The goal of this proposal is to achieve a better understanding of the pharmacological and behavioral determinant of the reinforcing effects of cocaine, a heavily abused substance in all social strata. Cocaine binds to the dopamine (DA), and to a lesser extent, the serotonin (5-HT) and norepinephrine (NE) transporters, blocking the reuptake of these monamines. Research with animals has shown that DA neurotransmission, in large part, mediates the reinforcing effects of cocaine. Less information, however, is available regarding the interactions of cocaine with the 5-HT system. The studies proposed in this project are designed to evaluate, using rhesus monkeys, the reinforcing efficacy of tropane analogs having differential selectivity and duration of action at the DA and 5-HT transporters, as well as their ability to affect cocaine self-administration using fixed-ratio and progressive-ratio schedules of reinforcement. Specifically, this proposal will 1) investigate the ability of these tropanes to maintain self-administration when substituted for cocaine; 2) determine the reinforcing efficacy of these tropanes relative to cocaine: 3) evaluate the ability of chronic treatment with these tropanes to selectively decrease cocaine self- administration; 4) investigate the effects of discontinuation of treatment on cocaine's reinforcing effects. When completed, this research will provide additional information regarding the relative importance of the DA and 5-HT systems in mediating the reinforcing effects of cocaine. In addition, it will evaluate the ability of longacting tropanes with differential selectivity for the DA and 5-HT transporters to decrease maintenance and relapse to cocaine self- administration, an animal model of cocaine abuse in humans.
| Lile, Joshua A (2006) Pharmacological determinants of the reinforcing effects of psychostimulants: relation to agonist substitution treatment. Exp Clin Psychopharmacol 14:20-33 |
| Lile, Joshua A; Wang, Zhixia; Woolverton, William L et al. (2003) The reinforcing efficacy of psychostimulants in rhesus monkeys: the role of pharmacokinetics and pharmacodynamics. J Pharmacol Exp Ther 307:356-66 |
| Lile, Joshua A; Morgan, Drake; Birmingham, Anne M et al. (2002) The reinforcing efficacy of the dopamine reuptake inhibitor 2beta-propanoyl-3beta-(4-tolyl)-tropane (PTT) as measured by a progressive-ratio schedule and a choice procedure in rhesus monkeys. J Pharmacol Exp Ther 303:640-8 |
