Effects of the adenosine A2A antagonist KW 6002 (istradefylline) on pimozide-induced oral tremor and striatal c-Fos expression: comparisons with the muscarinic antagonist tropicamide

Abstract

Typical antipsychotic drugs, including haloperidol and pimozide, have been shown to produce parkinsonian motor effects such as akinesia and tremor. Furthermore, there is an antagonistic interaction between adenosine A2A and dopamine D2 receptors in the basal ganglia, which is important for motor functions related to the production of parkinsonian symptoms. Several experiments were conducted to assess the effects of the selective adenosine A2A antagonist KW 6002 on both the motor and cellular effects of subchronic administration of pimozide. The motor test employed was tremulous jaw movements, which is used as a model of parkinsonian tremor. In addition, c-Fos expression in the ventrolateral neostriatum, which is the striatal area most associated with tremulous jaw movements, was used as a marker of striatal cell activity in animals that were tested in the behavioral experiments. Repeated administration of 1.0 mg/kg pimozide induced tremulous jaw movements and increased ventrolateral striatal c-Fos expression, while administration of 20.0 mg/kg of the atypical antipsychotic quetiapine did not. The tremulous jaw movements induced by pimozide were significantly reduced by co-administration of either the adenosine A2A antagonist KW 6002 or the muscarinic antagonist tropicamide. Pimozide-induced increases in ventrolateral striatal c-Fos expression were reduced by a behaviorally effective dose of KW 6002, but c-Fos expression in pimozide-treated rats was actually increased by tropicamide. These results indicate that two different drug manipulations that act to reduce tremulous jaw movements can have different effects on DA antagonist-induced c-Fos expression, suggesting that adenosine A2A antagonism and muscarinic receptor antagonism exert their motor effects by acting on different striatal circuits.