Serotonin 2A Receptors Differentially Contribute to Abuse-Related Effects of Cocaine and Cocaine-Induced Nigrostriatal and Mesolimbic Dopamine Overflow in Nonhuman Primates

• Type of Material: Article
• Authors: Kevin S. Murnane, Yerkes National Primate Research Center; Jake Winschel, Yerkes National Primate Research Center; Karl T. Schmidt, Yerkes National Primate Research Center; LaShaya M. Stewart, Yerkes National Primate Research Center; Samuel J. Rose, Yerkes National Primate Research Center; Kejun Cheng, National Institutes of Health; Kenner C. Rice, National Institutes of Health; Leonard Howell, Emory University
• Language: English
• Date: 2013-08-14
• Publisher: Society for Neuroscience
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2013 the authors
• Final Published Version (URL): http://www.jneurosci.org/content/33/33/13367
• Title of Journal or Parent Work: Journal of Neuroscience Nursing
• ISSN: 0270-6474
• Volume: 33
• Issue: 33
• Start Page: 13367
• End Page: 13374
• Grant/Funding Information: These studies were supported by United States Public Health Service Grants DA010344, DA012514, and RR00165, and is currently supported by the National Institutes of Health Office of Research Infrastructure Programs Grant ODP51OD11132. A portion of this work was supported by the Intramural Research Programs of the National Institute on Drug Abuse and the National Institute on Alcohol Abuse and Alcoholism
• Research Categories: Biology, Neuroscience

Abstract

Two of the most commonly used procedures to study the abuse-related effects of drugs in laboratory animals are intravenous drug self-administration and reinstatement of extinguished behavior previously maintained by drug delivery. Intravenous self-administration is widely accepted to model ongoing drug-taking behavior, whereas reinstatement procedures are accepted to model relapse to drug taking following abstinence. Previous studies indicate that 5-HT2A receptor antagonists attenuate the reinstatement of cocaine-maintained behavior but not cocaine self-administration in rodents. Although the abuse-related effects of cocaine have been closely linked to brain dopamine systems, no previous study has determined whether this dissociation is related to differential regulation of dopamine neurotransmission. To elucidate the neuropharmacological and neuroanatomical mechanisms underlying this phenomenon, we evaluated the effects of the selective 5-HT2A receptor antagonist M100907 on intravenous cocaine self-administration and drug- and cue-primed reinstatement in rhesus macaques (Macaca mulatta). In separate subjects, we evaluated the role of 5-HT2A receptors in cocaine-induced dopamine overflow in the nucleus accumbens (n = 4) and the caudate nucleus (n = 5) using in vivo microdialysis. Consistent with previous studies, M100907 (0.3 mg/kg, i.m.) significantly attenuated drug- and cue-induced reinstatement but had no significant effects on cocaine self-administration across a range of maintenance doses. Importantly, M100907 (0.3 mg/kg, i.m.) attenuated cocaine-induced (1.0 mg/kg, i.v.) dopamine overflow in the caudate nucleus but not in the nucleus accumbens. These data suggest that important abuse-related effects of cocaine are mediated by distinct striatal dopamine projection pathways.