Haloperidol-induced catalepsy, a model of acute antipsychotic-induced extrapyramidal side effects, is altered by inhibiting and inducing CYP2D in rat brain

Previous studies showed that 5-HT1A and 5-HT2 receptors play an important role in controlling the extrapyramidal motor disorders. However, the functions of other 5-HT receptor subtypes remain elusive. To elucidate the role of 5-HT receptors, specifically of 5-HT3∼5-HT7 subtypes, in modifying antipsychotic- induced extrapyramidal side effects (EPS), we studied the effects of the 5-HT stimulant 5-hydroxytryptophan (5-HTP) and various 5-HT receptor antagonists on haloperidol (HAL)-induced bradykinesia and catalepsy in mice and rats. Pretreatment of mice with 5-HTP (25–100 mg/kg, i.p.) dose-dependently enhanced HAL (0.3 mg/kg, i.p.)-induced bradykinesia and catalepsy. The potentiation of HAL-induced EPS by 5-HTP (50 mg/kg, i.p.) was significantly inhibited by ritanserin (5-HT2 antagonist, 0.3-3 mg/kg, i.p.), ondansetron (5-HT3 antagonist, 0.1–1 mg/kg, i.p.), or SB-258585 (5-HT6 antagonist, 1–10 mg/kg, i.p.) in a dose-dependent manner. However, neither WAY-100135 (5-HT1A antagonist, 1–10 mg/kg, i.p.), GR-125487 (5-HT4 antagonist, 1–10 mg/kg, i.p.), SB-699551 (5-HT5A antagonist, 1–10 mg/kg, i.p.) nor SB-269970 (5-HT7 antagonist, 1–10 mg/kg, i.p.) reduced the 5-HTP and HAL-induced bradykinesia or catalepsy. In addition, both ondansetron (0.1–1 mg/kg, i.p.) and SB-258585 (3 and 10 mg/kg, i.p.) also alleviated bradykinesia and catalepsy induced by HAL (0.5 mg/kg, i.p.) alone in mice. Furthermore, bilateral microinjection of ondansetron (5 μg (13.7 nmol) per side) or SB-258585 (5 μg (8.92 nmol) per side) into the dorsolateral striatum (dlST) attenuated haloperidol-induced catalepsy in rats. These results suggest that serotonergic stimulation augments extrapyramidal motor disorders by activating the striatal 5-HT3 and 5-HT6 receptors and the antagonism of these receptors effectively alleviates antipsychotic-induced EPS.