Postsynaptic Integration of Cholinergic and Dopaminergic Signals on Medium-Sized GABAergic Projection Neurons in the Neostriatum

Abstract

The effects of cholinergic drugs and the interaction between cholinergic and dopaminergic compounds were studied on electrically evoked [ 3H]γ-aminobutyric acid (GABA) overflow in slices of the rat neostriatum. Slices were prepared and loaded with [ 3H]GABA in the presence of β-alanine and then superfused with Krebs-bicarbonate buffer containing aminooxyacetic acid and nipecotic acid to inhibit GABA uptake and metabolism, respectively. The nonselective muscarinic agonist oxotremorine (0.1–10 μM) increased the release of [ 3H]GABA and the selective M1 receptor agonist McN-A-343 (0.1–10 μM) exerted similar effect. The stimulatory effect of oxotremorine (10 μM) on [ 3H][GABA overflow was antagonized by the nonselective muscarinic antagonist atropine (1 μM) and the selective M1 receptor antagonist pirenzepine (0.1–1.0 μM). The M2 receptor antagonist methoctramine (1.0 μM) did not alter the stimulatory effect of oxotremorine. Of the muscarinic receptor antagonists atropine, pirenzepine, and methoctramine (1.0 μM) failed to affect [ 3H]GABA overflow. The M3 receptor antagonist p-F-HHSiD (1 μM) increased [ 3H]GABA overflow and p-F-HHSiD and oxotremorine were found to be additive in increasing this effect. The D2 dopamine receptor antagonist sulpiride (10 μM) increased the electrical stimulation-induced [ 3H]GABA overflow, and this stimulation was counteracted by concomitant administration of atropine (1 μM). McN-A-343 and sulpiride also increased the KCl-induced [ 3H]GABA overflow from superfused neostriatal slices and tetrodotoxin (1 μM) did not affect these stimulations. These data indicate that the release of GABA in the neostriatum is under the control of M1 stimulatory and M3 inhibitory muscarinic receptors. Dopamine, which exerts inhibition on GABA release via D2 receptors, may counteract the M1 facilitation, and M1 and D2 receptors involved in the cholinergic-dopaminergic interaction may be located postsynaptically on medium-sized spiny GABAergic projection neurons.