title: Serotonin 5-HT2 receptor interactions with dopamine function: implications for therapeutics in cocaine use disorder.
abstract: Cocaine exhibits prominent abuse liability, and chronic abuse can result in cocaine use disorder with significant morbidity. Major advances have been made in delineating neurobiological mechanisms of cocaine abuse; however, effective medications to treat cocaine use disorder remain to be discovered. The present review will focus on the role of serotonin (5-HT; 5-hydroxytryptamine) neurotransmission in the neuropharmacology of cocaine and related abused stimulants. Extensive research suggests that the primary contribution of 5-HT to cocaine addiction is a consequence of interactions with dopamine (DA) neurotransmission. The literature on the neurobiological and behavioral effects of cocaine is well developed, so the focus of the review will be on cocaine with inferences made about other monoamine uptake inhibitors and releasers based on mechanistic considerations. 5-HT receptors are widely expressed throughout the brain, and several different 5-HT receptor subtypes have been implicated in mediating the effects of endogenous 5-HT on DA. However, the 5-HT2A and 5-HT2C receptors in particular have been implicated as likely candidates for mediating the influence of 5-HT in cocaine abuse as well as to traits (e.g., impulsivity) that contribute to the development of cocaine use disorder and relapse in humans. Lastly, new approaches are proposed to guide targeted development of serotonergic ligands for the treatment of cocaine use disorder.
authors.affiliation: Yerkes National Primate Research Center, Emory University, Atlanta, Georgia (L.L.H.); and Center for Addiction Research and Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas (K.A.C.) lhowell@emory.edu.
authors.forename: Leonard L
authors.initials: LL
authors.lastname: Howell
authors.affiliation: Yerkes National Primate Research Center, Emory University, Atlanta, Georgia (L.L.H.); and Center for Addiction Research and Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas (K.A.C.).
authors.forename: Kathryn A
authors.initials: KA
authors.lastname: Cunningham
mesh_terms: D000818:Animals; D016739:Behavior, Addictive / Q000188:drug therapy / Q000378:metabolism / Q000523:psychology; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D000697:Central Nervous System Stimulants / Q000009:adverse effects*; D003042:Cocaine / Q000009:adverse effects*; D019970:Cocaine-Related Disorders / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology / Q000523:psychology; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D015195:Drug Design; D006801:Humans; D058990:Molecular Targeted Therapy; D044402:Receptor, Serotonin, 5-HT2A / Q000187:drug effects* / Q000378:metabolism; D044405:Receptor, Serotonin, 5-HT2C / Q000187:drug effects* / Q000378:metabolism; D018490:Serotonin Agents / Q000627:therapeutic use*; D009435:Synaptic Transmission / Q000187:drug effects*
chemical_list: D000697:Central Nervous System Stimulants; D044402:Receptor, Serotonin, 5-HT2A; D044405:Receptor, Serotonin, 5-HT2C; D018490:Serotonin Agents; D003042:Cocaine; D004298:Dopamine