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Parkinson's disease (PD) is characterized by loss of dopaminergic neurons in the substantia nigra. Current treatments for PD focus on dopaminergic therapies, including L-dopa and dopamine receptor agonists. However, these treatments induce neuropsychiatric side effects. Psychosis, characterized by delusions and hallucinations, is one of the most serious such side effects. Adenosine A(2A) receptor antagonism is a nondopaminergic treatment for PD with clinical and preclinical efficacy. The present studies assessed A(2A) antagonists SCH 412348 and istradefylline in rodent prepulse inhibition (PPI), a model of psychosis. Dopamine receptor agonists pramipexole (0.3-3 mg/kg), pergolide (0.3-3 mg/kg), and apomorphine (0.3-3 mg/kg) significantly disrupted PPI; ropinirole (1-30 mg/kg) had no effect; L-dopa (100-300 mg/kg) disrupted rat but not mouse PPI. SCH 412348 (0.3-3 mg/kg) did not disrupt rodent PPI; istradefylline (0.1-1 mg/kg) marginally disrupted mouse but not rat PPI. These results suggest that A(2A) antagonists, unlike dopamine agonists, have an improved neuropsychiatric side effect profile.
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