title: 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.
abstract: The present series of experiments was undertaken to investigate the variables that influence the reinforcing efficacy of psychostimulants. The time of onset for dopamine transporter (DAT) occupancy of the long-acting, high-affinity DAT blocker 2beta-propanoyl-3beta-(4-tolyl)-tropane (PTT) was measured using an ex vivo binding assay in rodents and was determined to be significantly longer than for cocaine (30 min versus 2 min). To assess the reinforcing efficacy of PTT relative to cocaine, a discrete-trials drug-drug choice procedure (n = 3) and a progressive-ratio (PR) schedule (n = 4) were used in rhesus monkeys. Cocaine (0.003-0.56 mg/kg/injection) and PTT (0.003-0.03 mg/kg/injection) maintained responding greater than saline under the PR schedule. Maximal breaking points were significantly higher for cocaine compared with PTT. A separate group of monkeys prepared with double-lumen catheters was allowed to choose between cocaine (saline and 0.03-0.3 mg/kg/injection) and PTT (saline, and 0.01 and 0.03 mg/kg/injection). Under these conditions, PTT was not preferred over saline. When saline or 0.01 mg/kg/injection PTT was available as alternatives to cocaine, the highest dose of cocaine maintained greater than 80% choice. When 0.03 mg/kg/injection PTT was the alternative to cocaine, cocaine choice declined to approximately 50%, and total cocaine intake was decreased by ~70% at the highest cocaine dose. These results suggest that the reinforcing efficacy of PTT is less than cocaine in nonhuman primates. Data from studies with PTT indicate that slow-onset, long-acting DAT inhibitors can decrease cocaine self-administration while not functioning robustly as reinforcers, and support the further investigation of these drugs as treatment for cocaine addiction.
authors.affiliation: Center for the Neurobiological Investigation of Drug Abuse, Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157-1083, USA.
authors.forename: Joshua A
authors.initials: JA
authors.lastname: Lile
authors.forename: Drake
authors.initials: D
authors.lastname: Morgan
authors.forename: Anne M
authors.initials: AM
authors.lastname: Birmingham
authors.forename: Zhixia
authors.initials: Z
authors.lastname: Wang
authors.forename: William L
authors.initials: WL
authors.lastname: Woolverton
authors.forename: Huw M L
authors.initials: HM
authors.lastname: Davies
authors.forename: Michael A
authors.initials: MA
authors.lastname: Nader
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D003042:Cocaine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D003216:Conditioning, Operant / Q000187:drug effects*; D004192:Discrimination, Psychological / Q000187:drug effects; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D008253:Macaca mulatta; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012055:Reinforcement Schedule; D012054:Reinforcement, Psychology
chemical_list: D000697:Central Nervous System Stimulants; D018765:Dopamine Uptake Inhibitors; C087634:2-propanoyl-3-(4-tolyl)tropane; D003042:Cocaine