Therapeutic potential of alpha2 adrenoceptor antagonism for antipsychotic-induced extrapyramidal motor disorders

We examined the effects of JP-1302 (a selective alpha2C antagonist), BRL-44408 (a selective alpha2A antagonist) and yohimbine (a non-selective alpha2 antagonist) on haloperidol-induced bradykinesia and catalepsy in mice to elucidate the role of alpha2 adrenoceptor subtypes in modifying extrapyramidal motor disorders. JP-1302 (0.1-1 mg/kg, s.c.) dose-dependently ameliorated haloperidol-induced bradykinesia in the pole-test and reversed the catalepsy time increased by haloperidol. Antibradykinetic and anticataleptic actions of JP-1302 were statistically significant at 0.3 and 1 mg/kg, and these doses did not alter the ambulatory distance, rearing or center-perimeter residence time in the open-field test. BRL-44408 (1-10 mg/kg, s.c.) and yohimbine (0.3-3 mg/kg, i.p.) also ameliorated haloperidol-induced bradykinesia and catalepsy. However, both agents significantly decreased ambulatory distance and rearing in the open-field test, possibly reflecting their anxiogenic actions associated with alpha2A antagonism. The present study shows for the first time that blockade of alpha2C receptors can alleviate antipsychotic-induced extrapyramidal motor disorders without affecting gross behaviors.