THE PROTEIN KINASE Cβ INHIBITOR, ENZASTAURIN, DECREASES AMPHETAMINE‐MEDIATED BEHAVIORS IN RATS

Amphetamines elicit their motivating effects by increasing extracellular dopamine levels in the brain. Extracellular dopamine levels are regulated by the dopamine transporter (DAT), a transmembrane protein that transports dopamine from the extracellular space into the cell. Amphetamines are taken up by DAT and reverse the transporter to release dopamine into the synapse. One protein that has been shown to be important for the mechanism of amphetamine's action is protein kinase C β (PKCβ). The inhibition of PKCβ reduces amphetamine‐stimulated dopamine efflux through DAT in vitro and in vivo while having no effect on dopamine uptake. While the effects of PKC inhibitors on amphetamine‐stimulated dopamine efflux have been characterized , it is important to understand the effects of PKCβ inhibition on amphetamine‐stimulated behaviors. The goal of this study was to determine whether inhibition of PKCβ will decrease amphetamine‐stimulated locomotion and amphetamine self‐administration. For all experiments, the selective PKCβ inhibitor enzastaurin was administered to male Sprague‐Dawley rats by intracerebroventricular (i.c.v.) injection 18 hours prior to evaluating amphetamine‐mediated behaviors. Locomotor activity was measured in infrared beam break boxes following administration of a single dose (1 mg/kg) or cumulative doses (0.32–5.6 mg/kg) of amphetamine. In self‐administration studies under a fixed ratio 5 (FR5) schedule of reinforcement, rats earned infusions of amphetamine (0.032 mg/kg/infusion) or sucrose pellets in 60‐ or 20‐min daily sessions, respectively. Pretreatment with enzastaurin reduced amphetamine‐stimulated locomotion at lower amphetamine doses (0.32 and 1 mg/kg), but this effect was surmounted by larger doses (≥ 3.2 mg/kg) of amphetamine, demonstrating a rightward shift in the amphetamine dose effect curve for locomotion. In amphetamine self‐administration studies, enzastaurin decreased the number of amphetamine infusions by over 60%. This effect was specific for amphetamine because enzastaurin did not alter the number of sucrose pellets earned. This study demonstrated that PKCβ inhibition attenuated amphetamine mediated behaviors, likely in a surmountable fashion. PKCβ inhibitors may be useful therapeutic targets for decreasing amphetamine use and abuse without altering natural rewards. Future work will investigate the mechanisms by which PKCβ inhibition alters amphetamine‐stimulated behaviors. Support or Funding Information Funded by DA11697 and T32‐GM007767.