REPEATED METHYLPHENIDATE TREATMENT INDUCES BEHAVIORAL SENSITIZATION AND DECREASES PROTEIN-KINASE-A AND DOPAMINE-STIMULATED ADENYLYL-CYCLASEACTIVITY IN THE DORSAL STRIATUM

The behavioral effects of repeated methylphenidate (MPH) treatment wer e assessed in the adult rat. Protein kinase A (PKA) and adenylyl cycla se (basal and DA-stimulated) activity in the dorsal striatum (i.e., ca udate-putamen) were measured to determine whether MPH-induced alterati ons in these enzymes correlate with the occurrence of behavioral sensi tization. In two experiments, adult rats were injected (IF) on 5 conse cutive preexposure days with saline or MPH (5, 10, 15, or 20 mg/kg). S ensitization was tested after a single abstinence day, with rats recei ving a challenge injection of MPH prior to either a 40- or 150-min tes ting session (additional control groups received saline on the test da y). Immediately after the 40-min testing session, rats were killed and tissue from the dorsal striatum was dissected for later analysis of P KA and adenylyl cyclase activity. Results showed that repeated MPH tre atment sensitized the stereotyped sniffing, but not the locomotor acti vity, of adult rats. PKA activity was significantly depressed in rats treated with MPH (10 or 20 mg/kg) during both the pre-exposure and tes t day phases. DA-stimulated adenylyl cyclase activity was reduced afte r chronic MPH treatment, while basal adenylyl cyclase values were enha nced. Thus, the present study showed that MPH was able to sensitize th e stereotyped behaviors of adult rats, an action that corresponded wit h drug-induced changes in dorsal striatal DA signal transduction mecha nisms.