Abstract
This paper is a personal account on the discovery and characterization of the 5-HT2C receptor (first known as the 5-HT1C receptor) over 30 years ago and how it translated into a number of unsuspected features for a G protein-coupled receptor (GPCR) and a diversity of clinical applications. The 5-HT2C receptor is one of the most intriguing members of the GPCR superfamily. Initially referred to as 5-HT1CR, the 5-HT2CR was discovered while studying the pharmacological features and the distribution of [3H]mesulergine-labelled sites, primarily in the brain using radioligand binding and slice autoradiography. Mesulergine (SDZ CU-085), was, at the time, best defined as a ligand with serotonergic and dopaminergic properties. Autoradiographic studies showed remarkably strong [3H]mesulergine-labelling to the rat choroid plexus. [3H]mesulergine-labelled sites had pharmacological properties different from, at the time, known or purported 5-HT receptors. In spite of similarities with 5-HT2 binding, the new binding site was called 5-HT1C because of its very high affinity for 5-HT itself. Within the following 10 years, the 5-HT1CR (later named 5-HT2C) was extensively characterised pharmacologically, anatomically and functionally: it was one of the first 5-HT receptors to be sequenced and cloned. The 5-HT2CR is a GPCR, with a very complex gene structure. It constitutes a rarity in the GPCR family: many 5-HT2CR variants exist, especially in humans, due to RNA editing, in addition to a few 5-HT2CR splice variants. Intense research led to therapeutically active 5-HT2C receptor ligands, both antagonists (or inverse agonists) and agonists: kee** in mind that a number of antidepressants and antipsychotics are 5-HT2CR antagonists/inverse agonists. Agomelatine, a 5-HT2CR antagonist is registered for the treatment of major depression. The agonist Lorcaserin is registered for the treatment of aspects of obesity and has further potential in addiction, especially nicotine/ smoking. There is good evidence that the 5-HT2CR is involved in spinal cord injury-induced spasms of the lower limbs, which can be treated with 5-HT2CR antagonists/inverse agonists such as cyproheptadine or SB206553. The 5-HT2CR may play a role in schizophrenia and epilepsy. Vabicaserin, a 5-HT2CR agonist has been in development for the treatment of schizophrenia and obesity, but was stopped. As is common, there is potential for further indications for 5-HT2CR ligands, as suggested by a number of preclinical and/or genome-wide association studies (GWAS) on depression, suicide, sexual dysfunction, addictions and obesity. The 5-HT2CR is clearly affected by a number of established antidepressants/antipsychotics and may be one of the culprits in antipsychotic-induced weight gain.
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Abramowski D, Rigo M, Duc D, Hoyer D, Staufenbiel M (1995) Localization of the 5-hydroxytryptamine2C receptor protein in human and rat brain using specific antisera. Neuropharmacology 34:1635–1645
Alexander SP, Benson HE, Faccenda E, Pawson AJ, Sharman JL, McGrath JC, Catterall WA, Spedding M, Peters JA, Harmar AJ; CGTP Collaborators: Abul-Hasn N, Anderson CM, Anderson CM, Araiksinen MS, Arita M, Arthofer E, Barker EL, Barratt C, Barnes NM, Bathgate R, Beart PM, Belelli D, Bennett AJ, Birdsall NJ, Boison D, Bonner TI, Brailsford L, Bröer S, Brown P, Calo G, Carter WG, Catterall WA, Chan SL, Chao MV, Chiang N, Christopoulos A, Chun JJ, Cidlowski J, Clapham DE, Cockcroft S, Connor MA, Cox HM, Cuthbert A, Dautzenberg FM, Davenport AP, Dawson PA, Dent G, Dijksterhuis JP, Dollery CT, Dolphin AC, Donowitz M, Dubocovich ML, Eiden L, Eidne K, Evans BA, Fabbro D, Fahlke C, Farndale R, Fitzgerald GA, Fong TM, Fowler CJ, Fry JR, Funk CD, Futerman AH, Ganapathy V, Gaisnier B, Gershengorn MA, Goldin A, Goldman ID, Gundlach AL, Hagenbuch B, Hales TG, Hammond JR, Hamon M, Hancox JC, Hauger RL, Hay DL, Hobbs AJ, Hollenberg MD, Holliday ND, Hoyer D, Hynes NA, Inui KI, Ishii S, Jacobson KA, Jarvis GE, Jarvis MF, Jensen R, Jones CE, Jones RL, Kaibuchi K, Kanai Y, Kennedy C, Kerr ID, Khan AA, Klienz MJ, Kukkonen JP, Lapoint JY, Leurs R, Lingueglia E, Lippiat J, Lolait SJ, Lummis SC, Lynch JW, MacEwan D, Maguire JJ, Marshall IL, May JM, McArdle CA, McGrath JC, Michel MC, Millar NS, Miller LJ, Mitolo V, Monk PN, Moore PK, Moorhouse AJ, Mouillac B, Murphy PM, Neubig RR, Neumaier J, Niesler B, Obaidat A, Offermanns S, Ohlstein E, Panaro MA, Parsons S, Pertwee RG, Petersen J, Pin JP, Poyner DR, Prigent S, Prossnitz ER, Pyne NJ, Pyne S, Quigley JG, Ramachandran R, Richelson EL, Roberts RE, Roskoski R, Ross RA, Roth M, Rudnick G, Ryan RM, Said SI, Schild L, Sanger GJ, Scholich K, Schousboe A, Schulte G, Schulz S, Serhan CN, Sexton PM, Sibley DR, Siegel JM, Singh G, Sitsapesan R, Smart TG, Smith DM, Soga T, Stahl A, Stewart G, Stoddart LA, Summers RJ, Thorens B, Thwaites DT, Toll L, Traynor JR, Usdin TB, Vandenberg RJ, Villalon C, Vore M, Waldman SA, Ward DT, Willars GB, Wonnacott SJ, Wright E, Ye RD, Yonezawa A, Zimmermann M. (2013) The Concise Guide to PHARMACOLOGY 2013/14: overview. Br J Pharmacol 170(8): 1449-58. doi 10.1111/bph.12444
Alexander SP, Kelly E, Marrion N, Peters JA, Benson HE, Faccenda E, Pawson AJ, Sharman JL, Southan C, Buneman OP, Catterall WA, Cidlowski JA, Davenport AP, Fabbro D, Fan G, McGrath JC, Spedding M, Davies JA; CGTP Collaborators: Aldrich R, Attali B, Bäck ML, Barnes NM, Bathgate R, Beart PM, Becirovic E, Biel M, Birdsall NJ, Boison D, Bräuner-Osborne H, Bröer S, Bryant C, Burnstock G, Burris T, Cain D, Calo G, Chan SL, Chandy KG, Chiang N, Christakos S, Christopoulos A, Chun JJ, Chung JJ, Clapham DE, Connor MA, Coons L, Cox HM, Dautzenberg FM, Dent G, Douglas SD, Dubocovich ML, Edwards DP, Farndale R, Fong TM, Forrest D, Fowler CJ, Fuller P, Gainetdinov RR, Gershengorn MA, Goldin A, Goldstein SA, Grimm SL, Grissmer S, Gundlach AL, Hagenbuch B, Hammond JR, Hancox JC, Hartig S, Hauger RL, Hay DL, Hébert T, Hollenberg AN, Holliday ND, Hoyer D, Ijzerman AP, Inui KI, Ishii S, Jacobson KA, Jan LY, Jarvis GE, Jensen R, Jetten A, Jockers R, Kaczmarek LK, Kanai Y, Kang HS, Karnik S, Kerr ID, Korach KS, Lange CA, Larhammar D, Leeb-Lundberg F, Leurs R, Lolait SJ, Macewan D, Maguire JJ, May JM, Mazella J, Mcardle CA, Mcdonnell DP, Michel MC, Miller LJ, Mitolo V, Monie T, Monk PN, Mouillac B, Murphy PM, Nahon JL, Nerbonne J, Nichols CG, Norel X, Oakley R, Offermanns S, Palmer LG, Panaro MA, Perez-Reyes E, Pertwee RG, Pike JW, Pin JP, Pintor S, Plant LD, Poyner DR, Prossnitz ER, Pyne S, Ren D, Richer JK, Rondard P, Ross RA, Sackin H, Safi R, Sanguinetti MC, Sartorius CA, Segaloff DL, Sladek FM, Stewart G, Stoddart LA, Striessnig J, Summers RJ, Takeda Y, Tetel M, Toll L, Trimmer JS, Tsai MJ, Tsai SY, Tucker S, Usdin TB, Vilargada JP, Vore M, Ward DT, Waxman SG, Webb P, Wei AD, Weigel N, Willars GB, Winrow C, Wong SS, Wulff H, Ye RD, Young M, Zajac JM (2015) The Concise Guide to PHARMACOLOGY 2015/16: overview. Br J Pharmacol 172(24): 5729-5743. doi: 10.1111/bph.13347
Aloyo VJ, Berg KA, Spampinato U, Clarke WP, Harvey JA (2009) Current status of inverse agonism at serotonin(2A) (5-HT(2A)) and 5-HT(2C) receptors. Pharmacol Ther 121:160–173
Anastasio NC, Liu S, Maili L, Swinford SE, Lane SD, Fox RG, Hamon SC, Nielsen DA, Cunningham KA, Moeller FG (2014a) Variation within the serotonin (5-HT) 5-HT2C receptor system aligns with vulnerability to cocaine cue reactivity. Transl Psychiatry 4:e369
Anastasio NC, Stutz SJ, Fox RG, Sears RM, Emeson RB, DiLeone RJ, O'Neil RT, Fink LH, Li D, Green TA, Moeller FG, Cunningham KA (2014b) Functional status of the serotonin 5-HT2C receptor (5-HT2CR) drives interlocked phenotypes that precipitate relapse-like behaviors in cocaine dependence. Neuropsychopharmacology 39:370–382
Anastasio NC, Stutz SJ, Fink LH, Swinford-Jackson SE, Sears RM, DiLeone RJ, Rice KC, Moeller FG, Cunningham KA (2015) Serotonin (5-HT) 5-HT2A receptor (5-HT2AR): 5-HT2CR imbalance in medial prefrontal cortex associates with motor impulsivity. ACS Chem Neurosci 6:1248–1258
Bagdy G, Kecskemeti V, Riba P, Jakus R (2007) Serotonin and epilepsy. J Neurochem 100:857–873
Bankson MG, Cunningham KA (2002) Pharmacological studies of the acute effects of (+)-3,4- methylenedioxymethamphetamine on locomotor activity: role of 5-HT(1B/1D) and 5-HT(2) receptors. Neuropsychopharmacology 26:40–52
Basile VS, Masellis M, De Luca V, Meltzer HY, Kennedy JL (2002) 759C/T genetic variation of 5HT(2C) receptor and clozapine-induced weight gain. Lancet 360:1790–1791
Becamel C, Figge A, Poliak S, Dumuis A, Peles E, Bockaert J, Lubbert H, Ullmer C (2001) Interaction of serotonin 5-hydroxytryptamine type 2C receptors with PDZ10 of the multi-PDZ domain protein MUPP1. J Biol Chem 276:12974–12982
Becamel C, Alonso G, Galeotti N, Demey E, Jouin P, Ullmer C, Dumuis A, Bockaert J, Marin P (2002) Synaptic multiprotein complexes associated with 5-HT(2C) receptors: a proteomic approach. EMBO J 21:2332–2342
Becamel C, Gavarini S, Chanrion B, Alonso G, Galeotti N, Dumuis A, Bockaert J, Marin P (2004) The serotonin 5-HT2A and 5-HT2C receptors interact with specific sets of PDZ proteins. J Biol Chem 279:20257–20266
Benjamin D, Lal H, Meyerson LR (1990) The effects of 5-HT1B characterising agents in the mouse elevated plus-maze. Life Sci 47:195–203
Bennett MR (2000) The concept of transmitter receptors: 100 years on. Neuropharmacology 39:523–546
Berg KA, Clarke WP, Sailstad C, Saltzman A, Maayani S (1994) Signal transduction differences between 5-hydroxytryptamine type 2A and type 2C receptor systems. Mol Pharmacol 46:477–484
Berg KA, Maayani S, Goldfarb J, Clarke WP (1998a) Pleiotropic behavior of 5-HT2A and 5-HT2C receptor agonists. Ann NYAcad Sci 861:104–110
Berg KA, Maayani S, Goldfarb J, Scaramellini C, Leff P, Clarke WP (1998b) Effector pathway-dependent relative efficacy at serotonin type 2A and 2C receptors: evidence for agonist-directed trafficking of receptor stimulus. Mol Pharmacol 54:94–104
Berg KA, Stout BD, Cropper JD, Maayani S, Clarke WP (1999) Novel actions of inverse agonists on 5-HT2C receptor systems. Mol Pharmacol 55:863–872
Berg KA, Cropper JD, Niswender CM, Sanders-Bush E, Emeson RB, Clarke WP (2001) RNA-editing of the 5-HT(2C) receptor alters agonist-receptor-effector coupling specificity. Br J Pharmacol 134:386–392
Berg KA, Cropper JD, King BD, Clarke WP (2003) Effector pathway—dependence of ligand-independent 5-HT2C receptor activity. FASEB J 17:A1021
Berg KA, Clarke WP, Cunningham KA, Spampinato U (2008a) Fine-tuning serotonin2c receptor function in the brain: molecular and functional implications. Neuropharmacology 55:969–976
Berg KA, Dunlop J, Sanchez T, Silva M, Clarke WP (2008b) A conservative, single-amino acid substitution in the second cytoplasmic domain of the human Serotonin2C receptor alters both ligand-dependent and -independent receptor signaling. J Pharmacol Exp Ther 324:1084–1092
Berg KA, Clarke WP (2009) Functional selectivity at serotonin receptors, in Functional selectivity of G protein-coupled receptor ligands (Neve KA ed) pp 155–176, Humana Press.
