Evidence that neuroleptics increase striatal acetylcholine release through stimulation of dopamine D1 receptors

The relative role of D1 and D2 dopamine receptors in the neuroleptic-induced increase of striatal acetylcholine (ACh) release was investigated using brain microdialysis in freely moving rats. Administration of (-)-sulpiride, haloperidol and clozapine, produced a dose-related increase 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 10 mg/kg i.p. of (-)-sulpiride, haloperidol and clozapine, respectively. Administration of the D1 receptor antagonist SCH 23390 (0.1 mg/kg s.c.) decreased ACh output by 30%, completely suppressed the stimulant effect of (-)-sulpiride and haloperidol and only modestly reduced that of clozapine. The inhibitory effect of SCH 23390 vs. (-)-sulpiride or haloperidol-induced ACh output was shared by SCH 39166 (1 mg/kg i.p.), another specific D1 receptor antagonist. On the other hand, SCH 23390 (0.1 mg/kg s.c.) was ineffective in reducing atropine-induced increase in ACh release. A combined treatment with reserpine (5 mg/kg i.p.) and alpha-methyltyrosine (150 mg/kg i.p.), 6 h beforehand, prevented the enhancement of ACh release induced by both (-)-sulpiride and haloperidol, whereas only reduced that by clozapine. The results indicate that neuroleptics increase striatal ACh release by enhancing endogenous extracellular dopamine acting on D1 receptors, and suggest that these receptors play a major physiological role in controlling ACh release in the striatum.