Tremorolytic effects of adenosine A2A antagonists: implications for parkinsonism.

Drug-induced tremulous jaw movements in rats have been used as a model of parkinsonian tremor. Because adenosine A2A antagonists have antiparkinsonian effects, the present experiments were conducted to study the ability of adenosine A2A antagonism to reverse the tremulous jaw movements produced by the antipsychotic drugs pimozide, haloperidol and reserpine. In one group of studies, rats received daily injections of the dopamine antagonist pimozide, and on day 8 they received injections of pimozide plus various doses of the A2A antagonists KW 6002 or MSX-3. KW 6002 and MSX-3 suppressed pimozide-induced tremulous jaw movements, reduced catalepsy, and increased locomotion. MSX-3 also suppressed the jaw movements induced by haloperidol and reserpine. In addition, local injections of MSX-3 into the ventrolateral neostriatum suppressed pimozide-induced tremulous jaw movements. Thus, adenosine A2A antagonism can reverse the tremulous movements induced by antipsychotic drugs, which is consistent with the hypothesis that antagonism of adenosine A2A receptors can result in antiparkinsonian effects. Adenosine A2A antagonists may be useful for their tremorolytic effects, and may help in treating both idiopathic and antipsychotic-induced parkinsonian symptoms.

Injections of the selective adenosine A2A antagonist MSX-3 into the nucleus accumbens core attenuate the locomotor suppression induced by haloperidol in rats.

There is considerable evidence of interactions between adenosine A2A receptors and dopamine D2 receptors in striatal areas, and antagonists of the A2A receptor have been shown to reverse the motor effects of DA antagonists in animal models. The D2 antagonist haloperidol produces parkinsonism in humans, and also induces motor effects in rats, such as suppression of locomotion. The present experiments were conducted to study the ability of the adenosine A2A antagonist MSX-3 to reverse the locomotor effects of acute or subchronic administration of haloperidol in rats. Systemic (i.p.) injections of MSX-3 (2.5-10.0 mg/kg) were capable of attenuating the suppression of locomotion induced by either acute or repeated (i.e., 14 day) administration of 0.5 mg/kg haloperidol. Bilateral infusions of MSX-3 directly into the nucleus accumbens core (2.5 microg or 5.0 microg in 0.5 microl per side) produced a dose-related increase in locomotor activity in rats treated with 0.5 mg/kg haloperidol either acutely or repeatedly. There were no overall significant effects of MSX-3 infused directly into the dorsomedial nucleus accumbens shell or the ventrolateral neostriatum. These results indicate that antagonism of adenosine A2A receptors can attenuate the locomotor suppression produced by DA antagonism, and that this effect may be at least partially mediated by A2A receptors in the nucleus accumbens core. These studies suggest that adenosine and dopamine systems interact to modulate the locomotor and behavioral activation functions of nucleus accumbens core.