title: Synergism between a serotonin 5-HT2A receptor (5-HT2AR) antagonist and 5-HT2CR agonist suggests new pharmacotherapeutics for cocaine addiction.
abstract: Relapse to cocaine dependence, even after extended abstinence, involves a number of liability factors including impulsivity (predisposition toward rapid, unplanned reactions to stimuli without regard to negative consequences) and cue reactivity (sensitivity to cues associated with cocaine-taking which can promote cocaine-seeking). These factors have been mechanistically linked to serotonin (5-hydroxytryptamine, 5-HT) signaling through the 5-HT(2A) receptor (5-HT(2A)R) and 5-HT(2C)R; either a selective 5-HT(2A)R antagonist or a 5-HT(2C)R agonist suppresses impulsivity and cocaine-seeking in preclinical models. We conducted proof-of-concept analyses to evaluate whether a combination of 5-HT(2A)R antagonist plus 5-HT(2C)R agonist would have synergistic effects over these liability factors for relapse as measured in a 1-choice serial reaction time task and cocaine self-administration/reinstatement assay. Combined administration of a dose of the selective 5-HT(2A)R antagonist M100907 plus the 5-HT(2C)R agonist WAY163909, each ineffective alone, synergistically suppressed cocaine-induced hyperactivity, inherent and cocaine-evoked impulsive action, as well as cue- and cocaine-primed reinstatement of cocaine-seeking behavior. The identification of synergism between a 5-HT(2A)R antagonist plus a 5-HT(2C)R agonist to attenuate these factors important in relapse indicates the promise of a bifunctional ligand as an anti-addiction pharmacotherapeutic, setting the stage to develop new ligands with improved efficacy, potency, selectivity, and in vivo profiles over the individual molecules.
authors: Center for Addiction Research, Department of Pharmacology and Toxicology, Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, Texas, United States. kcunning@utmb.edu
authors: Kathryn A
authors: KA
authors: Cunningham
authors: Noelle C
authors: NC
authors: Anastasio
authors: Robert G
authors: RG
authors: Fox
authors: Sonja J
authors: SJ
authors: Stutz
authors: Marcy J
authors: MJ
authors: Bubar
authors: Sarah E
authors: SE
authors: Swinford
authors: Cheryl S
authors: CS
authors: Watson
authors: Scott R
authors: SR
authors: Gilbertson
authors: Kenner C
authors: KC
authors: Rice
authors: Sharon
authors: S
authors: Rosenzweig-Lipson
authors: F Gerard
authors: FG
authors: Moeller
mesh_terms: D000818:Animals; D001381:Azepines / Q000627:therapeutic use*; D019970:Cocaine-Related Disorders / Q000188:drug therapy*; D003463:Cues; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004357:Drug Synergism; D005464:Fluorobenzenes / Q000627:therapeutic use*; D006801:Humans; D006948:Hyperkinesis / Q000188:drug therapy; D007175:Impulsive Behavior / Q000188:drug therapy; D007211:Indoles / Q000627:therapeutic use*; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D010880:Piperidines / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects; D012055:Reinforcement Schedule; D058830:Serotonin 5-HT2 Receptor Antagonists / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: C501656:1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta(b)(1,4)diazepino(6,7,1hj)indole; D001381:Azepines; D004338:Drug Combinations; D005464:Fluorobenzenes; D007211:Indoles; D010880:Piperidines; D058830:Serotonin 5-HT2 Receptor Antagonists; C079049:volinanserin