Modification of discriminative‐stimulus effects of methamphetamine by aripiprazole

Aripiprazole has D2‐family partial agonist actions that may modulate abuse‐related effects of stimulant drugs like methamphetamine. The present studies were conducted to examine the effects of aripiprazole and, for comparison, the D2 partial agonist roxindole in monkeys trained to discriminate methamphetamine (MA) from vehicle. Subjects were trained under a fixed‐ratio 10 schedule to respond on one of two levers after i.m. injection of vehicle and the other lever after injection of either 0.056 (n=4) or 0.32 mg/kg MA (n=4). First, i.m. dosing procedures were used to study substitution by roxindole (0.1–1.0 mg/kg) and aripiprazole ((0.032–0.32 mg/kg). Both roxindole and aripiprazole engendered responding on the MA‐associated lever in both groups of subjects, with a maximum of 50–80% substitution following 0.32 mg/kg aripiprazole and 1.0 mg/kg roxindole. These doses also produced marked (>50%) decreases in response rate in all subjects. In a second set of experiments in monkeys trained with 0.32 mg/kg MA, pretreatment with aripiprazole (0.32 mg/kg) or roxindole (1.0 mg/kg) diminished the effects of methamphetamine, resulting in incomplete substitution for MA or a 3‐fold rightward shift in the MA dose‐effect function, respectively. These findings are consistent with the view that D2 partial agonists may reduce abuse‐related effects of methamphetamine. (supported by NIH/NIDA DA03774, DA10566)