Effect of aripiprazole, a partial dopamine D2 receptor agonist, on increased rate of methamphetamine self-administration in rats with prolonged session duration

Aripiprazole is a dopamine (DA) D-2 receptor partial agonist, approved by the Food and Drug Administration (FDA) for the treatment of schizophrenia. DA receptor partial agonists have been previously assessed as potential therapeutic agents for cocaine dependence. The present experiment examined the effect of aripiprazole on methamphetamine self-administration in a rodent model of an increasing drug self-administration with prolonged session duration. Wistar rats were allowed to self-administer methamphetamine (0.05 mg/kg/injection, intravenously) in either 1-h (short access: ShA rats) or 6-h sessions (long access: LgA rats). After 15 sessions, the dose -response function of methamphetamine was determined under either a progressive- or a fixed-ratio schedule. Next, the effect of aripiprazole (0.3-10 mg/kg, subcutaneuously (s. c.)) on the dose -response function was examined. LgA rats exhibited an increasing rate of methamphetamine self-administration. Responding for methamphetamine by LgA rats was higher than that of ShA rats under both schedules. Pretreatment with aripiprazole shifted the dose-response function of methamphetamine to the right in both LgA and ShA rats. However, the effect of aripiprazole was greater in LgA than ShA rats. In in vitro receptor binding assay, no change in the level of D2 DA receptors in the nucleus accumbens and the striatum was found in any group. The present data suggest increased sensitivity of the dopaminergic system to aripiprazole in LgA rats compared with ShA rats. However, mechanisms other than downregulation of D-2 DA receptors in the nucleus accumbens and the striatum may be responsible for the increased sensitivity of the dopaminergic function in LgA rats.