Bergen SS Jr (1964) Appetite stimulating properties of cyproheptadine. Am J Dis Child 108:270–273
Berglund ED, Liu C, Sohn JW, Liu T, Kim MH, Lee CE, Vianna CR, Williams KW, Xu Y, Elmquist JK (2013) Serotonin 2C receptors in pro-opiomelanocortin neurons regulate energy and glucose homeostasis. J Clinical Investigation 123:5061–5070
Besson M, Pelloux Y, Dilleen R, Theobald DE, Lyon A, Belin-Rauscent A, Robbins TW, Dalley JW, Everitt BJ, Belin D (2013) Cocaine modulation of frontostriatal expression of Zif268, D2, and 5-HT2c receptors in high and low impulsive rats. Neuropsychopharmacology 38:1963–1973
Bigford GE, Chaudhry NS, Keane RW, Holohean AM (2012) 5-hydroxytryptamine 5HT2C receptors form a protein complex with N-methyl-D-aspartate GluN2A subunits and activate phosphorylation of Src protein to modulate motoneuronal depolarization. J Biol Chem 287:11049–11059
Bilkei-Gorzo A, Gyertyan I, Levay G (1998) mCPP-induced anxiety in the light-dark box in rats—a new method for screening anxiolytic activity. Psychopharmacology 136:291–298
Blundell JE (1999) The control of appetite: basic concepts and practical implications. Schweiz Med Wochenschr 129:182–188
Bombail V, Qing W, Chapman KE, Holmes MC (2014) Prevention of 5-hydroxytryptamine2C receptor RNA editing and alternate splicing in C57BL/6 mice activates the hypothalamic-pituitary-adrenal axis and alters mood. Eur J Neurosci 40:3663–3673
Bonhaus DW, Weinhardt KK, Taylor M, DeSouza A, Mcneeley PM, Szczepanski K, Fontana DJ, Trinh J, Rocha CL, Dawson MW, Flippin LA, Eglen RM (1997) RS-102221: a novel high affinity and selective, 5-HT2C receptor antagonist. Neuropharmacology 36:621–629
Bradley PB, Engel G, Feniuk W, Fozard JR, Humphrey PPA, Middlemiss DN, Mylecharane EJ, Richardson BP, Saxena PR (1986) Proposals for the classification and nomenclature of functional receptors for 5-hydroxytryptamine. Neuropharmacol 25:563–576
Brennan TJ, Seeley WW, Kilgard M, Schreiner CE, Tecott LH (1997) Sound-induced seizures in serotonin 5-HT2C receptor mutant mice. Nature Genet 16:387–390
Bromidge SM, Duckworth M, Forbes IT, Ham P, King FD, Thewlis KM, Blaney FE, Naylor CB, Blackburn TP, Kennett GA, Wood MD, Clarke SE (1997) 6-Chloro-5-methyl-1-[[2-[(2-methyl-3-pyridyl)oxy]-5-pyridyl]carbamoyl]- indoline (SB-242084): the first selective and brain penetrant 5-HT2C receptor antagonist. J Med Chem 40:3494–3496
Bubar MJ, Cunningham KA (2006) Serotonin 5-HT2A and 5-HT2C receptors as potential targets for modulation of psychostimulant use and dependence. Curr Top Med Chem 6:1971–1985
Bubar MJ, Cunningham KA (2007) Distribution of serotonin 5-HT2C receptors in the ventral tegmental area. Neuroscience 146:286–297
Bubar MJ, Cunningham KA (2008) Prospects for serotonin 5-HT2R pharmacotherapy in psychostimulant abuse. Prog Brain Res 172:319–346
Bubar MJ, Stutz SJ, Cunningham KA (2011) 5-HT(2C) receptors localize to dopamine and GABA neurons in the rat mesoaccumbens pathway. PLoS One 6:e20508
Burbassi S, Cervo L (2008) Stimulation of serotonin(2C) receptors influences cocaine-seeking behavior in response to drug-associated stimuli in rats. Psychopharmacology 196:15–27
Burke LK, Doslikova B, D'Agostino G, Greenwald-Yarnell M, Georgescu T, Chianese R, Martinez de Morentin PB, Ogunnowo-Bada E, Cansell C, Valencia-Torres L, Garfield AS, Apergis-Schoute J, Lam DD, Speakman JR, Rubinstein M, Low MJ, Rochford JJ, Myers MG, Evans ML, Heisler LK (2016) Sex difference in physical activity, energy expenditure and obesity driven by a subpopulation of hypothalamic POMC neurons. Mol Metab 5:245–252
Burns CM, Chu H, Rueter SM, Hutchinson LK, Canton H, Sanders-Bush E, Emeson RB (1997) Regulation of serotonin-2C receptor G-protein coupling by RNA editing. Nature 387:303–308
Buydens-Branchey L, Branchey M, Fergeson P, Hudson J, McKernin C (1997) The meta-chlorophenylpiperazine challenge test in cocaine addicts: hormonal and psychological responses. Biol Psychiat 41:1071–1086
Campbell BM, Merchant KM (2003) Serotonin 2C receptors within the basolateral amygdala induce acute fear-like responses in an open-field environment. Brain Res 993:1–9
Canton H, Emeson RB, Barker EL, Backstrom JR, Lu JT, Chang MS, Sanders-Bush E (1996) Identification, molecular cloning, and distribution of a short variant of the 5-hydroxytryptamine2C receptor produced by alternative splicing. Mol Pharmacol 50:799–807
Carmel L, Koonin EV, Dracheva S (2012) Dependencies among editing sites in serotonin 2C receptor mRNA. PLoS Comput Biol 8:e1002663
Cathala A, Devroye C, Maitre M, Piazza PV, Abrous DN, Revest JM, Spampinato U (2015) Serotonin2C receptors modulate dopamine transmission in the nucleus accumbens independently of dopamine release: behavioral, neurochemical and molecular studies with cocaine. Addict Biol 20:445–457
Chinuck RS, Fortnum H, Baldwin DR (2007) Appetite stimulants in cystic fibrosis: a systematic review. J Hum Nutr Diet 20:526–537
Christianson JP, Ragole T, Amat J, Greenwood BN, Strong PV, Paul ED, Fleshner M, Watkins LR, Maier SF (2010) 5-hydroxytryptamine 2C receptors in the basolateral amygdala are involved in the expression of anxiety after uncontrollable traumatic stress. Biol Psychiatry 67:339–345
Clifton PG, Lee MD, Dourish CT (2000) Similarities in the action of Ro 60-0175, a 5-HT2C receptor agonist and d-fenfluramine on feeding patterns in the rat. Psychopharmacology 152:256–267
ClinicalTrials (2014) https://clinicaltrials.gov/ct2/show/results/NCT00563706?term=vabicaserin&rank=2).
