EVIDENCE THAT NEUROLEPTICS INCREASE STRIATAL ACETYLCHOLINE-RELEASE THROUGH STIMULATION OF DOPAMINE-D(1) RECEPTORS

The relative role of D1 and D2 dopamine receptors in the neuroleptic-i nduced increase of striatal acetylcholine (ACh) release was investigat ed using brain microdialysis in freely moving rats. Administration of (-)-sulpiride, haloperidol and clozapine, produced a dose-related incr ease in ACh release in the striatum. Maximal increase by 52, 45 and 73 % over basal values was produced by the dose of 20, 0.25 and 1 0 mg/kg i. p. of (-)-sulpiride, haloperidol and clozapine, respectively. Admi nistration of the D1 receptor antagonist SCH 23390 (0.1 mg/kg s.c.) de creased ACh output by 30%, completely suppressed the stimulant effect of (-)-sulpiride and haloperidol and only modestly reduced that of clo zapine. The inhibitory effect of SCH 23390 vs. (-)-sulpiride or halope ridol-induced ACh output was shared by SCH 39166 (1 mg/kg i.p.), anoth er specific D1 receptor antagonist. On the other hand, SCH 23390 (0.1 mg/kg s.c.) was ineffective in reducing atropine-induced increase in A Ch release. A combined treatment with reserpine (5 mg/kg i.p.) and alp ha-methyltyrosine (150 mg/kg i.p.), 6 h beforehand, prevented the enha ncement of ACh release induced by both (-)-sulpiride and haloperidol, whereas only reduced that by clozapine. The results indicate that neur oleptics increase striatal ACh release by enhancing endogenous extrace llular dopamine acting on D1 receptors, and suggest that these recepto rs play a major physiological role in controlling ACh release in the s triatum.