This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The purpose of this project is to better understand the mechanisms by which drug-associated cues are capable of eliciting drug-seeking behavior in cocaine abusers, as well as to identify pharmacotherapeutic targets for the treatment of cocaine addiction and relapse. We proposed to train nonhuman primates on a novel operant-conditioning procedure whereby environmental stimuli are predictive of either intravenous cocaine (S+) or saline (S-) infusions. Early experiments demonstrated that the group II metabotropic glutamate receptor agonist LY479268 selectively reduced responding elicited by drug-associated stimuli. However, this behavioral schedule proved difficult to entrain in an adequate number of experimental subjects due to its inherent complexity, and we have therefore modified our experimental procedures. A full cohort of subjects are now trained according to a more traditional schedule of second-order cocaine self-administration that lacks the S+/S- contingency, and we will use the reinstatement procedure as our model of cue- or drug-induced relapse. Additionally, we have halted our work with LY379268 due to the appearance of adverse side effects as well as its reported actions at dopamine D2 receptors. We have begun pilot studies investigating other pharmacological targets, specifically the serotonin (5-HT) 2a and 2c receptors. To date, we have demonstrated that systemic administration of the 5-HT 2c receptor agonists mCPP or Ro 60-0175 attenuates the behavioral-stimulant and relapse-inducing effects of cocaine. Current studies are investigating the effects of these compounds on the reinforcing effects of cocaine using self-administration procedures.
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