Closse A (1983) [3H]mesulergine, a selective ligand for serotonin-2 receptors. Life Sci 32:2485–2495
Conn PJ, Sanders-Bush E (1986) Agonist-induced phosphoinositide hydrolysis in choroid plexus. J Neurochem 47:1754–1760
Conn PJ, Sanders-Bush E, Hoffman BJ, Hartig PR (1986) A unique serotonin receptor in choroid plexus is linked to phosphatidylinositol turnover. Proc Natl Acad Sci U S A 83:4086–4088
Cremers TI, Giorgetti M, Bosker FJ, Hogg S, Arnt J, Mork A, Honig G, Bogeso KP, Westerink BH, den BH, Wikstrom HV, Tecott LH (2004) Inactivation of 5-HT(2C) receptors potentiates consequences of serotonin reuptake blockade. Neuropsychopharmacology 29:1782–1789
Cremers TI, Rea K, Bosker FJ, Wikstrom HV, Hogg S, Mork A, Westerink BH (2007) Augmentation of SSRI effects on serotonin by 5-HT2C antagonists: mechanistic studies. Neuropsychopharmacology 32:1550–1557
Cryan JF, Lucki I (2000) Antidepressant-like behavioral effects mediated by 5-hydroxytryptamine(2C) receptors. J Pharmacol ExpTher 295:1120–1126
Cunningham KA, Anastasio NC (2014) Serotonin at the nexus of impulsivity and cue reactivity in cocaine addiction. Neuropharmacology 76 Pt B:460–478
Cunningham KA, Anastasio NC, Fox RG, Stutz SJ, Bubar MJ, Swinford SE, Watson CS, Gilbertson SR, Rice KC, Rosenzweig-Lipson S, Moeller FG (2013) Synergism between a serotonin 5-HT2A receptor (5-HT2AR) antagonist and 5-HT2CR agonist suggests new pharmacotherapeutics for cocaine addiction. ACS Chem Neurosci 4:110–121
Cunningham KA, Fox RG, Anastasio NC, Bubar MJ, Stutz SJ, Moeller FG, Gilbertson SR, Rosenzweig-Lipson S (2011) Selective serotonin 5-HT2C receptor activation suppresses the reinforcing efficacy of cocaine and sucrose but differentially affects the incentive-salience value of cocaine- vs. sucrose-associated cues. Neuropharmacology 61:513–523
Dalton GL, Lee MD, Kennett GA, Dourish CT, Clifton PG (2006) Serotonin 1B and 2C receptor interactions in the modulation of feeding behaviour in the mouse. Psychopharmacology 185:45–57
Davis JD, Smith GP, Singh B and McCann DL (2001) The impact of sucrose-derived unconditioned and conditioned negative feedback on the microstructure of ingestive behavior. Physiol Behav 72:393-402
De Luca V, Muller DJ, Hwang R, Lieberman JA, Volavka J, Meltzer HY, Kennedy JL (2007) HTR2C haplotypes and antipsychotics-induced weight gain: x-linked multimarker analysis. Human Psychopharmacology-Clinical and Experimental 22:463–467
Di Giovanni G, De Deurwaerdere P (2016) New therapeutic opportunities for 5-HT receptor ligands in neuropsychiatric disorders. Pharmacol Ther 157:125–162
Di Giovanni G, De Deurwaerdére P, Di Mascio M, Di Matteo V, Esposito E, Spampinato U (1999) Selective blockade of serotonin-2C/2B receptors enhances mesolimbic and mesostriatal dopaminergic function: a combined in vivo electrophysiological and microdialysis study. Neuroscience 91:587–597
Di Giovanni G, Di MV, La GV, Esposito E (2001) M-chlorophenylpiperazine excites non-dopaminergic neurons in the rat substantia nigra and ventral tegmental area by activating serotonin-2C receptors. Neuroscience 103:111–116
Di Giovanni G, Di Matteo V, Pierucci M, Benigno A, Esposito E (2006) Central serotonin2C receptor: from physiology to pathology. CurrTopMedChem 6:1909–1925
Di Matteo V, Di Giovanni G, Di Mascio M, Esposito E (2000) Biochemical and electrophysiological evidence that RO 60-0175 inhibits mesolimbic dopaminergic function through serotonin(2C) receptors. Brain Res 865:85–90
Di Narzo AF, Kozlenkov A, Ge Y, Zhang B, Sanelli L, May Z, Li Y, Fouad K, Cardozo C, Koonin EV, Bennett DJ, Dracheva S (2015) Decrease of mRNA editing after spinal cord injury is caused by down-regulation of ADAR2 that is triggered by inflammatory response. Scientific reports 5:12615
Di Narzo AF, Kozlenkov A, Roussos P, Hao K, Hurd Y, Lewis DA, Sibille E, Siever LJ, Koonin E, Dracheva S (2014) A unique gene expression signature associated with serotonin 2C receptor RNA editing in the prefrontal cortex and altered in suicide. Hum Mol Genet 23:4801–4813
Dixon RAF, Kobilka BK, Strader DJ, Benovic JL, Dohlman HG, Frielle T et al (1986) Cloning of the gene and cDNA for mammalian beta-adrenergic-receptor and homology with rhodopsin. Nature 321:75–79
Doods HN, Boddeke HO, Kalkman HO, Hoyer D, Mathy MJ, van Zwieten PA (1988) Central 5-HT1A receptors and the mechanism of the central hypotensive effect of (+)8-OH-DPAT, DP-5-CT, R28935 and urapidil. J Cardiovasc Pharmacol 11:432–437
Doyle VM, Creba JA, Rüegg UT, Hoyer D (1986) Serotonin increases the production of inositol phosphates and mobilises calcium via the 5-HT2 receptor in A7r5 smooth muscle cells. Naunyn Schmiedeberg's Arch Pharmacol 333:98–103
Dracheva S, Chin B, Haroutunian V (2008a) Altered serotonin 2C receptor RNA splicing in suicide: association with editing. Neuroreport 19:379–382
Dracheva S, Elhakem SL, Marcus SM, Siever LJ, McGurk SR, Haroutunian V (2003) RNA editing and alternative splicing of human serotonin 2C receptor in schizophrenia. J Neurochem 87:1402–1412
Dracheva S, Lyddon R, Barley K, Marcus SM, Hurd YL, Byne WM (2009) Editing of serotonin 2C receptor mRNA in the prefrontal cortex characterizes high-novelty locomotor response behavioral trait. Neuropsychopharmacology 34:2237–2251
Dracheva S, Patel N, Woo DA, Marcus SM, Siever LJ, Haroutunian V (2008b) Increased serotonin 2C receptor mRNA editing: a possible risk factor for suicide. MolPsychiatry 13:1001–1010
Du Y, Davisson MT, Kafadar K, Gardiner K (2006) A-to-I pre-mRNA editing of the serotonin 2C receptor: comparisons among inbred mouse strains. Gene 382:39–46
Du Y, Stasko M, Costa AC, Davisson MT, Gardiner KJ (2007) Editing of the serotonin 2C receptor pre-mRNA: effects of the Morris water maze. Gene 391:186–197
Dunlop J, Marquis KL, Lim HK, Leung L, Kao J, Cheesman C, Rosenzweig-Lipson S (2006) Pharmacological profile of the 5-HT(2C) receptor agonist WAY-163909; therapeutic potential in multiple indications. CNS Drug Rev 12:167–177
Dunlop J, Sabb AL, Mazandarani H, Zhang J, Kalgaonker S, Shukhina E, Sukoff S, Vogel RL, Stack G, Schechter L, Harrison BL, Rosenzweig-Lipson S (2005) WAY-163909 ((7bR,10aR)-1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta-[b][1,4]diazepino[ 6,7,1hi]indole): a novel 5-HT2C receptor selective agonist with anorectic activity. J Pharmacol Exp Ther 313:862–869
Dunlop J, Watts SW, Barrett JE, Coupet J, Harrison B, Mazandarani H, Nawoschik S, Pangalos MN, Ramamoorthy S, Schechter L, Smith D, Stack G, Zhang J, Zhang G, Rosenzweig-Lipson S (2011) Characterization of vabicaserin (SCA-136), a selective 5-hydroxytryptamine 2C receptor agonist. J Pharmacol Exp Ther 337:673–680
Eisai (2014) (http://www.eisai.com/news/news201465.html).
EMA/633676/2014, EPAR summary for the public: valdoxan, agomelatine.
EMA/695134/2016, EPAR summary for the public: thymanax, agomelatine
Engel G, Göthert M, Hoyer D, Schlicker E, Hillenbrand K (1986) Identity of inhibitory presynaptic 5-hydroxytryptamine (5-HT) autoreceptors in the rat brain cortex with 5-HT1B binding sites. Naunyn- SchmiedArchPharmacol 332:1–7
Engel G, Hoyer D, Berthold R, Wagner H (1981) (+/−)[125Iodo] cyanopindolol, a new ligand for beta-adrenoceptors: identification and quantitation of subclasses of beta-adrenoceptors in guinea pig. Naunyn Schmiedeberg's Arch Pharmacol 317:277–285
Engel G, Hoyer D, Kalkman HO, Wick MB (1984) Identification of 5HT2- receptors on longitudinal muscle of the guinea pig ileum. JReceptRes 4:113–126
Enz A, Donatsch P, Nordmann R (1984) Dopaminergic properties of mesulergine (CU 32-085) and its metabolites. J.Neural Transm. 60:225–238
Fargin A, Raymond JR, Lohse MJ, Kobilka BK, Caron MG, Lefkowitz RJ (1988) The genomic clone G-21 which resembles a beta-adrenergic-receptor sequence encodes the 5-HT1A receptor. Nature 335:358–360
FDA (2012) http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm309993.htm).
Filip M, Cunningham KA (2002) Serotonin 5-HT(2C) receptors in nucleus accumbens regulate expression of the hyperlocomotive and discriminative stimulus effects of cocaine. Pharmacol Biochem Behav 71:745–756
Fitzgerald LW, Burn TC, Brown BS, Patterson JP, Corjay MH, Valentine PA, Sun JH, Link JR, Abbaszade I, Hollis JM, Largent BL, Hartig PR, Hollis GF, Meunier PC, Robichaud AJ, Robertson DW (2000) Possible role of valvular serotonin 5-HT(2B) receptors in the cardiopathy associated with fenfluramine. Mol Pharmacol 57:75–81
Fitzgerald LW, Iyer G, Conklin DS, Krause CM, Marshall A, Patterson JP, Tran DP, Jonak GJ, Hartig PR (1999) Messenger RNA editing of the human serotonin 5-HT2C receptor. Neuropsychopharmacology 21:82S–90S
Fletcher PJ, Grottick AJ, Higgins GA (2002a) Differential effects of the 5-HT2A receptor antagonist M100,907 and the 5-HT2C receptor antagonist SB242,084 on cocaine-induced locomotor activity, cocaine self-administration and cocaine-induced reinstatement of responding. Neuropsychopharmacology 27:576–586
Fletcher PJ, Korth KM, Robinson SR, Baker GB (2002b) Multiple 5-HT receptors are involved in the effects of acute MDMA treatment: studies on locomotor activity and responding for conditioned reinforcement. Psychopharmacology 162:282–291
Fletcher PJ, Chintoh AF, Sinyard J, Higgins GA (2004) Injection of the 5-HT2C receptor agonist Ro60-0175 into the ventral tegmental area reduces cocaine-induced locomotor activity and cocaine self-administration. Neuropsychopharmacology 29:308–318
Fletcher PJ, Rizos Z, Sinyard J, Tampakeras M, Higgins GA (2008) The 5-HT(2C) receptor agonist RO 60-0175 reduces cocaine self-administration, reinstatement induced by the stressor yohimbine and contextual cues. Neuropsychopharmacology 33:1402–1412
Fletcher PJ, Rizos Z, Noble K, Higgins GA (2011) Impulsive action induced by amphetamine, cocaine and MK801 is reduced by 5-HT(2C) receptor stimulation and 5-HT(2A) receptor blockade. Neuropharmacology 61:468–477
Fletcher PJ, Rizos Z, Noble K, Soko AD, Silenieks LB, Le AD, Higgins GA (2012) Effects of the 5-HT2C receptor agonist Ro60-0175 and the 5-HT2A receptor antagonist M100907 on nicotine self-administration and reinstatement. Neuropharmacology 62:2288–2298
Flomen R, Knight J, Sham P, Kerwin R, Makoff A (2004) Evidence that RNA editing modulates splice site selection in the 5-HT2C receptor gene. Nucleic Acids Res 32:2113–2122
Foguet M, Hoyer D, Pardo LA, Parekh A, Kluxen FW, Kalkman HO, Stühmer W, Lübbert H (1992a) Cloning and functional characterization of the rat stomach fundus serotonin receptor. EMBO J 11:3481–3487
Foguet M, Nguyen H, Le H, Lubbert H (1992b) Structure of the mouse 5-HT1C, 5-HT2 and stomach fundus serotonin receptor genes. Neuroreport 3:345–348
Fouad K, Rank MM, Vavrek R, Murray KC, Sanelli L, Bennett DJ (2010) Locomotion after spinal cord injury depends on constitutive activity in serotonin receptors. J Neurophysiol 104:2975–2984
Gaddum JH, Picarelli ZP (1957) Two kinds of tryptamine receptor. Br J Pharmacol Chemother 12:323–328
Gatch MB (2003) Discriminative stimulus effects of m-chlorophenylpiperazine as a model of the role of serotonin receptors in anxiety. Life Sci 73:1347–1367
Gautron L, Elmquist JK, Williams KW (2015) Neural control of energy balance: translating circuits to therapies. Cell 161:133–145
Gavarini S, Becamel C, Altier C, Lory P, Poncet J, Wijnholds J, Bockaert J, Marin P (2006) Opposite effects of PSD-95 and MPP3 PDZ proteins on serotonin 5-hydroxytryptamine2C receptor desensitization and membrane stability. Mol Biol Cell 17:4619–4631
Giger RKA, Engel G (2006) Albert Hofmann's pioneering work on ergot alkaloids and its impact on the search of novel drugs at Sandoz, a predecessor company of novartis—dedicated to Dr. Albert Hofmann on the occasion of his 100th birthday. Chimia 60:83–87
Gobert A, Rivet JM, Lejeune F, Newman-Tancredi A, Adhumeau-Auclair A, Nicolas JP, Cistarelli L, Melon C, Millan MJ (2000) Serotonin(2C) receptors tonically suppress the activity of mesocortical dopaminergic and adrenergic, but not serotonergic, pathways: a combined dialysis and electrophysiological analysis in the rat. Synapse 36:205–221
