective 5-HT(2C)R agonist, WAY 163909, in cocaine and sucrose self-administration and reinstatement assays employing parallel experimental designs in free-fed rats. WAY 163909 dose-dependently reduced the reinforcing efficacy of cocaine (ID(50)�=�1.19�mg/kg) and sucrose (ID(50)�=�0.7�mg/kg) as well as reinstatement (ID(50)�=�0.5�mg/kg) elicited by exposure to cocaine-associated contextual cues, but not sucrose-associated contextual cues. The ID(50) of WAY 163909 predicted to decrease the reinforcing efficacy of cocaine or sucrose as well as reinstatement upon exposure to cocaine-associated cues was ?5-12-fold lower than that predicted to suppress horizontal ambulation (ID(50)�=�5.89�mg/kg) and ?2-5-fold lower than that predicted to suppress vertical activity (ID(50)�=�2.3�mg/kg). Thus, selective stimulation of the 5-HT(2C)R decreases the reinforcing efficacy of cocaine and sucrose in freely-fed rats, but differentially alters the incentive-salience value of cocaine- vs. sucrose-associated cues at doses that do not impair locomotor activity. Future research is needed to tease apart the precise contribution of 5-HT(2C)R neurocircuitry in reward and motivation and the learning and memory processes that carry the encoding for associations between environmental cues and consumption of rewarding stimuli. A more complete preclinical evaluation of these questions will ultimately allow educated proof-of-concept trials to test the efficacy of selective 5-HT(2C)R agonists as adjunctive therapy in chronic health maladies including obesity, eating disorders and drug addiction. This article is part of a Special Issue entitled 'Serotonin'. [PubMed Citation] [Order full text from Infotrieve]