Effects of the dopamine reuptake inhibitor PTT on reinstatement and on food- and cocaine-maintained responding in rhesus monkeys

Rationale: High-affinity, slow-onset, long-acting dopamine transporter (DAT) inhibitors are being considered as potential agonist replacement therapies for cocaine addiction, and therefore the ability of these drugs to reinstate cocaine seeking and to selectively decrease cocaine-maintained responding should be assessed. Objectives: The purpose of these experiments was to evaluate the effects of the active enantiomer of a high-affinity, slow-onset, long-acting DAT inhibitor, (-)2β-propanoyl-3β-(4-tolyl)-tropane (PTT), and cocaine on food- and cocaine-maintained responding and on extinguished responding previously maintained by cocaine in non-human primates using a within-subjects design. Methods: Rhesus monkeys (n=3) responded under a multiple fixed-ratio schedule of food (1 g) and drug reinforcement, and cocaine dose-response curves (saline, 0.003-0.3 mg/kg per injection) were determined. The effects of pretreatment with (-)PTT (0.001-0.056 mg/kg, IV) and cocaine (0.03-0.3 mg/kg, IV) were determined when the dose of cocaine that maintained peak response rates (0.03 mg/kg per injection) or saline was available. Results: (-)PTT and cocaine reduced cocaine intake; (-)PTT affected cocaine self-administration only at doses that also decreased food-maintained responding. (-)PTT and cocaine reinstated responding that was previously reinforced by cocaine at lower doses than were necessary to decrease cocaine-maintained responding. For all studies, PTT was at least 1.0 log-unit more potent than cocaine. Compared to cocaine, PTT had a longer duration of action in all behavioral measures. Conclusions: These results suggest that PTT would decrease cocaine use, but only at doses that disrupted other behaviors. It appears that the potency of this class of drugs to reinstate cocaine-seeking is substantially greater than their potency at decreasing cocaine self-administration.