Gozlan H, el Mestikawy S, Pichat L, Glowinski J, Hamon M (1983) Identification of presynaptic serotonin autoreceptors using a new ligand: 3H-PAT. Nature 305:140–142
Grauer SM, Graf R, Navarra R, Sung A, Logue SF, Stack G, Huselton C, Liu Z, Comery TA, Marquis KL, Rosenzweig-Lipson S (2009) WAY-163909, a 5-HT2C agonist, enhances the preclinical potency of current antipsychotics. Psychopharmacology 204:37–48
Graves SM, Napier TC (2012) SB 206553, a putative 5-HT2C inverse agonist, attenuates methamphetamine-seeking in rats. BMC Neurosci 13:65
Grottick AJ, Fletcher PJ, Higgins GA (2000) Studies to investigate the role of 5-HT(2C) receptors on cocaine- and food-maintained behavior. J Pharmacol Exp Ther 295:1183–1191
Grottick AJ, Corrigall WA, Higgins GA (2001) Activation of 5-HT2C receptors reduces the locomotor and rewarding effects of nicotine. Psychopharmacology 157:292–298
Grottick AJ, Whelan K, Sanabria EK, Behan DP, Morgan M, Sage C (2015) Investigating interactions between phentermine, dexfenfluramine, and 5-HT2C agonists, on food intake in the rat. Psychopharmacology 232:1973–1982
Gurevich I, Tamir H, Arango V, Dwork AJ, Mann JJ, Schmauss C (2002) Altered editing of serotonin 2C receptor pre-mRNA in the prefrontal cortex of depressed suicide victims. Neuron 34:349–356
Hackler EA, Airey DC, Shannon CC, Sodhi MS, Sanders-Bush E (2006) 5-HT(2C) receptor RNA editing in the amygdala of C57BL/6J, DBA/2J, and BALB/cJ mice. Neurosci Res 55:96–104
Hackler EA, Turner GH, Gresch PJ, Sengupta S, Deutch AY, Avison MJ, Gore JC, Sanders-Bush E (2007) 5-Hydroxytryptamine2C receptor contribution to m-chlorophenylpiperazine and N-methyl-beta-carboline-3-carboxamide-induced anxiety-like behavior and limbic brain activation. J Pharmacol Exp Ther 320:1023–1029
Halford JC, Blundell JE (2000) Separate systems for serotonin and leptin in appetite control. Ann Med 32:222–232
Halford JC, Lawton CL, Blundell JE (1997) The 5-HT2 receptor agonist MK-212 reduces food intake and increases resting but prevents the behavioural satiety sequence. Pharmacol Biochem Behav 56:41–46
Halford JC, Wanninayake SC, Blundell JE (1998) Behavioral satiety sequence (BSS) for the diagnosis of drug action on food intake. Pharmacol Biochem Behav 61:159–168
Harada K, Aota M, Inoue T, Matsuda R, Mihara T, Yamaji T, Ishibashi K, Matsuoka N (2006) Anxiolytic activity of a novel potent serotonin 5-HT2C receptor antagonist FR260010: a comparison with diazepam and buspirone. Eur J Pharmacol 553:171–184
Hartig PR, Hoyer D, Humphrey PP, Martin GR (1996) Alignement of receptor nomenclature with the human genome: classification of 5-HT1B and 5-HT1D receptor subtypes. Trends Pharmacol.Sci. 17:103–105
Harvey-Lewis C, Li Z, Higgins GA, Fletcher PJ (2016) The 5-HT2C receptor agonist lorcaserin reduces cocaine self-administration, reinstatement of cocaine-seeking and cocaine induced locomotor activity. Neuropharmacology 101:237–245
Hayasaka Y, Purgato M, Magni LR, Ogawa Y, Takeshima N, Cipriani A, Barbui C, Leucht S, Furukawa TA (2015) Dose equivalents of antidepressants: evidence-based recommendations from randomized controlled trials. J Affect Disord 180:179–184
Heisler LK, Tecott LH (2000) A paradoxical locomotor response in serotonin 5-HT(2C) receptor mutant mice. J Neurosci 20:RC71
Heisler LK, Chu HM, Tecott LH (1998) Epilepsy and obesity in serotonin 5-HT2C receptor mutant mice. Ann N Y Acad Sci 861:74–78
Heisler LK, Cowley MA, Tecott LH, Fan W, Low MJ, Smart JL, Rubinstein M, Tatro JB, Marcus JN, Holstege H, Lee CE, Cone RD, Elmquist JK (2002) Activation of central melanocortin pathways by fenfluramine. Science 297:609–611
Heisler LK, Pronchuk N, Nonogaki K, Zhou L, Raber J, Tung L, Yeo GS, O'Rahilly S, Colmers WF, Elmquist JK, Tecott LH (2007a) Serotonin activates the hypothalamic-pituitary-adrenal axis via serotonin 2C receptor stimulation. J Neurosci 27:6956–6964
Heisler LK, Zhou L, Bajwa P, Hsu J, Tecott LH (2007b) Serotonin 5-HT(2C) receptors regulate anxiety-like behavior. Genes Brain Behav 6:491–496
Herrick-Davis K (2013) Functional significance of serotonin receptor dimerization. Exp Brain Res 230:375–386
Herrick-Davis K, Farrington DT (2011) 5-HT2C receptor dimerization, in 5-HT2C receptors in the pathophysiology of CNS disease (Di Giovanni G, Esposito E, Di Matteo V eds) pp 129–155, Humana Press
Herrick-Davis K, Grinde E, Niswender CM (1999) Serotonin 5-HT2C receptor RNA editing alters receptor basal activity: implications for serotonergic signal transduction. J Neurochem 73:1711–1717
Herrick-Davis K, Grinde E, Teitler M (2000) Inverse agonist activity of atypical antipsychotic drugs at human 5-hydroxytryptamine2C receptors. J Pharmacol Exp Ther 295:226–232
Herrick-Davis K, Grinde E, Mazurkiewicz JE (2004) Biochemical and biophysical characterization of serotonin 5-HT2C receptor homodimers on the plasma membrane of living cells. Biochemistry 43:13963–13971
Herrick-Davis K, Grinde E, Harrigan TJ, Mazurkiewicz JE (2005) Inhibition of serotonin 5-hydroxytryptamine2c receptor function through heterodimerization: receptor dimers bind two molecules of ligand and one G-protein. J Biol Chem 280:40144–40151
Herrick-Davis K, Weaver BA, Grinde E, Mazurkiewicz JE (2006) Serotonin 5-HT2C receptor homodimer biogenesis in the endoplasmic reticulum: real-time visualization with confocal fluorescence resonance energy transfer. J Biol Chem 281:27109–27116
Herrick-Davis K, Grinde E, Weaver BA (2007) Serotonin 5-HT(2C) receptor homodimerization is not regulated by agonist or inverse agonist treatment. Eur J Pharmacol 568:45–53
Herrick-Davis K, Grinde E, Lindsley T, Cowan A, Mazurkiewicz JE (2012) Oligomer size of the serotonin 5-hydroxytryptamine 2C (5-HT2C) receptor revealed by fluorescence correlation spectroscopy with photon counting histogram analysis: evidence for homodimers without monomers or tetramers. J Biol Chem 287:23604–23614
Herrick-Davis K, Grinde E, Cowan A, Mazurkiewicz JE (2013) Fluorescence correlation spectroscopy analysis of serotonin, adrenergic, muscarinic, and dopamine receptor dimerization: the oligomer number puzzle. Mol Pharmacol 84:630–642
Herrick-Davis K, Grinde E, Lindsley T, Teitler M, Mancia F, Cowan A, Mazurkiewicz JE (2015) Native serotonin 5-HT2C receptors are expressed as homodimers on the apical surface of choroid plexus epithelial cells. Mol Pharmacol 87:660–673
Hewitt KN, Lee MD, Dourish CT, Clifton PG (2002) Serotonin 2C receptor agonists and the behavioural satiety sequence in mice. Pharmacol Biochem Behav 71:691–700
Hietala J, Kuonnamaki M, Palvimaki EP, Laakso A, Majasuo H, Syvalahti E (2001) Sertindole is a serotonin 5-HT2c inverse agonist and decreases agonist but not antagonist binding to 5-HT2c receptors after chronic treatment. Psychopharmacology 157:180–187
Higgins GA, Silenieks LB, Rossmann A, Rizos Z, Noble K, Soko AD, Fletcher PJ (2012) The 5-HT2C receptor agonist lorcaserin reduces nicotine self-administration, discrimination, and reinstatement: relationship to feeding behavior and impulse control. Neuropsychopharmacology 37:1177–1191
Higgs S, Cooper AJ, Barnes NM (2016) The 5-HT(2)C receptor agonist, lorcaserin, and the 5-HT(6) receptor antagonist, SB-742457, promote satiety; a microstructural analysis of feeding behaviour. Psychopharmacology 233:417–424
Hjorth S, Carlsson A, Lindberg P, Sanchez D, Wilkström H, Arvidsson LE, Hacksell U, Nilsson JLG (1982) 8-hydroxy-2-(di-n-propylamino)tetralin, 8-OH-DPAT, a potent and selective simplified ergot congener with central 5-HT-receptor stimulating activity. JNeural Transm 55:169–188
Hoffman BJ, Mezey E (1989) Distribution of serotonin 5-HT1C receptor mRNA in adult rat brain. FEBS Lett 247:453–462
Howell LL, Cunningham KA (2015) Serotonin 5-HT2 receptor interactions with dopamine function: implications for therapeutics in cocaine use disorder. Pharmacol Rev 67:176–197
Howes SR, Dalley JW, Morrison CH, Robbins TW, Everitt BJ (2000) Leftward shift in the acquisition of cocaine self-administration in isolation-reared rats: relationship to extracellular levels of dopamine, serotonin and glutamate in the nucleus accumbens and amygdala-striatal FOS expression. Psychopharmacology 151:55–63
Hoyer D (1988a) Molecular pharmacology and biology of 5-HT1C receptors. TIPS 9:89–94
Hoyer D (1988b) Functional correlates to serotonin 5-HT1 recognition sites. J Rec Res 8:59–81
Hoyer D, Middlemiss DN (1989) Species differences in the pharmacology of terminal 5-HT autoreceptors in mammalian brain. Trends PharmacolSci 10:130–132
Hoyer D, Clarke DE, Fozard JR, Hartig PR, Martin GR, Mylecharane EJ, Saxena PR, Humphrey PPA (1994) VII. International Union of Pharmacology classification of receptors for 5-hydroxytryptamine (serotonin). Pharmacol Rev 46:157–204
Hoyer D, Engel G, Berthold R (1982) Binding characteristics of (+)-, (+/− )- and (−)-[125iodo] cyanopindolol to guinea-pig left ventricle membranes. Naunyn Schmiedeberg's Arch Pharmacol 318:319–329
Hoyer D, Engel G, Kalkman HO (1985b) Characterization ot the 5-HT1B recognition site in rat brain: binding studies with 125I-iodocyanopindolol. EurJPharmacol 118:1–12
Hoyer D, Engel G, Kalkman HO (1985a) Molecular pharmacology of 5-HT1 and 5-HT2 recognition sites in rat and pig brain membranes: radioligand binding studies with [3H]5-HT, [3H]8-OH-DPAT, (−)[125I]iodocyanopindolol, [3H]mesulergine and [3H]ketanserin. Eur J Pharmacol 118:13–23
Hoyer D, Hannon JP, Martin GR (2002) Molecular, pharmacological and functional diversity of 5-HT receptors. Pharmacol Biochem Behav 71:533–554
Hoyer D, Pazos A, Probst A, Palacios JM (1986a) Serotonin receptors in the human brain. II. Characterization and autoradiographic localization of 5-HT1C and 5-HT2 recognition sites. Brain Res 376:97–107
Hoyer D, Pazos A, Probst A, Palacios JM (1986b) Serotonin receptors in the human brain. I. Characterization and autoradiographic localization of 5-HT1A recognition sites. Apparent absence of 5-HT1B recognition sites. Brain Res 376:85–96
Hoyer D, Srivatsa S, Pazos A, Engel G, Palacios JM (1986c) [125I]LSD labels 5-HT1C recognition sites in pig choroid plexus membranes. Comparison with [3H]mesulergine and [3H]5-HT binding. NeurosciLett 69:269–274
Hoyer D, Karpf A (1988) [125I]SCH 23982, a “selective” D1 receptor antagonist, labels with high affinity 5-HT1C sites in pig choroid plexus. Eur J Pharmacol 150:181–184
Hoyer D, Schoeffter P (1988) 5-HT1D receptors inhibit forskolin-stimulated adenylate cyclase activity in calf substantia nigra. Eur J Pharmacol 147:145–147
Hoyer D, Waeber C, Pazos A, Probst A, Palacios JM (1988) Identification of a 5‑HT1 recognition site in human brain membranes different from 5‑HT1A, 5‑HT1B and 5‑HT1C sites. Neurosci Lett 85:357‑362
Hoyer D, Waeber C, Schoeffter P, Palacios JM, Dravid A (1989) 5-HT1C receptor-mediated stimulation of inositol phosphate production in pig choroid plexus. A pharmacological characterization. Naunyn Schmiedeberg's Arch Pharmacol 339:252–258
Hoyer D (1990) 5-HT3, 5-HT4 and 5-HT-M receptors. Neuropsychopharmacology 3:371–383
Humphrey PPA, Hartig PR, Hoyer D (1993) A new nomenclature for 5-HT receptors. Trends Pharmacol Sci 14:233–236
Husch A, Van Patten GN, Hong DN, Scaperotti MM, Cramer N, Harris-Warrick RM (2012) Spinal cord injury induces serotonin SUpersensitivity without increasing intrinsic excitability of mouse V2a interneurons. J Neurosci 32:13145–13154
Isaac M (2005) Serotonergic 5-HT2C receptors as a potential therapeutic target for the design antieptileptic drugs. Curr Top Med Chem 5:59–67
Ishii Y, Blundell JE, Halford JC, Rodgers RJ (2003) Palatability, food intake and the behavioural satiety sequence in male rats. Physiol Behav 80:37–47
Iwamoto K, Kato T (2003) RNA editing of serotonin 2C receptor in human postmortem brains of major mental disorders. Neurosci Lett 346:169–172
Iwamoto K, Bundo M, Kato T (2011) RNA editing of 5-HT2C receptor and neuropsychiatric diseases, in 5-HT2C receptors in the pathophysiology of CNS disease (Di Giovanni G, Esposito E, Di Matteo V eds) pp 157–167, Humana Press.
