Gifford A N, Johnson K M
Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston 77555-1031.
Eur J Pharmacol. 1993 Jun 24;237(2-3):169-75. doi: 10.1016/0014-2999(93)90265-j.
To examine the proposal that (+)-AJ 76 and (+)-UH 232 are dopamine receptor antagonists showing preference for the dopamine autoreceptors over postsynaptic dopamine receptors, the potencies of these two compounds, as well as several typical and atypical antipsychotic drugs, were compared in a model for presynaptic dopamine autoreceptors: reversal of the quinpirole-induced inhibition of [3H]dopamine release from striatal slices, and in two models for postsynaptic dopamine receptors: reversal of the quinpirole-induced inhibition of [14C]acetylcholine release from striatal slices and competition for [3H]spiperone binding in striatal homogenates. The IC50 values of the antipsychotic drugs, as well as (+)-AJ 76 and (+)-UH 232, against [3H]dopamine release correlated closely with their IC50 values against [14C]acetylcholine release and Ki values against [3H]spiperone binding, thus suggesting a close pharmacological similarity between these three populations of dopamine receptors. This implies that previous biochemical and behavioral findings obtained with (+)-AJ 76 and (+)-UH 232 cannot be explained by a selective action of these compounds on terminal dopamine autoreceptors regulating dopamine release, at least relative to the postsynaptic dopamine receptors on cholinergic neurons. Furthermore, comparison of the IC50 values for the drugs tested in our transmitter release assays with previously published values of their affinity for cloned dopamine D2, D3 and D4 receptors suggested that the dopamine receptors controlling both dopamine and acetylcholine release were by far most similar to dopamine D2 receptors.
为了检验(+)-AJ 76和(+)-UH 232是对多巴胺自身受体比对突触后多巴胺受体更具选择性的多巴胺受体拮抗剂这一假设，在一个用于突触前多巴胺自身受体的模型中，比较了这两种化合物以及几种典型和非典型抗精神病药物的效力：对喹吡罗诱导的纹状体切片中[3H]多巴胺释放抑制的逆转；在两个用于突触后多巴胺受体的模型中：对喹吡罗诱导的纹状体切片中[14C]乙酰胆碱释放抑制的逆转以及在纹状体匀浆中对[3H]螺哌隆结合的竞争。抗精神病药物以及(+)-AJ 76和(+)-UH 232对[3H]多巴胺释放的IC50值与其对[14C]乙酰胆碱释放的IC50值以及对[3H]螺哌隆结合的Ki值密切相关，因此表明这三类多巴胺受体在药理学上具有密切相似性。这意味着，至少相对于胆碱能神经元上的突触后多巴胺受体而言，先前用(+)-AJ 76和(+)-UH 232获得的生化和行为学结果不能用这些化合物对调节多巴胺释放的终末多巴胺自身受体的选择性作用来解释。此外，将我们在递质释放试验中测试的药物的IC50值与先前发表的它们对克隆的多巴胺D2、D3和D4受体的亲和力值进行比较表明，控制多巴胺和乙酰胆碱释放的多巴胺受体与多巴胺D2受体最为相似。
