Intermittent systemic exposure to psychostimulants such as amphetamine leads to several forms of long-lasting behavioral plasticity including nonassociative sensitization and associative conditioning. In the nucleus accumbens (NAcc), the protein serine/threonine kinase cyclin-dependent kinase 5 (Cdk5) and its phosphorylation target, the guanine-nucleotide exchange factor kalirin-7 (Kal7), may contribute to the neuroadaptations underlying each of these forms of plasticity. Pharmacological inhibition of Cdk5 in the NAcc prevents the increases in dendritic spine density in this site and enhances the locomotor sensitization normally observed following repeated cocaine. Mice lacking the Kal7 gene display similar phenotypes suggesting that locomotor sensitization and increased NAcc spine density need not be positively correlated. As increases in spine density may relate to the formation of associative memories and both Cdk5 and Kal7 regulate the generation of spines following repeated drug exposure, we hypothesized that either inhibiting Cdk5 or preventing its phosphorylation of Kal7 in the NAcc may prevent the induction of drug conditioning. In the present experiments, blockade in rats of NAcc Cdk5 activity with roscovitine (40 nmol/0.5μl/side) prior to each of 4 injections of amphetamine (1.5 mg/kg; i.p.) prevented the accrual of contextual locomotor conditioning but spared the induction of locomotor sensitization as revealed on tests conducted one week later. Similarly, transient viral expression in the NAcc exclusively during amphetamine exposure of a threoninealanine mutant form of Kal7 [mKal7(T1590A)] that is not phosphorylated by Cdk5 also prevented the accrual of contextual conditioning and spared the induction of sensitization. These results indicate that signaling via Cdk5 and Kal7 in the NAcc is necessary for the formation of context-drug associations, potentially through the modulation of dendritic spine dynamics in this site.

When psychostimulant drugs like amphetamine are administered repeatedly in the presence of a contextual stimulus complex, long-lasting associations form between the unconditioned effects of the drug and the contextual stimuli. Here we assessed the role played by the proline-directed serine/threonine kinase cyclin-dependent kinase 5 (Cdk5) in the nucleus accumbens (NAcc) on the expression of the conditioned locomotion normally observed when rats are returned to a context previously paired with amphetamine. Infusing the Cdk5 inhibitor roscovitine (40 nmol/0.5μl/side) into the NAcc 30-min before the test for conditioning significantly enhanced the conditioned locomotor response observed in rats previously administered amphetamine in the test environment. This effect was specific to the expression of a conditioned response as inhibiting Cdk5 produced no effect in control rats previously administered saline or previously administered amphetamine elsewhere. As inhibiting Cdk5 during exposure to amphetamine has been found to block the accrual of locomotor conditioning, the present results suggest distinct roles for NAcc Cdk5 in the induction and expression of excitatory conditioning by amphetamine.

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