Evaluation Of The Selective A2a Receptor Antagonist, Sch 412348, And The D2/D3 Receptor Agonist Pramipexole In Rat Models Of Psychotic And Obsessive Behavior

Dopamine D2/D3 receptor agonists, used to treat Parkinson's Disease (PD), have serious side effects, including hallucinations and obsessive behavior. Adenosine A2A receptor antagonists have been proposed as a PD treatment, but little has been done to evaluate potential psychiatric side‐effects. We tested the D2/D3 receptor agonist pramipexole, and the selective A2A receptor antagonist SCH 412348 in rodent prepulse inhibition (PPI). Pramipexole (0.3–3 mg/kg) induced a significant PPI deficit in rats and mice. PPI is used to preclinically model psychotic‐like behavior. Ropinirole (1–30 mg/kg) and SCH 412348 (0.3–3 mg/kg) had no effect. Currently there is no preclinical model of the obsessive behavior side effect associated with D2/D3 receptor agonists. To address this, we trained water‐deprived rats that licking a water spout would result in a mild footshock. We hypothesized that pramipexole‐treated animals would favor the rewarding stimulus over the punishing stimulus manifested as increased licking relative to vehicle‐treated animals. The resembles the clinical phenomenon in which individuals treated with a D2/D3 agonist appear to become hypersensitive to the rewarding effects of behaviors, but discount the negative consequences. Pramipexole (3 mg/kg) significantly increased licking; neither SCH 412348 nor ropinerole did. This represents a novel animal model of pramipexole‐induced obsessive behaviors. Taken together, these data indicate that treatment with an A2A receptor antagonist will not have the psychotic or obsessive side effects associated with pramipexole.