A proposed mechanism for amphetamine-induced behavioral sensitization involving the vesicular monoamine transporter

The vesicular monoamine transporter (VMAT) was examined as a modulator for expression of amphetamine (AMPH) sensitization involving (1) AMPH-evoked and (2) depolarization-elicited behaviors. The global hypothesis was that, after AMPH sensitization, VMAT is functionally altered to redistribute dopamine (DA) between the cytoplasmic and vesicular pools based on demands for drug-mediated release versus exocytotic-like release. It was predicted that blocking access of AMPH to VMAT during a sensitization protocol should attenuate AMPH-evoked and depolarization-based behavioral sensitization. Rats were pretreated with a VMAT blocker, tetrabenazine (TBZ), before 7 daily AMPH injections (Induction Phase). Seven days later, two behaviors reflecting different underlying neural mechanisms were assessed (Expression Phase): 1) AMPH-evoked rotational behavior using rats with unilateral striatal DA depletions and 2) electrically stimulated rotational behavior (ESRB) using rats with electrode implants into the medial forebrain bundle (MFB). During the Induction Phase,1) unilateral-depleted rats given AMPH showed sensitization of lateralized rotations, but groups pretreated with TBZ before AMPH displayed a decrease in behavior, suggesting acute effects of TBZ. 2) Intact rats (tested for ESRB) showed locomotor activation that did not demonstrate sensitization using rotometers. TBZ during the Induction Phase had no significant effect on AMPH-evoked locomotion from intact rats. During Expression Phase testing, 1) AMPH-treated unilateral rats continued to display sensitization of AMPH-evoked rotational behavior. 2) AMPH-treated intact rats demonstrated sensitization of ESRB. Significantly, TBZ pretreatment blocked the sensitization of both 1) AMPH- and 2) electrical stimulation-evoked turning. These behavioral results support the hypothesis that VMAT modulates AMPH-sensitization via a mechanism for redistributing intraneuronal DA pools.