Intra-accumbens infusion of pertussis toxin (PTX) results in a progressive and persistent locomotor hyperactivity and sensitizes rats to the locomotor-activating effects of cocaine. The present study further defined the hyperactivity resulting from inactivation of accumbens G i /G o proteins and tested the hypothesis that PTX-induced hyperactivity is mediated by dopamine D1 receptors. PTX (0.15 μg/side) infused bilaterally into the nucleus accumbens of rats resulted in a progressive increase in locomotor activity that peaked at 218% of preinjection activity levels 15 days after injection and persisted for greater than 5 weeks postinjection. Administration of the D1 receptor antagonist SCH23390 16 and 23 days after PTX injections dose dependently attenuated PTX-induced hyperactivity. D1 receptor blockade did not significantly alter activity in sham-injected animals. These findings support the hypothesis that the hyperactivity resulting from PTX-mediated inactivation of G i / o proteins reflects increased nucleus accumbens D1 receptor activation and suggest that striatal D1 receptors are important mediators of activity-related behavior, such as cocaine-induced hyperactivity.