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.
Imaki
Junta
J
Laboratory of Pharmacology, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094, Japan.
Mae
Yukari
Y
Shimizu
Saki
S
Ohno
Yukihiro
Y
D000166:Acridines / Q000627:therapeutic use; D058669:Adrenergic alpha-2 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists / Q000627:therapeutic use; D000704:Analysis of Variance; D000818:Animals; D014150:Antipsychotic Agents / Q000633:toxicity; D002375:Catalepsy / Q000139:chemically induced / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D006220:Haloperidol / Q000633:toxicity*; D018476:Hypokinesia / Q000139:chemically induced / Q000188:drug therapy*; D007093:Imidazoles / Q000627:therapeutic use; D054833:Isoindoles / Q000627:therapeutic use; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D010879:Piperazines / Q000627:therapeutic use; D015016:Yohimbine / Q000627:therapeutic use
D000166:Acridines; D058669:Adrenergic alpha-2 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists; D014150:Antipsychotic Agents; D007093:Imidazoles; D054833:Isoindoles; C518829:JP-1302; D010879:Piperazines; D015016:Yohimbine; D006220:Haloperidol; C072125:BRL 44408