INFLUENCE OF DOPAMINE ON GABA RELEASE IN STRIATUM - EVIDENCE FOR D-1-D-2 INTERACTIONS AND NONSYNAPTIC INFLUENCES

Striatal slices from the rat were preincubated with [H-3]GABA and supe rfused in the presence of nipecotic acid and aminooxyacetic acid, inhi bitors of high-affinity GABA transport and GABA aminotransferase, resp ectively. GABA efflux was estimated by monitoring tritium efflux, 98% of which was in the form of [H-3]GABA. The following three major obser vations were made: (1) The overflow of GABA evoked by electrical field stimulation (8 Hz) was increased two-fold by SKF-38393 (10 mu M), an agonist at the D-1 family of dopamine receptors. This increase was com pletely blocked by the D-1 receptor antagonist SCH-23390 (10 mu M). Ho wever, SCH-23390 had no effect on GABA overflow when given alone. Thus , dopamine agonists appear to exert an excitatory influence on GABA re lease; however, this effect was not elicited by endogenous dopamine un der the conditions of this experiment. (2) Electrically evoked GABA ov erflow was reduced 50%, by quinpirole (10 mu M), an agonist at the D-2 family of dopamine receptors, and this effect was blocked by the D-2 antagonist sulpiride (10 mu M). Moreover, exposure to sulpiride alone caused a 60% increase in GABA overflow, and this effect was abolished by 3-iodotyrosine (2 mM), a dopamine synthesis inhibitor. Thus, D-2 ag onists appear to exert an inhibitory influence on dopamine release, an effect that can be exerted by endogenous stores of dopamine. (3) The stimulatory effect of SKF-38393 was attenuated by quinpirole, whereas the sulpiride-induced increase in GABA efflux was attenuated by SCH-23 390. Sulpiride also increased [H-3]GABA efflux during KCl-induced depo larization, an effect that was antagonized by SCH-23390 as in the case of electrical stimulation. However, although tetrodotoxin did not alt er the stimulatory effect of sulpiride, it did block the ability of SC H-23390 to antagonize the sulpiride-induced increase in GABA overflow. These latter results suggest that there is an interaction between D-1 and D-2 receptors whereby the effects of dopamine mediated via D-1 si tes are inhibited by an action on D-2 sites. In conclusion, our result s suggest that (i) dopamine agonists can exert an excitatory influence on depolarization-induced GABA release within neostriatum via D-1 rec eptors and an inhibitory influence via D-2 receptors; (ii) under the c onditions of these experiments, endogenous dopamine fails to act on D- 1 sites but does exert an inhibitory influence via D-2 sites: and (iii ) there is an interaction between D-1 and D-2 receptors such that the actions of dopamine mediated via D-1 sites are inhibited as a result o f the concomitant actions exerted via D-2 sites. (C) 1997 IBRO.