Repeated methylphenidate treatment induces behavioral sensitization and decreases protein kinase A and dopamine-stimulated adenylyl cyclase activity in the dorsal striatum.

The behavioral effects of repeated methylphenidate (MPH) treatment were assessed in the adult rat. Protein kinase A (PKA) and adenylyl cyclase (basal and DA-stimulated) activity in the dorsal striatum (i.e., caudate-putamen) were measured to determine whether MPH-induced alterations in these enzymes correlate with the occurrence of behavioral sensitization. In two experiments, adult rats were injected (i.p.) on 5 consecutive pre-exposure days with saline or MPH (5, 10, 15, or 20 mg/kg). Sensitization was tested after a single abstinence day, with rats receiving a challenge injection of MPH prior to either a 40- or 150-min testing session (additional control groups received saline on the test day). Immediately after the 40-min testing session, rats were killed and tissue from the dorsal striatum was dissected for later analysis of PKA and adenylyl cyclase activity. Results showed that repeated MPH treatment sensitized the stereotyped sniffing, but not the locomotor activity, of adult rats. PKA activity was significantly depressed in rats treated with MPH (10 or 20 mg/kg) during both the pre-exposure and test day phases. DA-stimulated adenylyl cyclase activity was reduced after chronic MPH treatment, while basal adenylyl cyclase values were enhanced. Thus, the present study showed that MPH was able to sensitize the stereotyped behaviors of adult rats, an action that corresponded with drug-induced changes in dorsal striatal DA signal transduction mechanisms.