EFFECT OF SCH-39166, A NOVEL DOPAMINE-D1 RECEPTOR ANTAGONIST, ON [H-3] ACETYLCHOLINE-RELEASE IN RAT STRIATAL SLICES

SCH 39166 is a novel and selective dopamine D1 receptor antagonist. It has been reported to have potential antipsychotic properties and reduced extrapyramidal side-effect liabilities (EPS). The current studies investigated the pharmacological effects of SCH 39166 on striatal cholinergic function in order to further characterize its dopamine D1 receptor selectivity and to address its EPS liability. Electrically stimulated [H-3]acetylcholine (ACh) release from rat striatal slices was measured and comparisons were made between SCH 39166, SCH 23390, (-)-sulpiride, haloperidol or apomorphine on their effect on [H-3]ACh release. Results indicated that apomorphine inhibited [H-3]ACh release from striatal slices (IC50 = 0.31-mu-M). (-)-Sulpiride and haloperidol completely reversed the inhibition of [H-3]ACh release seen with apomorphine. In contrast, SCH 39166, as well as, SCH 23390 did not reverse the inhibition of [H-3]ACh release induced by apomorphine. These findings indicate that dopamine D2 receptors are primarily involved in modulation of [H-3]ACh release. Furthermore, selective dopamine D1 receptor antagonists, such as SCH 39166, are ineffective in modulating striatal [H-3]ACh release, suggesting that striatal cholinergic hyperactivity and possibly EPS will not be a consequence of dopamine D1 receptor blockade.