Iwamoto K, Nakatani N, Bundo M, Yoshikawa T, Kato T (2005) Altered RNA editing of serotonin 2C receptor in a rat model of depression. NeurosciRes 53:69–76
Jakus R, Graf M, Juhasz G, Gerber K, Levay G, Halasz P, Bagdy G (2003) 5-HT2C receptors inhibit and 5-HT1A receptors activate the generation of spike-wave discharges in a genetic rat model of absence epilepsy. Exp Neurol 184:964–972
Jenck F, Bos M, Wichmann J, Stadler H, Martin JR, Moreau JL (1998) The role of 5-HT2C receptors in affective disorders. Expert Opin Investig Drugs 7:1587–1599
Ji SP, Zhang Y, Van CJ, Jiang W, Liao M, Li L, Wan Q, Backstrom JR, Zhang X (2006) Disruption of PTEN coupling with 5-HT2C receptors suppresses behavioral responses induced by drugs of abuse. NatMed 12:324–329
Julius D, MacDermott AB, Axel R, Jessell JM (1988) Molecular characterization of a functional cDNA encoding the serotonin 1C receptor. Science 241:558–564
Julius D, Huang KN, Livelli TJ, Axel R, Jessell TM (1989) The 5HT2 receptor defines a family of structurally distinct but functionally conserved serotonin receptors. Proc Natl Acad Sci U S A 87:928–932
Juruena MF, de Sena EP, de Oliveira IR (2011) Sertindole in the management of schizophrenia. Journal of central nervous system disease 3:75–85
Kahn RS, Wetzler S (1991) M-chlorophenylpiperazine as a probe of serotonin function. BiolPsychiat 30:1139–1166
Kalkman HO, Engel G, Hoyer D (1984) Three distinct subtypes of serotonergic receptors mediate the triphasic blood pressure response to 5‑HT in rats. J Hypertension 2:143–145
Kalkman HO, Engel G, Hoyer D (1986) Inhibition of 5-carboxamidotryptamine-induced relaxation of guinea-pig ileum correlates with [125I]LSD binding. Eur.J.Pharmacol. 129:139–145
Kamal M, Gbahou F, Guillaume JL, Daulat AM, Benleulmi-Chaachoua A, Luka M, Chen P, Kalbasi Anaraki D, Baroncini M, Mannoury la Cour C, Millan MJ, Prevot V, Delagrange P, Jockers R (2015) Convergence of melatonin and serotonin (5-HT) signaling at MT2/5-HT2C receptor heteromers. J Biol Chem 290:11537–11546
Kasper JM, Tikamdas R, Kim MS, Macfadyen K, Aramini R, Ladd J, Bisceglia S, Booth R, Peris J (2013) The serotonin-2 receptor modulator, (−)-trans-PAT, decreases voluntary ethanol consumption in rats. Eur J Pharmacol 718:98–104
Kennett G, Lightowler S, Trail B, Bright F, Bromidge S (2000) Effects of RO 60 0175, a 5-HT(2C) receptor agonist, in three animal models of anxiety. Eur J Pharmacol 387:197–204
Kennett GA, Curzon G (1988) Evidence that hypophagia induced by mCPP and TFMPP requires 5-HT1C and 5-HT1B receptors; hypophagia induced by RU 24969 only requires 5-HT1B receptors. Psychopharmacology 96:93–100
Kennett GA, Pittaway K, Blackburn TP (1994) Evidence that 5-HT2C receptor antagonists are anxiolytic in the rat Geller-Seifter model of anxiety. Psychopharmacology 114:90–96
Kennett GA, Whitton P, Shah K, Curzon G (1989) Anxiogenic-like effects of mCPP and TFMPP in animal models are opposed by 5-HT1C receptor antagonists. Eur J Pharmacol 164:445–454
Kennett GA, Wood MD, Bright F, Cilia J, Piper DC, Gager T, Thomas D, Baxter GS, Forbes IT, Ham P, Blackburn TP (1996) In vitro and in vivo profile of SB 206553, a potent 5-HT2C/5-HT2B receptor antagonist with anxiolytic-like properties. Br J Pharmacol 117:427–434
Kennett GA, Wood MD, Bright F, Trail B, Riley G, Holland V, Avenell KY, Stean T, Upton N, Bromidge S, Forbes IT, Brown AM, Middlemiss DN, Blackburn TP (1997) SB 242084, a selective and brain penetrant 5-HT2C receptor antagonist. Neuropharmacology 36:609–620
Kirk SL, Glazebrook J, Grayson B, Neill JC, Reynolds GP (2009) Olanzapine-induced weight gain in the rat: role of 5-HT2C and histamine H1 receptors. Psychopharmacology 207:119–125
Kishore S, Stamm S (2006) The snoRNA HBII-52 regulates alternative splicing of the serotonin receptor 2C. Science 311:230–232
Kishore S, Khanna A, Zhang Z, Hui J, Balwierz PJ, Stefan M, Beach C, Nicholls RD, Zavolan M, Stamm S (2010) The snoRNA MBII-52 (SNORD 115) is processed into smaller RNAs and regulates alternative splicing. Hum Mol Genet 19:1153–1164
Kleene R, Chaudhary H, Karl N, Katic J, Kotarska A, Guitart K, Loers G, Schachner M (2015) Interaction between CHL1 and serotonin receptor 2c regulates signal transduction and behavior in mice. J Cell Sci 128:4642–4652
Labasque M, Reiter E, Becamel C, Bockaert J, Marin P (2008) Physical interaction of calmodulin with the 5-hydroxytryptamine2C receptor C-terminus is essential for G protein-independent, arrestin-dependent receptor signaling. Mol Biol Cell 19:4640–4650
Laduron PM (1984) Criteria for receptor sites in binding studies. Biochem Pharmacol 33:833–839
Lam DD, Przydzial MJ, Ridley SH, Yeo GSH, Rochford JJ, O'Rahilly S, Heisler LK (2008) Serotonin 5-HT2C receptor agonist promotes hypophagia via downstream activation of melanocortin 4 receptors. Endocrinology 149:1323–1328
Lee MA, Meltzer HY (1994) Blunted oral body temperature response to MK-212 in cocaine addicts. Drug Alcohol Depend 35:217–222
Lefkowitz RJ (2004) Historical review: a brief history, personal retrospective of seven-transmembrane receptors. Trends Pharmacol Sci 25:413–422
Leggio GM, Cathala A, Neny M, Rouge-Pont F, Drago F, Piazza PV, Spampinato U (2009) In vivo evidence that constitutive activity of serotonin2C receptors in the medial prefrontal cortex participates in the control of dopamine release in the rat nucleus accumbens: differential effects of inverse agonist versus antagonist. J Neurochem 111:614–623
Levin ED, Johnson JE, Slade S, Wells C, Cauley M, Petro A, Rose JE (2011) Lorcaserin, a 5-HT2C agonist, decreases nicotine self-administration in female rats. J Pharmacol Exp Ther 338:890–896
Leysen JE, Niemegeers CJE, Tollenaere JP, Laduron PM (1978) Serotonergic component of neuroleptic receptors. Nature 272: 168-171
Lindvall-Axelsson M, Mathew C, Nilsson C, Owman C (1988) Effect of 5-hydroxytryptamine on the rate of cerebrospinal fluid production in rabbit. ExpNeurol 99:362–368
Liu S, Lane SD, Schmitz JM, Waters AJ, Cunningham KA, Moeller FG (2011) Relationship between attentional bias to cocaine-related stimuli and impulsivity in cocaine-dependent subjects. Am J Drug Alcohol Abuse 37:117–122
Liu S, Lane SD, Schmitz JM, Green CE, Cunningham KA, Moeller FG (2012) Increased intra-individual reaction time variability in cocaine-dependent subjects: role of cocaine-related cues. Addict Behav 37:193–197
Liu Y, Emeson RB, Samuel CE (1999) 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
Lopez-Gimenez JF, Mengod G, Palacios JM, Vilaro MT (2001) Regional distribution and cellular localization of 5-HT2C receptor mRNA in monkey brain: comparison with [3H]mesulergine binding sites and choline acetyltransferase mRNA. Synapse 42:12–26
Lowy MT, Meltzer HY (1988) Stimulation of serum cortisol and prolactin secretion in humans by MK-212, a centrally active serotonin agonist. Biol Psychiatry 23:818–828
Lubbert H, Hoffman BJ, Snutch TP, van Dyke T, Levine AJ, Hartig PR, Lester HA, Davidson N (1987) cDNA cloning of a serotonin 5-HT1C receptor by electrophysiological assays of mRNA-injected Xenopus oocytes. Proc Natl Acad Sci U S A 84:4332–4336
Lucki I (1998) The spectrum of behaviors influenced by serotonin. Biol Psychiatry 44:151–162
Lyddon R, Dwork AJ, Keddache M, Siever LJ, Dracheva S (2013) Serotonin 2c receptor RNA editing in major depression and suicide. The world journal of biological psychiatry 14:590–601
Maillet JC, Zhang Y, Li X, Zhang X (2008) PTEN-5-HT2C coupling: a new target for treating drug addiction. Prog Brain Res 172:407–420
Manvich DF, Kimmel HL, Cooper DA, Howell LL (2012a) The serotonin 2C receptor antagonist SB 242084 exhibits abuse-related effects typical of stimulants in squirrel monkeys. J Pharmacol Exp Ther 342:761–769
Manvich DF, Kimmel HL, Howell LL (2012b) Effects of serotonin 2C receptor agonists on the behavioral and neurochemical effects of cocaine in squirrel monkeys. J Pharmacol Exp Ther 341:424–434
Marion S, Weiner DM, Caron MG (2004) RNA editing induces variation in desensitization and trafficking of 5-hydroxytryptamine 2c receptor isoforms. J Biol Chem 279:2945–2954
Markstein R (1983) Mesulergine and its 1,20-N,N-bidemethylated metabolite interact directly with D1- and D2-receptors. Eur JPharmacol 95:101–107
Markstein R, Hoyer D, Engel G (1986) 5-HT1A-receptors mediate stimulation of adenylate cyclase in rat hippocampus. Naunyn Schmiedeberg's Arch Pharmacol 333:335–341
Marquis KL, Sabb AL, Logue SF, Brennan JA, Piesla MJ, Comery TA, Grauer SM, Ashby CR Jr, Nguyen HQ, Dawson LA, Barrett JE, Stack G, Meltzer HY, Harrison BL, Rosenzweig-Lipson S (2007) WAY-163909 [(7bR,10aR)-1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta-[b][1,4]diazepino[ 6,7,1hi]indole]: a novel 5-hydroxytryptamine 2C receptor-selective agonist with preclinical antipsychotic-like activity. J Pharmacol Exp Ther 320:486–496
Martin CB, Hamon M, Lanfumey L, Mongeau R (2014) Controversies on the role of 5-HT(2C) receptors in the mechanisms of action of antidepressant drugs. Neurosci Biobehav Rev 42:208–223
Martin CB, Martin VS, Trigo JM, Chevarin C, Maldonado R, Fink LH, Cunningham KA, Hamon M, Lanfumey L, Mongeau R (2015) 5-HT2C receptor desensitization moderates anxiety in 5-HTT deficient mice: from behavioral to cellular evidence. Int J Neuropsychopharmacol 18:1–12
Martin CB, Ramond F, Farrington DT, Aguiar AS Jr, Chevarin C, Berthiau AS, Caussanel S, Lanfumey L, Herrick-Davis K, Hamon M, Madjar JJ, Mongeau R (2013) RNA splicing and editing modulation of 5-HT(2C) receptor function: relevance to anxiety and aggression in VGV mice. Mol Psychiatry 18:656–665
