INVITRO ACETYLCHOLINE-RELEASE FROM RAT CAUDATE-NUCLEUS AS A NEW MODEL FOR TESTING DRUGS WITH DOPAMINE-RECEPTOR ACTIVITY

The effects of a number of dopamine-receptor agonists on depolarization-induced (26 mM K+) release of 3H-acetylcholine from slices of rat caudate nucleus were examined with a superfusion method. Apomorphine (10-6 M) and N,N-dipropyliso-ADTN (10-7 M) inhibited acetylcholine-release in vitro by about 50% and these inhibitory effects were antagonized by haloperidol. For N,N-dipropyl-iso-ADTN an EC50 of approximately 3×10-9 M was estimated from its dose-response curve. However, dopamine (10-6 M) itself and bromocriptine (10-6 M) inhibited acetylcholine-release less. Presumably: the weak effect of exogenous dopamine is due to its (partial) uptake in dopaminergic nerve terminals and to the fact that released endogenous dopamine already partially activates the receptors involved in the inhibition of acetylcholine-release. Pretreatment of young rats with 6-hydroxydopamine (+ desipramine) increased the inhibitory effects of dopamine-receptor agonists, including dopamine itself, on acetylcholine-release from caudate slices, indicating dopamine-receptor supersensitivity. This was corroborated by the finding that apomorphine-induced stereotyped behavior was significantly higher in rats lesioned with 6-hydroxydopamine than in controls. It is suggested that K+-induced release of radiolabelled acetylcholine from caudate nucleus slices provides a functional model to study the characteristics of post-synaptic dopamine-receptors in vitro. The concentrations of dopamine-receptor agonists needed to inhibit acetylcholine-release appear to be in the nanomolar range, in agreement with their affinities as determined in dopamine-receptor binding studies. In contrast, these concentrations are much lower than those required for stimulation of dopamine-sensitive adenylate cyclase activity. © 1979 Springer-Verlag.