%A Rodriguez,Michelle M.
%A Overshiner,Carl
%A Leander,J. David
%A Li,Xia
%A Morrow,Denise
%A Conway,Richard G.
%A Nelson,David L.
%A Briner,Karin
%A Witkin,Jeffrey M.
%D 2017
%J Frontiers in Psychiatry
%C
%F
%G English
%K Obsessive Compulsive Disorder,5-HT2C receptors,Schedule-induced polydipsia,Marble-burying,Fluoxetine,Ro 60-0175,SB242084
%Q
%R 10.3389/fpsyt.2017.00089
%W
%L
%M
%P
%7
%8 2017-May-22
%9 Original Research
%+ Jeffrey M. Witkin,Neuroscience Discovery Research and Discovery Chemistry, Lilly Research Laboratories, Eli Lilly and Company,USA,jwitkin@lilly.com
%#
%! 5-HT2C for OCD
%*
%<
%T Behavioral Effects of a Novel Benzofuranyl-Piperazine Serotonin-2C Receptor Agonist Suggest a Potential Therapeutic Application in the Treatment of Obsessive–Compulsive Disorder
%U https://www.frontiersin.org/articles/10.3389/fpsyt.2017.00089
%V 8
%0 JOURNAL ARTICLE
%@ 1664-0640
%X Selective serotonin reuptake inhibitors (SSRIs) are the only effective pharmacological treatments for obsessive–compulsive disorder (OCD). Nonetheless, their generally limited efficacy, side-effects, and delayed onset of action require improved medications for this highly prevalent disorder. Preclinical and clinical findings have suggested serotonin2C (5-HT2C) receptors as a potential drug target. Data in rats and mice are presented here on the effects of a novel 5-HT2C receptor agonist ((3S)-3-Methyl-1-[4-(trifluoromethyl)-7-benzofuranyl]-piperazine) (CPD 1) with high potency and full efficacy at 5-HT2C receptors and less potency and partial agonism at 5-HT2A and 5-HT2B receptors. Effects of CPD 1 on consummatory (schedule-induced polydipsia in rats) and non-consummatory behaviors (marble-burying and nestlet-shredding in mice) that are repetitive and non-habituating were studied. We also evaluated the effects of CPD 1 in rats with isoproterenol- and deprivation-induced drinking in rats to compare with the polydipsia studies. The SSRIs, fluoxetine, and chlomipramine decreased the high rates of drinking in rats engendered by a schedule of intermittent food delivery (schedule-induced polydipsia). The effects of fluoxetine, but not of d-amphetamine, were prevented by the selective 5-HT2C receptor antagonist SB242084. The 5-HT2C receptor agonists Ro 60-0175 and CPD 1 also decreased drinking, but unlike the SSRIs and Ro 60-0175, CPD 1 dose-dependently decreased excessive drinking without affecting lever press responses that produced food. The effects of CPD 1 were prevented by SB242084. CPD 1 also suppressed drinking induced by isoproterenol and by water deprivation without affecting normative drinking behavior. CPD 1, like fluoxetine, also suppressed marble-burying and nestlet-shredding in mice at doses that did not affect rotarod performance or locomotor activity. The behavioral specificity of effects of CPD 1 against repetitive and excessive behaviors suggests a potential therapeutic application in OCD.