Martin JR, Bos M, Jenck F, Moreau JL, Mutel V, Sleight AJ, Wichmann J, Andrews JS, Berendsen HHG, Broekkamp CLE, Ruigt GSF, Kohler C, Van Delft AML (1998) 5-HT2C receptor agonists: pharmacological characteristics and therapeutic potential. Journal of Pharmacology & Experimental Therapeutics 286:913–924
Maurel S, De Vry J, Schreiber R (1999) 5-HT receptor ligands differentially affect operant oral self-administration of ethanol in the rat. Eur J Pharmacol 370:217–223
McCorvy JD, Roth BL (2015) Structure and function of serotonin G protein-coupled receptors. Pharmacol Ther 150: 129–142
Meltzer HY (1999) The role of serotonin in antipsychotic drug action. Neuropsychopharmacology 21:106S–115S
Mengod G, Nguyen H, Le H, Waeber C, Lübbert H, Palacios JM (1990) The distribution and cellular localization of the serotonin 1C receptor mRNA in the rodent brain examined by in situ hybridization histochemistry. Comparison with receptor binding distribution. Neuroscience 35:577–591
Mengod G, Cortés R, Vilaró MT, Hoyer D (2010) Distribution of 5-HT receptors in the central nervous system. In: Mueller C, Jacobs B (eds). Handbook of the Behavioral Neurobiology of Serotonin. Academic Press / Elsevier, pp 123-138
Middlemiss DN, Fozard JR (1983) 8-hydroxy-2-(di-n-propylamino)- tetralin discriminates between subtypes of the 5-HT1 recognition site. Eur J Pharmacol 90:151–153
Milatovich A, Hsieh CL, Bonaminio G, Tecott L, Julius D, Francke U (1992) Serotonin receptor 1c gene assigned to X chromosome in human (band q24) and mouse (bands D-F4). Hum Mol Genet 1:681–684
Millan MJ (2003) The neurobiology and control of anxious states. Prog Neurobiol 70:83–244
Millan MJ (2005) Serotonin 5-HT2C receptors as a target for the treatment of depressive, anxious states: focus on novel therapeutic strategies. Therapie 60:441–460
Millan MJ, Brocco M, Gobert A, Dekeyne A (2005) Anxiolytic properties of agomelatine, an antidepressant with melatoninergic and serotonergic properties: role of 5-HT2C receptor blockade. Psychopharmacology 177:448–458
Millan MJ, Gobert A, Lejeune F, Dekeyne A, Newman-Tancredi A, Pasteau V, Rivet JM, Cussac D (2003) The novel melatonin agonist agomelatine (S20098) is an antagonist at 5-hydroxytryptamine2C receptors, blockade of which enhances the activity of frontocortical dopaminergic and adrenergic pathways. J Pharmacol Exp Ther 306:954–964
Millan MJ, Marin P, Bockaert J, Mannoury la Cour C (2008) Signaling at G-protein-coupled serotonin receptors: recent advances and future research directions. Trends Pharmacol Sci 29:454–464
Millan MJ, Marin P, Kamal M, Jockers R, Chanrion B, Labasque M, Bockaert J, Mannoury la Cour C (2011) The melatonergic agonist and clinically active antidepressant, agomelatine, is a neutral antagonist at 5-HT2C receptors. IntJNeuropsychopharmacol 14:768–783
Miller KJ (2005) Serotonin 5-ht2c receptor agonists: potential for the treatment of obesity. Mol Interv 5:282–291
Molineaux SM, Jessell TM, Axel R, Julius D (1989) 5-HT1c receptor is a prominent serotonin receptor subtype in the central nervous system. Proc Natl Acad Sci U S A 86:6793–6797
Moreau JL, Bos M, Jenck F, Martin JR, Mortas P, Wichmann J (1996) 5HT2C receptor agonists exhibit antidepressant-like properties in the anhedonia model of depression in rats. Eur Neuropsychopharmacol 6:169–175
Moya PR, Berg KA, Gutierrez-Hernandez MA, Saez-Briones P, Reyes-Parada M, Cassels BK, Clarke WP (2007) Functional selectivity of hallucinogenic phenethylamine and phenylisopropylamine derivatives at human 5-hydroxytryptamine (5-HT)2A and 5-HT2C receptors. J Pharmacol Exp Ther 321:1054–1061
Murotani T, Ishizuka T, Isogawa Y, Karashima M, Yamatodani A (2011) Possible involvement of serotonin 5-HT2 receptor in the regulation of feeding behavior through the histaminergic system. Neuropharmacology 61:228–233
Murray KC, Nakae A, Stephens MJ, Rank M, D’Amico J, Harvey PJ, Li X, Harris RLW, Ballou EW, Anell R, Heckman CJ, Mashimo T, Vavre R, Sanelli L, Gorassini MA, Bennett DJ, Fouad K (2010) Recovery of motoneuron and locomotor function after spinal cord injury depends on constitutive activity in 5-HT2C receptors. Nature Med 16:694–700
Murray KC, Stephens MJ, Ballou EW, Heckman CJ, Bennett DJ (2011) Motoneuron excitability and muscle spasms are regulated by 5-HT2C and 5-HT2B receptor activity. Neurophysiol 105:731–748
Navailles S, De Deurwaerdere P, Porras G, Spampinato U (2004) In vivo evidence that 5-HT2C receptor antagonist but not agonist modulates cocaine-induced dopamine outflow in the rat nucleus accumbens and striatum. Neuropsychopharmacology 29:319–326
Navailles S, Moison D, Cunningham KA, Spampinato U (2008) Differential regulation of the mesoaccumbens dopamine circuit by serotonin2C receptors in the ventral tegmental area and the nucleus accumbens: an in vivo microdialysis study with cocaine. Neuropsychopharmacology 33:237–246
Navailles S, Lagiere M, Le Moine C, De Deurwaerdere P (2013a) Role of 5-HT2C receptors in the enhancement of c-fos expression induced by a 5-HT2B/2C inverse agonist and 5-HT 2 agonists in the rat basal ganglia. Exp Brain Res 230:525–535
Navailles S, Lagiere M, Roumegous A, Polito M, Boujema MB, Cador M, Dunlop J, Chesselet MF, Millan MJ, De Deurwaerdere P (2013b) 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 16:593–606
Neisewander JL, Acosta JI (2007) Stimulation of 5-HT2C receptors attenuates cue and cocaine-primed reinstatement of cocaine-seeking behavior in rats. Behav Pharmacol 18:791–800
Nic Dhonnchadha BA, Bourin M, Hascoet M (2003) Anxiolytic-like effects of 5-HT2 ligands on three mouse models of anxiety. Behav Brain Res 140:203–214
Nichols DE (2004) Hallucinogens. Pharmacol Ther 101:131–181
Niswender CM, Copeland SC, Herrick-Davis K, Emeson RB, Sanders-Bush E (1999) RNA editing of the human serotonin 5-hydroxytryptamine 2C receptor silences constitutive activity. J Biol Chem 274:9472–9478
Niswender CM, Herrick-Davis K, Dilley GE, Meltzer HY, Overholser JC, Stockmeier CA, Emeson RB, Sanders-Bush E (2001) RNA editing of the human serotonin 5-HT2C receptor: alterations in suicide and implications for serotonergic pharmacotherapy. Neuropsychopharmacology 24:478–491
Nonogaki K, Ohba Y, Sumii M, Oka Y (2008) Serotonin systems upregulate the expression of hypothalamic NUCB2 via 5-HT2C receptors and induce anorexia via a leptin-independent pathway in mice. Biochem Biophys Res Commun 372:186–190
Nonogaki K, Strack AM, Dallman MF, Tecott LH (1998) Leptin-independent hyperphagia and type 2 diabetes in mice with a mutated serotonin 5-HT2C receptor gene. Nat Med 4:1152–1156
Nozulak J, Kalkman HO, Floersheim P, Hoyer D, Buerki HR (1995) (+)-cis-4,5,7a,8,9,10,11a-octahydro-7H-10-methyl-iondolo[1,7-bc][2,6]naphtyridine (SDZ SER 082), a centrally acting 5-HT2C receptor antagonist with low 5-HT2A receptor affinity. J Med Chem 38:28–33
O'Neill MF, Heron-Maxwell CL, Shaw G (1999) 5-HT2 receptor antagonism reduces hyperactivity induced by amphetamine, cocaine, and MK-801 but not D1 agonist C-APB. Pharmacol Biochem Behav 63:237–243
Palacios JM, Markstein R, Pazos A (1986) Serotonin-1C sites in the choroid plexus are not linked in a stimulatory or inhibitory way to adenylate cyclase. Brain Res 380:151–154
Palacios JM, Waeber C, Mengod G, Hoyer D (1990) Visualization of serotonin receptor binding and their messenger RNAs in the mammalian brain: an update. Serotonin: from cell biology to pharmacology and therapeutics. R Paoletti et al. Eds. Kluwer Academic Publishers. pp 383‑387
Palacios JM, Pazos A, Hoyer D (2010). The making of the 5-HT2C receptor. In: Di Matteo V., Esposito E., Di Giovanni G (eds). The pathophysiology of central 5-HT 2C receptors, Springer Humana Press. DOI 10.1007/978-1-60761-941-3_1
Parker LL, Backstrom JR, Sanders-Bush E, Shieh BH (2003) Agonist-induced phosphorylation of the serotonin 5-HT2C receptor regulates its interaction with multiple PDZ protein 1. J Biol Chem 278:21576–21583
Parsons LH, Justice JB Jr (1993) Perfusate serotonin increases extracellular dopamine in the nucleus accumbens as measured by in vivo microdialysis. Brain Res 606:195–199
Parsons LH, Koob GF, Weiss F (1995) Extracellular serotonin is decreased in the nucleus accumbens during withdrawal from cocaine self-administration. Behav Brain Res 73:225–228
Patkar AA, Mannelli P, Peindl K, Hill KP, Gopalakrishnan R, Berrettini WH (2006) Relationship of disinhibition and aggression to blunted prolactin response to meta-chlorophenylpiperazine in cocaine-dependent patients. Psychopharmacology 185:123–132
Pazos A, Palacios JM (1985) Quantitative autoradiographic map** of serotonin receptors in the rat brain. I. Serotonin-1 receptors. Brain Res 346:205–230
Pazos A, Cortes R, Palacios JM (1985) Quantitative autoradiographic map** of serotonin receptors in rat brain. II. Serotonin-2 receptors. Brain Res 346:231–249
Pazos A, Hoyer D, Palacios JM (1984a) The binding of serotonergic ligands to the porcine choroid plexus: characterization of a new type of serotonin recognition site. Eur J Pharmacol 106:539–546
Pazos A, Hoyer D, Palacios JM (1984b) Mesulergine, a selective serotonin-2 ligand in the rat cortex, does not label these receptors in porcine and human cortex: evidence for species differences in brain serotonin-2 receptors. Eur J Pharmacol 106:531–538
Pazos A, Probst A, Palacios JM (1987a) Serotonin receptors in the human brain—III. Autoradiographic map** of serotonin-1 receptors. Neuroscience 21:97–122
