A pharmacological analysis of the effects of (+)-AJ 76 and (+)-UH 232 at release regulating pre- and postsynaptic receptors

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 quinpiroleinduced 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, againts [²H]dopamine release correlated closely with their IC₅₀ values against [¹⁴C]acetylcholine release and K_i values againts [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 teh 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.