Rationale: Pathological amphetamine (AMPH) use is a serious public health concern with no pharmacological treatment options. Protein kinase Cβ (PKCβ) has been implicated in the mechanism of action of AMPH, such that inhibition of PKCβ attenuates AMPH-stimulated dopamine efflux in vivo. With this in mind, inhibition of PKCβ may be a viable therapeutic target for AMPH use disorder.
Objective: The purpose of this study is to demonstrate that selective pharmacological inhibition of PKCβ alters AMPH-stimulated behaviors in rats.
Methods: Rats were administered intracerebroventricular (i.c.v.) injections of the PKCβ-selective inhibitor enzastaurin 0.5, 3, 6, or 18 h before evaluating AMPH-stimulated locomotion (0.32-3.2 mg/kg). Rats were trained to make responses for different doses of AMPH infusions or sucrose under a fixed ratio 5 schedule of reinforcement, and the effects of enzastaurin pretreatment 3 or 18 h prior to a self-administration session were determined. Also, the effect of enzastaurin on AMPH-stimulated PKC activity in the ventral striatum was evaluated.
Results: A large dose of enzastaurin (1 nmol) decreased AMPH-stimulated locomotor activity 0.5 h following enzastaurin administration. Small doses of enzastaurin (10-30 pmol) attenuated AMPH-stimulated locomotor activity and shifted the AMPH dose-effect curve to the right following an 18-h pretreatment. Rats pretreated with enzastaurin 18 h, but not 3, prior to a self-administration session showed a decrease in the number of responses for AMPH, shifted the ascending limb of the amphetamine dose effect curve, and produced no change in responses for sucrose. AMPH-stimulated PKC activity was decreased following a 0.5- or 18-h pretreatment, but not a 3-h pretreatment of enzastaurin.
Conclusions: These results demonstrate that inhibition of PKCβ will decrease AMPH-stimulated behaviors and neurobiological changes and suggest that PKCβ is potentially a viable target for AMPH use disorder.
Keywords: Addiction; Amphetamine; Behavior; Protein kinase Cβ; Self-administration.