Pazos A, Probst A, Palacios JM (1987b) Serotonin receptors in the human brain. IV. Autoradiographic map** of serotonin-2 receptors. Neurosci 21:123–139
Pedigo NW, Yamamura HI, Nelson DL (1981) Discrimination of multiple [3H]5-hydroxytriptamine-binding sites by the neuroleptic spiperone in rat brain. JNeurochem 36:220–226
Pelloux Y, Dilleen R, Economidou D, Theobald D, Everitt BJ (2012) Reduced forebrain serotonin transmission is causally involved in the development of compulsive cocaine seeking in rats. Neuropsychopharmacology 37:2505–2514
Peroutka SJ, Snyder SH (1979) Multiple serotonin receptors: differential binding of [3H]5-hydroxytryptamine, [3H]lysergic acid diethylamide and [3H]spiroperidol. Mol Pharmacol 16:687–699
Peyron C, Petit JM, Rampon C, Jouvet M, Luppi PH (1998) Forebrain afferents to the rat dorsal raphe nucleus demonstrated by retrograde and anterograde tracing methods. Neuroscience 82:443–468
Pompeiano M, Palacios JM, Mengod G (1994) Distribution of the serotonin 5-HT2 receptor family mRNAs: comparison between 5-HT2A and 5-HT2C receptors. Mol Brain Res 23:163–178
Pooley EC, Fairburn CG, Cooper Z, Sodhi MS, Cowen PJ, Harrison PJ (2004) A 5-HT2C receptor promoter polymorphism (HTR2C - 759C/T) is associated with obesity in women, and with resistance to weight loss in heterozygotes. Am J Med Genet B Neuropsychiatr Genet 126B:124–127
Price RD, Sanders-Bush E (2000) RNA editing of the human serotonin 5-HT(2C) receptor delays agonist-stimulated calcium release. Mol Pharmacol 58:859–862
Price RD, Weiner DM, Chang MS, Sanders-Bush E (2001) RNA editing of the human serotonin 5-HT2C receptor alters receptor-mediated activation of G13 protein. J Biol Chem 276:44663–44668
Prisco S, Esposito E (1995) Differential effects of acute and chronic fluoxetine administration on the spontaneous activity of dopaminergic neurones in the ventral temental area. Br J Pharmacol 116:1923–1931
Pritchett DB, Bach AW, Wozny M, Taleb O, Dal Toso R, Shih JC, Seeburg PH (1988) Structure and functional expression of cloned rat serotonin 5HT-2 receptor. EMBO J 7:4135–4140
Qiu J, Fang Y, Ronnekleiv OK, Kelly MJ (2010) Leptin excites proopiomelanocortin neurons via activation of TRPC channels. J Neurosci 30:1560–1565
Qiu J, Xue C, Bosch MA, Murphy JG, Fan W, Ronnekleiv OK, Kelly MJ (2007) Serotonin 5-hydroxytryptamine2C receptor signaling in hypothalamic proopiomelanocortin neurons: role in energy homeostasis in females. Mol Pharmacol 72:885–896
Rauser L, Savage JE, Meltzer HY, Roth BL (2001) Inverse agonist actions of typical and atypical antipsychotic drugs at the human 5-hydroxytryptamine(2C) receptor. J Pharmacol Exp Ther 299:83–89
Reynolds GP, Templeman LA, Zhang ZJ (2005) The role of 5-HT2C receptor polymorphisms in the pharmacogenetics of antipsychotic drug treatment. Prog Neuro-Psychopharmacol Biol Psychiatry 29:1021–1028
Reynolds GP, Zhang Z, Zhang X (2003) Polymorphism of the promoter region of the serotonin 5-HT(2C) receptor gene and clozapine-induced weight gain. Am J Psychiatry 160:677–679
Rezvani AH, Cauley MC, Levin ED (2014) Lorcaserin, a selective 5-HT(2C) receptor agonist, decreases alcohol intake in female alcohol preferring rats. Pharmacol Biochem Behav 125:8–14
Rippberger H, van Gaalen MM, Schwarting RK, Wohr M (2015) Environmental and pharmacological modulation of amphetamine-induced 50-kHz ultrasonic vocalizations in rats. Curr Neuropharmacol 13:220–232
Rocha B, DiScala G, Rigo M, Hoyer D, Sandner G (1993) Effects of 5,7-dihydroxytryptamine (5,7-DHT) lesion on mianserin-induced conditioned place aversion and 5-HT1C receptors in the rat brain. Neuroscience 56:687–693
Rocha B, Rigo M, DiScala G, Sandner G, Hoyer D (1994) Acute and chronic treatments by mianserin and eltoprazine in rats: effects on the elevated-plus maze and on 5-HT1C receptors in the amygdala. Eur J Pharmacol 262:125–131
Rocha BA, Goulding EH, O'Dell LE, Mead AN, Coufal NG, Parsons LH, Tecott LH (2002) Enhanced locomotor, reinforcing, and neurochemical effects of cocaine in serotonin 5-hydroxytryptamine 2C receptor mutant mice. J Neurosci 22:10039–10045
Rosenzweig-Lipson S, Comery TA, Marquis KL, Gross J, Dunlop J (2012) 5-HT(2C) agonists as therapeutics for the treatment of schizophrenia. Handb Exp Pharmacol:147–165
Rosenzweig-Lipson S, Dunlop J, Marquis KL (2007a) 5-HT2C receptor agonists as an innovative approach for psychiatric disorders. Drug News Perspect 20:565–571
Rosenzweig-Lipson S, Sabb A, Stack G, Mitchell P, Lucki I, Malberg JE, Grauer S, Brennan J, Cryan JF, Sukoff Rizzo SJ, Dunlop J, Barrett JE, Marquis KL (2007b) Antidepressant-like effects of the novel, selective, 5-HT2C receptor agonist WAY-163909 in rodents. Psychopharmacology 192:159–170
Roth BL (2007) Drugs and valvular heart disease. N Engl J Med 356:6–9
Ruedi-Bettschen D, Spealman RD, Platt DM (2015) Attenuation of cocaine-induced reinstatement of drug seeking in squirrel monkeys by direct and indirect activation of 5-HT2C receptors. Psychopharmacology 232:2959–2968
Rueter SM, Dawson TR, Emeson RB (1999) Regulation of alternative splicing by RNA editing. Nature 399:75–80
Saltzman AG, Morse B, Whitman MM, Ivanshchenko Y, Jaye M, Felder S (1991) Cloning of the human serotonin 5-HT2 and 5-HT1C receptor subtypes. Biochem Biophys Res Commun 181:1469–1478
Schellekens H, De Francesco PN, Kandil D, Theeuwes WF, McCarthy T, van Oeffelen WE, Perello M, Giblin L, Dinan TG, Cryan JF (2015) Ghrelin’s orexigenic effect is modulated via a serotonin 2C receptor interaction. ACS Chem Neurosci 6:1186–1197
Schoeffter P, Waeber C, Palacios JM, Hoyer D (1988) The serotonin 5-HT1D receptor subtype is negatively coupled to adenylate cyclase in calf substantia nigra. Naunyn Schmiedeberg's Arch Pharmacol 337:602–608
Schoeffter P, Hoyer D (1989) 5-hydroxytryptamine 5-HT1B and 5-HT1D receptors mediating inhibition of adenylate cyclase activity. Pharmacological comparison with special reference to the effects of yohimbine, rauwolscine and some beta-adrenoceptor antagonists. Naunyn Schmiedeberg’s Arch Pharmacol 340:285–292
Schoeffter P, Hoyer D (1990) 5-hydroxytryptamine (5-HT) induced endothelium-dependent relaxation of pig coronary arteries is mediated by 5-HT receptors similar to the 5-HT1D receptor subtype. J Pharmacol Exp Therap 252:387–395
Serrats J, Mengod G, Cortes R (2005) Expression of serotonin 5-HT2C receptors in GABAergic cells of the anterior raphe nuclei. J Chem Neuroanat 29:83–91
Sevy S, Brown S-L, Wetzler S, Kotler M, Molcho A, Plutchik R, Van Praag HM (1994) Effects of alprazolam on increases in hormonal and anxiety levels induced by meta-chlorophenylpiperazine. Psychiatry Res 53:219–229
Shen JH, Zhao Y, Rosenzweig-Lipson S, Popp D, Williams JB, Giller E, Detke MJ, Kane JM (2014) A 6-week randomized, double-blind, placebo-controlled, comparator referenced trial of vabicaserin in acute schizophrenia. J Psychiatr Res 53:14–22
Shen M, Bellaousov S, Hiller M, de La Grange P, Creamer TP, Malina O, Sperling R, Mathews DH, Stoilov P, Stamm S (2013) Pyrvinium pamoate changes alternative splicing of the serotonin receptor 2C by influencing its RNA structure. Nucleic Acids Res 41:3819–3832
Shepherd JK, Grewal SS, Fletcher A, Bill DJ, Dourish CT (1994) Behavioural and pharmacological characterisation of the elevated "zero-maze" as an animal model of anxiety. Psychopharmacology 116:56–64
Siuciak JA, Chapin DS, McCarthy SA, Guanowsky V, Brown J, Chiang P, Marala R, Patterson T, Seymour PA, Swick A, Iredale PA (2007) CP-809,101, a selective 5-HT2C agonist, shows activity in animal models of antipsychotic activity. Neuropharmacology 52:279–290
Smith SR, Prosser WA, Donahue DJ, Morgan M, Anderson CM, Shanahan WR, Group S (2009) Lorcaserin (APD356), a selective 5-HT(2C) agonist, reduces body weight in obese men and women. Obesity(SilverSpring) 17:494–503
Smith SR, Weissman NJ, Anderson CM, Sanchez M, Chuang E, Stubbe S, Bays H, Shanahan WR (2010) Multicenter, placebo-controlled trial of lorcaserin for weight management. N Engl J Med 363:245–256
Sodhi MS, Burnet PW, Makoff AJ, Kerwin RW, Harrison PJ (2001) RNA editing of the 5-HT(2C) receptor is reduced in schizophrenia. MolPsychiatry 6:373–379
Sodhi MSK, Airey DC, Lambert W, Burnet PWJ, Harrison PJ, Sanders-Bush E (2005) A rapid new assay to detect RNA editing reveals antipsychotic-induced changes in serotonin-2C transcripts. Mol Pharmacol 68:711–719
Somerville EM, Horwood JM, Lee MD, Kennett GA, Clifton PG (2007) 5-HT(2C) receptor activation inhibits appetitive and consummatory components of feeding and increases brain c-fos immunoreactivity in mice. Eur J Neurosci 25:3115–3124
Southwick SM, Krystal JH, Bremner JD, Morgan CA 3rd, Nicolaou AL, Nagy LM, Johnson DR, Heninger GR, Charney DS (1997) Noradrenergic and serotonergic function in posttraumatic stress disorder. Arch Gen Psychiatry 54:749–758
Stam NJ, Vanderheyden P, Van Alebeek C, Klomp J, De Boer T, Van Delft AML, Olijve W (1994) Genomic organisation and functional expression of the gene encoding the human serotonin 5-HT2C receptor. Eur J Pharmacol Mol Pharmacol 269:339–348
Steed E, Jones CA, McCreary AC (2011) Serotonergic involvement in methamphetamine-induced locomotor activity: a detailed pharmacological study. Behav Brain Res 220:9–19
Strong PV, Christianson JP, Loughridge AB, Amat J, Maier SF, Fleshner M, Greenwood BN (2011) 5-hydroxytryptamine 2C receptors in the dorsal striatum mediate stress-induced interference with negatively reinforced instrumental escape behavior. Neuroscience 197:132–144
