This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. There is a critical need to develop effective medications to treat cocaine addiction. The project continues to focus on behavioral and in vivo neurochemical interactions between serotonin and cocaine in the context of self-administration behavior in nonhuman primates. The long-term goal is to identify pharmacotherapeutic targets for the treatment of cocaine addiction and relapse. We are currently working to examine the role of the serotonin 5-HT2C receptor subtype. To date, our results indicate that systemic administration of the preferential 5-HT2C receptor agonist m-chlorophenylpiperazine (mCPP) or the selective 5-HT2C receptor agonist Ro 60-0175 attenuates the behavioral-stimulant and reinforcing effects of cocaine in squirrel monkeys. Importantly, both compounds reduce drug-seeking behavior in the reinstatement procedure, a preclinical research assay with relevance to relapse in human drug abusers. Additionally, Ro 60-0175 has demonstrated the capacity to selectively alter drug-seeking behavior while sparing other nondrug-mediated behaviors, indicative of a minimal side effect profile. Interestingly, SB 242084 potentiates cocaine-primed reinstatement. Hence, 5-HT2C receptors can bidirectionally modulate the behavioral effects of cocaine. Collectively, the results obtained during the previous year have important implications concerning the effectiveness of serotonergic systems as potential targets for the development of pharmacotherapies to treat stimulant abuse. Moreover, serotonin has significant therapeutic potential in the treatment of a variety of psychiatric disorders. Accordingly, the elucidation of basic neurochemical interactions between serotonin and dopamine in vivo in nonhuman primates should have significant impact on the development of therapeutics outside the field of drug addiction.
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