Serotonergic modulation of extrapyramidal motor disorders in mice and rats: role of striatal 5-HT3 and 5-HT6 receptors.
Previous studies showed that 5-HT(1A) and 5-HT(2) 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-HT(3) ∼5-HT(7) 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 (25-100mg/kg, i.p.) dose-dependently enhanced HAL (0.3mg/kg, i.p.)-induced bradykinesia and catalepsy. The potentiation of HAL-induced EPS by 5-HTP (50mg/kg, i.p.) was significantly inhibited by ritanserin (5-HT(2) antagonist, 0.3-3mg/kg, i.p.), ondansetron (5-HT(3) antagonist, 0.1-1mg/kg, i.p.), or SB-258585 (5-HT(6) antagonist, 1-10mg/kg, i.p.) in a dose-dependent manner. However, neither WAY-100135 (5-HT(1A) antagonist, 1-10mg/kg, i.p.), GR-125487 (5-HT(4) antagonist, 1-10mg/kg, i.p.), SB-699551 (5-HT(5A) antagonist, 1-10mg/kg, i.p.) nor SB-269970 (5-HT(7) antagonist, 1-10mg/kg, i.p.) reduced the 5-HTP and HAL-induced bradykinesia or catalepsy. In addition, both ondansetron (0.1-1mg/kg, i.p.) and SB-258585 (3 and 10mg/kg, i.p.) also alleviated bradykinesia and catalepsy induced by HAL (0.5mg/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-HT(3) and 5-HT(6) receptors and the antagonism of these receptors effectively alleviates antipsychotic-induced EPS.
Ohno
Yukihiro
Y
Laboratory of Pharmacology, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094, Japan. yohno@gly.oups.ac.jp
Imaki
Junta
J
Mae
Yukari
Y
Takahashi
Tsuyoshi
T
Tatara
Ayaka
A
D000818:Animals; D001480:Basal Ganglia Diseases / Q000188:drug therapy* / Q000503:physiopathology*; D003342:Corpus Striatum / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051379:Mice; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000378:metabolism / Q000502:physiology*; D044406:Receptors, Serotonin, 5-HT3 / Q000378:metabolism / Q000502:physiology*; D012702:Serotonin Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology
D011985:Receptors, Serotonin; D044406:Receptors, Serotonin, 5-HT3; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; C097216:serotonin 6 receptor