NK-3 receptor antagonism prevents behavioral sensitization to cocaine: a role of glycogen synthase kinase-3 in the nucleus accumbens.

Repeated administration of cocaine induces heightened behavioral hyperactivity termed sensitization. Although NK-3 receptors have been shown to modulate acute cocaine-induced behaviors, their role in behavioral sensitization is unknown. The present study investigated whether NK-3 receptor blockade altered behavioral sensitization to cocaine. Additionally, glycogen synthase kinase-3 (GSK3) has been shown to be involved in dopamine receptor signaling and in development of sensitization; therefore regulation of GSK3 activity in the nucleus accumbens was also investigated. Administration of the NK-3 receptor antagonist SB 222200 (5 mg/kg, s.c.) prior to repeated cocaine (20 mg/kg, i.p.) prevented the development of sensitized responses after a cocaine challenge. Pre-treatment with SB 222200 before a cocaine challenge also blocked expression of sensitization. Decrease in GSK3 activity demonstrated by increased phosphorylation of GSK3α and GSK3β was detected 20 mins after an acute cocaine injection. In contrast, a cocaine challenge failed to alter phosphorylation of GSK3α and GSK3β in sensitized mice. SB 222200 prior to repeated cocaine resulted in increased phosphorylation of GSK3α and GSK3β akin to changes following acute cocaine. Collectively, these findings demonstrate the involvement of NK-3 receptors in development and expression of behavioral sensitization and in regulation of GSK3 activity in the nucleus accumbens after repeated cocaine.