Mice were given a saline preinjection and habituation to the testing environment followed by injection of amphetamine (0.675-5.0 mg/kg IP) and apomorphine (AP, 15-80 micrograms/kg SC) 15 min later. AP produced a dose-dependent inhibition of the amphetamine-induced locomotor activity. A dose of 40 micrograms/kg AP increased approximately threefold the amphetamine dose required to induce the same increase in activity. Repeated administration of AP (30 mg/kg IP once daily for 14 days) resulted in an enhanced response (in the early portion of the time response) to amphetamine challenge, while the ability of subsequent microgram challenge doses of AP to reduce the response were unaffected. Similarly, repeated administration (twice-daily IP injections for 5 days) of amphetamine (5.0 mg/kg) resulted in an enhanced locomotor response to amphetamine challenge and no change in the ability of AP to inhibit the response. These results suggest that repeated administrations of dopamine agonists, although acting through different mechanisms (i.e., indirect versus direct), increase the initial release of neurotransmitter. However, the repeated administration of these agonists does not attenuate the ability of AP to inhibit the release of the neurotransmitter induced by amphetamine. The regulatory functions (i.e., presynaptic receptor control) of release appears to remain intact, but the level of neuronal activity has been increased.