Synergism between a serotonin 5-HT2A receptor (5-HT 2AR) antagonist and 5-HT2CR agonist suggests new pharmacotherapeutics for cocaine addiction

Kathryn A. Cunningham, Noelle C. Anastasio, Robert G. Fox, Sonja J. Stutz, Marcy J. Bubar, Sarah E. Swinford, Cheryl Watson, Scott R. Gilbertson, Kenner C. Rice, Sharon Rosenzweig-Lipson, F. Gerard Moeller

Research output: Contribution to journalArticlepeer-review

82 Scopus citations


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-HT2A receptor (5-HT2AR) and 5-HT2CR; either a selective 5-HT 2AR antagonist or a 5-HT2CR agonist suppresses impulsivity and cocaine-seeking in preclinical models. We conducted proof-of-concept analyses to evaluate whether a combination of 5-HT2AR antagonist plus 5-HT2CR 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-HT2AR antagonist M100907 plus the 5-HT 2CR 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-HT2AR antagonist plus a 5-HT2CR 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.

Original languageEnglish (US)
Pages (from-to)110-121
Number of pages12
JournalACS chemical neuroscience
Issue number1
StatePublished - Jan 16 2013


  • 1-Choice serial reaction time task
  • 5-HT receptor, 5-HT receptor
  • cocaine
  • cue reactivity
  • impulsivity, self-administration
  • serotonin

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Cognitive Neuroscience
  • Cell Biology


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