Effects of SM-9018, a novel 5-HT2 and D2 receptor antagonist, on electrically-evoked [3H]acetylcholine release from rat striatal slices.

ABSTRACT

1. Electrical stimulation (1 Hz) of striatal slices evoked Ca(+2)-dependent [3H]ACh release, which was inhibited by the D2 agonist quinpirole (QPL). 2. SM-9018 and other neuroleptics antagonized the QPL-induced inhibition of the evoked [3H]ACh release. The relative potencies of the neuroleptics in antagonizing the QPL action were nemonapride > haloperidol approximately equal to SM-9018 > > chlorpromazine > > SCH 23390, and the rank order, except for nemonapride, was consistent with their binding affinities to striatal D2 receptors. 3. SM-9018 was weaker than haloperidol in enhancing the [3H]ACh release evoked by higher frequency (3 Hz) stimulation, the enhancement being abolished by the depletion of endogenous dopamine with reserpine pretreatment. 4. The selective 5-HT2 antagonist LY 53857 significantly attenuated the stimulatory effects of haloperidol on the 3 Hz-evoked [3H]ACh release. 5. These findings suggest that SM-9018 is as potent as haloperidol in antagonizing the QPL action on [3H]ACh release at striatal D2 receptors, but is weaker than haloperidol in enhancing the [3H]ACh release under high-frequency stimulation. The 5-HT2 blocking activity of SM-9018 seems to be involved in the latter effects.