Strong PV, Greenwood BN, Fleshner M (2009) The effects of the selective 5-HT(2C) receptor antagonist SB 242084 on learned helplessness in male Fischer 344 rats. Psychopharmacology 203:665–675
Sullivan LC, Clarke WP, Berg KA (2015) Atypical antipsychotics and inverse agonism at 5-HT2 receptors. Curr Pharm Des 21:3732–3738
Swinford-Jackson SE, Anastasio NC, Fox RG, Stutz SJ, Cunningham KA (2016) Incubation of cocaine cue reactivity associates with neuroadaptations in the cortical serotonin (5-HT) 5-HT2C receptor (5-HT2CR) system. Neuroscience 324:50–61
Tecott LH, Abdallah L (2003) Mouse genetic approaches to feeding regulation: serotonin 5-HT2C receptor mutant mice. CNSSpectr 8:584–588
Tecott LH, Sun LM, Akana SF, Strack AM, Lowenstein DH, Dallman MF, Julius D (1995) Eating disorder and epilepsy in mice lacking 5-HT2c serotonin receptors. Nature 374:542–546
Templeman LA, Reynolds GP, Arranz B, San L (2005) Polymorphisms of the 5-HT2C receptor and leptin genes are associated with antipsychotic drug-induced weight gain in Caucasian subjects with a first-episode psychosis. Pharmacogenet Genomics 15:195–200
Thomas JM, Dourish CT, Tomlinson JW, Hassan-Smith Z, Higgs S (2014) Effects of the 5-HT2C receptor agonist meta-chlorophenylpiperazine on appetite, food intake and emotional processing in healthy volunteers. Psychopharmacology 231:2449–2459
Thomsen WJ, Grottick AJ, Menzaghi F, Reyes-Saldana H, Espitia S, Yuskin D, Whelan K, Martin M, Morgan M, Chen W, Al-Shamma H, Smith B, Chalmers D, Behan D (2008) Lorcaserin, a novel selective human 5-hydroxytryptamine2C agonist: in vitro and in vivo pharmacological characterization. J Pharmacol Exp Ther 325:577–587
Tomkins DM, Joharchi N, Tampakeras M, Martin JR, Wichmann J, Higgins GA (2002) An investigation of the role of 5-HT(2C) receptors in modifying ethanol self-administration behaviour. Pharmacol Biochem Behav 71:735–744
Tsai SJ, Hong CJ, Yu YW, Lin CH (2002) 759C/T genetic variation of 5HT(2C) receptor and clozapine-induced weight gain. Lancet 360:1790
van de Kar LD, Lorens SA (1979) Differential serotonergic innervation of individual hypothalamic nuclei and other forebrain regions by the dorsal and median midbrain raphe nuclei. Brain Res 162:45–54
Venzi M, David F, Bellet J, Cavaccini A, Bombardi C, Crunelli V, Di Giovanni G (2016) Role for serotonin2A (5-HT2A) and 2C (5-HT2C) receptors in experimental absence seizures. Neuropharmacology 108:292–304
Vickers SP, Clifton PG, Dourish CT, Tecott LH (1999) Reduced satiating effect of d-fenfluramine in serotonin 5-HT2C receptor mutant mice. Psychopharmacology 143:309–314
Voigt JP, Fink H (2015) Serotonin controlling feeding and satiety. Behav Brain Res 277:14–31
Wacker D, Wang C, Katritch V, Han GW, Huang XP, Vardy E et al (2013) Structural features for functional selectivity at serotonin receptors. Science 340:615–619
Wade JM, Juneja P, MacKay AW, Graham J, Havel PJ, Tecott LH, Goulding EH (2008) Synergistic impairment of glucose homeostasis in Ob/Ob mice lacking functional serotonin 2C receptors. Endocrinology 149:955–961
Waeber C, Dixon K, Hoyer D, Palacios JM (1988) Localization by autoradiography of neuronal 5‑HT3 receptors in mouse CNS. Eur J Pharmacol 151:351–352
Wallace TJ, Zai CC, Brandl EJ, Muller DJ (2011) Role of 5-HT(2C) receptor gene variants in antipsychotic-induced weight gain. Pharmacogenomics and personalized medicine 4:83–93
Wang B, Chehab FF (2006) Deletion of the serotonin 2c receptor from transgenic mice overexpressing leptin does not affect their lipodystrophy but exacerbates their diet-induced obesity. Biochem Biophys Res Commun 351:418–423
Wang Q, O'Brien PJ, Chen CX, Cho DS, Murray JM, Nishikura K (2000) Altered G protein-coupling functions of RNA editing isoform and splicing variant serotonin2C receptors. J Neurochem 74:1290–1300
Wang Y, Joharchi N, Fletcher PJ, Sellers EM, Higgins GA (1995) Further studies to examine the nature of dexfenfluramine- induced suppression of heroin self-administration. Psychopharmacology 120:134–141
Wang C, Jiang Y, Ma J, Wu H, Wacker D, Katritch V, Han GW, Liu W, Huang XP, Vardy E, McCorvy JD, Gao X, Zhou E, Melcher K, Zhang C, Bai F, Yang H, Yang L, Jiang H, Roth BL, Cherezov V, Stevens RC, Xu H (2013) Structural basis for molecular recognition at serotonin receptors. Science 340:610–614
Watanabe Y, Yoshimoto K, Tatebe H, Kita M, Nishikura K, Kimura M, Tanaka M (2014) Enhancement of alcohol drinking in mice depends on alterations in RNA editing of serotonin 2C receptors. Int J Neuropsychopharmacol 17:739–751
Werry TD, Gregory KJ, Sexton PM, Christopoulos A (2005) Characterization of serotonin 5-HT2C receptor signaling to extracellular signal-regulated kinases 1 and 2. J Neurochem 93:1603–1615
Werry TD, Stewart GD, Crouch MF, Watts A, Sexton PM, Christopoulos A (2008) Pharmacology of 5HT(2C) receptor-mediated ERK1/2 phosphorylation: agonist-specific activation pathways and the impact of RNA editing. Biochem Pharmacol 76:1276–1287
Winstanley CA, Theobald DE, Dalley JW, Glennon JC, Robbins TW (2004) 5-HT2A and 5-HT2C receptor antagonists have opposing effects on a measure of impulsivity: interactions with global 5-HT depletion. Psychopharmacology 176:376–385
Wirshing DA, Wirshing WC, Kysar L, Berisford MA, Goldstein D, Pashdag J, Mintz J, Marder SR (1999) Novel antipsychotics: comparison of weight gain liabilities. J Clin Psychiatry 60:358–363
Wohr M, Rippberger H, Schwarting RK, van Gaalen MM (2015) Critical involvement of 5-HT2C receptor function in amphetamine-induced 50-kHz ultrasonic vocalizations in rats. Psychopharmacology 232:1817–1829
Wood MD, Reavill C, Trail B, Wilson A, Stean T, Kennett GA, Lightowler S, Blackburn TP, Thomas D, Gager TL (2001) SB-243213; a selective 5-HT2C receptor inverse agonist with improved anxiolytic profile: lack of tolerance and withdrawal anxiety. Neuropharmacology 41:186–199
Wu X, Pang G, Zhang YM, Li G, Xu S, Dong L, Stackman RW Jr, Zhang G (2015) Activation of serotonin 5-HT(2C) receptor suppresses behavioral sensitization, naloxone-precipitated withdrawal symptoms in heroin-treated mice. Neurosci Lett 607:23–28
**e EZ, Zhu LY, Zhao LY, Chang LS (1996) The human serotonin 5-HT2C receptor: complete cDNA, genomic structure, and alternatively spliced variant. Genomics 35:551–561
Xu Y, Berglund ED, Sohn JW, Holland WL, Chuang JC, Fukuda M, Rossi J, Williams KW, Jones JE, Zigman JM, Lowell BB, Scherer PE, Elmquist JK (2010) 5-HT2CRs expressed by pro-opiomelanocortin neurons regulate insulin sensitivity in liver. Nat Neurosci 13:1457–1459
Xu Y, Jones JE, Kohno D, Williams KW, Lee CE, Choi MJ, Anderson JG, Heisler LK, Zigman JM, Lowell BB, Elmquist JK (2008) 5-HT2CRs expressed by pro-opiomelanocortin neurons regulate energy homeostasis. Neuron 60:582–589
Yagaloff KA, Hartig PR (1985) 125I-lysergic acid diethylamide binds to a novel serotonergic site on rat choroid plexus epithelial cells. J Neurosci 5:3178-3183
Yamashita PS, de Bortoli VC, Zangrossi H Jr (2011) 5-HT2C receptor regulation of defensive responses in the rat dorsal periaqueductal gray. Neuropharmacology 60:216–222
Yan C, Yang Y, Saito K, Xu P, Wang C, Hinton AO Jr, Yan X, Wu Q, Tong Q, Elmquist JK, Fukuda M, Xu Y (2015) Meta-chlorophenylpiperazine enhances leptin sensitivity in diet-induced obese mice. Br J Pharmacol 172:3510–3521
Yang W, Wang Q, Kanes SJ, Murray JM, Nishikura K (2004) Altered RNA editing of serotonin 5-HT2C receptor induced by interferon: implications for depression associated with cytokine therapy. Brain Res Mol Brain Res 124:70–78
Yoshimoto K, Watanabe Y, Tanaka M, Kimura M (2012) Serotonin2C receptors in the nucleus accumbens are involved in enhanced alcohol-drinking behavior. Eur J Neurosci 35:1368–1380
Yu L, Nguyen H, Le H, Bloem LJ, Kozak CA, Hoffman BJ, Snutch TP, Lester HA, Davidson N, Lübbert H (1991) The mouse 5-HT1C receptor contains eight hydrophobic domains and is X-linked. Mol Brain Res 11:143–149
Yuan X, Yamada K, Ishiyama-Shigemoto S, Koyama W, Nonaka K (2000) Identification of polymorphic loci in the promoter region of the serotonin 5-HT2C receptor gene and their association with obesity and type II diabetes. Diabetologia 43:373–376
Zhang G, Wu X, Zhang YM, Liu H, Jiang Q, Pang G, Tao X, Dong L, Stackman RW Jr (2016) Activation of serotonin 5-HT(2C) receptor suppresses behavioral sensitization and naloxone-precipitated withdrawal symptoms in morphine-dependent mice. Neuropharmacology 101:246–254
Zhou L, Sutton GM, Rochford JJ, Semple RK, Lam DD, Oksanen LJ, Thornton-Jones ZD, Clifton PG, Yueh CY, Evans ML, McCrimmon RJ, Elmquist JK, Butler AA, Heisler LK (2007) Serotonin 2C receptor agonists improve type 2 diabetes via melanocortin-4 receptor signaling pathways. Cell Metab 6:398–405
Zhu H, Urban DJ, Blashka J, McPheeters MT, Kroeze WK, Mieczkowski P, Overholser JC, Jurjus GJ, Dieter L, Mahajan GJ, Rajkowska G, Wang Z, Sullivan PF, Stockmeier CA, Roth BL (2012) Quantitative analysis of focused A-to-I RNA editing sites by ultra-high-throughput sequencing in psychiatric disorders. PLoS One 7:e43227
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Palacios, J.M., Pazos, A. & Hoyer, D. A short history of the 5-HT2C receptor: from the choroid plexus to depression, obesity and addiction treatment. Psychopharmacology 234, 1395–1418 (2017). https://doi.org/10.1007/s00213-017-4545-5
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DOI: https://doi.org/10.1007/s00213-017-4545-5