Role of cortical and striatal 5-HT1A receptors in alleviating antipsychotic-induced extrapyramidal disorders.
Previous studies have revealed that 5-HT(1A) agonists ameliorate antipsychotic-induced extrapyramidal symptoms (EPS) through postsynaptic 5-HT(1A) receptors. Here, we conducted an intracerebral microinjection study of (+/-)-8-hydroxy-2-(di-n-propylamino)-tetralin ((+/-)8-OH-DPAT) to determine the action site of the 5-HT(1A) agonist in alleviating EPS. Bilateral microinjection of(+/-)8-OH-DPAT (5 microg/1microL per side) either into the primary motor cortex (MC) or the dorsolateral striatum (dlST) significantly attenuated haloperidol-induced catalepsy in rats. The anticataleptic action of (+/-)8-OH-DPAT was more prominent with the MC injection than with the dlST injection. WAY-100135 (a selective 5-HT(1A) antagonist) completely antagonized the reversal of haloperidol-induced catalepsy both by intracortical and intrastriatal (+/-)8-OH-DPAT. Furthermore, lesioning of dopamine neurons with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (30 mg/kg/day, i.p., for 4 days) did not alter the anti-EPS actions of (+/-)8-OH-DPAT in a mouse pole test. The present results strongly suggest that 5-HT(1A) agonist alleviates antipsychotic-induced EPS by activating postsynaptic 5-HT(1A) receptors in the MC and dlST, probably through non-dopaminergic mechanisms.
Shimizu
Saki
S
Laboratory of Pharmacology, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094, Japan.
Tatara
Ayaka
A
Imaki
Junta
J
Ohno
Yukihiro
Y
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D001480:Basal Ganglia Diseases / Q000139:chemically induced / Q000378:metabolism*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D006220:Haloperidol / Q000494:pharmacology*; D006892:Hydroxydopamines / Q000494:pharmacology; D008297:Male; D008845:Microinjections; D009044:Motor Cortex / Q000187:drug effects / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology; D018709:Statistics, Nonparametric
D014150:Antipsychotic Agents; D006892:Hydroxydopamines; D010879:Piperazines; D012702:Serotonin Antagonists; D044282:Receptor, Serotonin, 5-HT1A; C081293:WAY 100135; D006220:Haloperidol