Association between the expression of amphetamine-induced behavioral sensitization and Cdk5/p35 activity in dorsal striatum

Abstract

Sensitization to psychostimulants is strongly influenced by the environmental context in which the drug is administered and little is known about the molecular mechanisms that regulate this process. Chronic treatment with psychostimulants has been shown to up-regulate the expression of cyclin-dependent kinase 5 (Cdk5) in the striatum, as a downstream target gene of ΔFosB. This study was therefore designed to analyze neurochemical changes underlying the expression of amphetamine-induced sensitization. To this end, periadolescent rats were given saline or 4 mg/kg amphetamine in a NOVEL or a HOME environment. After one day, subjects were challenged with vehicle or 2 mg/kg amphetamine in the same context in which they received the first administration of the drug. Locomotor activity and the expression levels of p35 and Cdk5 activity in synaptosomes of the dorsal striatum were analyzed. The expression of behavioral sensitization was observed only in the NOVEL condition. Furthermore, only animals trained and tested in the NOVEL condition showed increased p35 protein levels and Cdk5 activity. Our findings provide clear behavioral and neurochemical evidence of a specific association between increased p35 and Cdk5 activity in the dorsal striatum and the expression of amphetamine-behavioral sensitization, allowing us to propose p35 as a biochemical marker of behavioral sensitization to amphetamine.