Role of cortical and striatal 5-HT1A receptors in alleviating antipsychotic-induced extrapyramidal disorders

Previous studies have revealed that 5-HT1A agonists ameliorate antipsychotic-induced extrapyramidal symptoms (EPS) through postsynaptic 5-HT1A 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-HT1A agonist in alleviating EPS. Bilateral microinjection of(±)8-OH-DPAT (5 µg/1 µL 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-HT1A 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-HT1A agonist alleviates antipsychotic-induced EPS by activating postsynaptic 5-HT1A receptors in the MC and dlST, probably through non-dopaminergic mechanisms.