Effect of SCH 39166, a novel dopamine D 1 receptor antagonist, on [ 3H]acetylcholine release in rat striatal slices

Abstract

SCH 39166 is a novel and selective dopamine D 1 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 D 1 receptor selectivity and to address its EPS liability. Electrically stimulated [ 3H]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 [ 3H]ACh release. Results indicated that apomorphine inhibited [ 3H]ACh release from striatal slices (IC 50 = 0.31 μM). (−)-Sulpiride and haloperidol completely reversed the inhibition of [ 3H]ACh release seen with apomorphine. In contrast, SCH 39166, as well as, SCH 23390 did not reverse the inhibition of [ 3H]ACh release induced by apomorphine. These findings indicate that dopamine D 2 receptors are primarily involved in modulation of [ 3H]ACh release, Furthermore, selective dopamine D 1 receptor antagonists, such as SCH 39166, are ineffective in modulating striatal [ 3H]ACh release, suggesting that striatal cholinergic hyperactivity and possibly EPS will not be a consequence of dopamine D 1 receptor blockade.