Jennifer L Martelle1, Michael A Nader. 1. Department of Physiology and Pharmacology, Wake Forest University School of Medicine, 546 NRC, Medical Center Boulevard, Winston-Salem, NC 27157-1083, USA.
Abstract
RATIONALE: Drug discrimination (DD) and drug self-administration (SA) are frequently used preclinical assays. All preclinical studies with cocaine have examined the discriminative stimulus (S(D)) and reinforcing (S(R)) effects in separate groups of subjects. OBJECTIVE: The objective of the study is to train drug-naïve rhesus macaques to discriminate self-administered cocaine from saline and to assess S(D) and S(R) effects using a within-subjects design. MATERIALS AND METHODS: Adult male rhesus monkeys (n = 4) were trained to self-administer cocaine (0.1 mg/kg per injection) under a progressive-ratio (PR) reinforcement schedule. Next, they were trained to discriminate self-administered cocaine (0.45 or 0.56 mg/kg) or saline under a fixed-ratio (FR) 50 schedule of food presentation. The final schedule combined DD and SA into a multiple [chained FR 50 SA (cocaine or saline), food-reinforced DD] and PR SA schedule. RESULTS: Each subject acquired SA under a PR schedule with significant differences in breakpoint between saline and cocaine evident by session 5. Self-administered cocaine was established as an S(D), such that 80% of responding before delivery of the first reinforcer and 90% of all responding occurred on the injection-appropriate lever. In all monkeys, there was at least one cocaine dose that did not engender cocaine-appropriate responding during DD (i.e., <20% cocaine-appropriate responding) yet functioned as a reinforcer during PR SA, suggesting that cocaine-like S(D) effects are not necessary for cocaine reinforcement. CONCLUSIONS: This within-subject model may provide new information related to the behavioral mechanisms of action leading to the high abuse potential of cocaine; such information may lead to novel pharmacological treatment strategies for addiction.
RATIONALE: Drug discrimination (DD) and drug self-administration (SA) are frequently used preclinical assays. All preclinical studies with cocaine have examined the discriminative stimulus (S(D)) and reinforcing (S(R)) effects in separate groups of subjects. OBJECTIVE: The objective of the study is to train drug-naïve rhesus macaques to discriminate self-administered cocaine from saline and to assess S(D) and S(R) effects using a within-subjects design. MATERIALS AND METHODS: Adult male rhesus monkeys (n = 4) were trained to self-administer cocaine (0.1 mg/kg per injection) under a progressive-ratio (PR) reinforcement schedule. Next, they were trained to discriminate self-administered cocaine (0.45 or 0.56 mg/kg) or saline under a fixed-ratio (FR) 50 schedule of food presentation. The final schedule combined DD and SA into a multiple [chained FR 50 SA (cocaine or saline), food-reinforced DD] and PR SA schedule. RESULTS: Each subject acquired SA under a PR schedule with significant differences in breakpoint between saline and cocaine evident by session 5. Self-administered cocaine was established as an S(D), such that 80% of responding before delivery of the first reinforcer and 90% of all responding occurred on the injection-appropriate lever. In all monkeys, there was at least one cocaine dose that did not engender cocaine-appropriate responding during DD (i.e., <20% cocaine-appropriate responding) yet functioned as a reinforcer during PR SA, suggesting that cocaine-like S(D) effects are not necessary for cocaine reinforcement. CONCLUSIONS: This within-subject model may provide new information related to the behavioral mechanisms of action leading to the high abuse potential of cocaine; such information may lead to novel pharmacological treatment strategies for addiction.
Authors: Joshua A Lile; Drake Morgan; Anne M Birmingham; Zhixia Wang; William L Woolverton; Huw M L Davies; Michael A Nader Journal: J Pharmacol Exp Ther Date: 2002-11 Impact factor: 4.030
Authors: Joshua A Lile; Zhixia Wang; William L Woolverton; Jessica E France; Timothy C Gregg; Huw M L Davies; Michael A Nader Journal: J Pharmacol Exp Ther Date: 2003-09-03 Impact factor: 4.030
Authors: Amy Hauck Newman; Brandi L Blaylock; Michael A Nader; Jack Bergman; David R Sibley; Phil Skolnick Journal: Biochem Pharmacol Date: 2012-07-03 Impact factor: 5.858