MUSCIMOL INCREASES ACETYLCHOLINE-RELEASE BY DIRECTLY STIMULATING ADULT STRIATAL CHOLINERGIC INTERNEURONS

Because GabaA ligands increase acetylcholine (ACh) release from adult striatal slices, we hypothesized that activation of GabaA receptors on striatal cholinergic interneurons directly stimulates ACh secretion. Fractional [H-3]ACh release was recorded during perifusion of acutely dissociated, [H-3]choline-labeled, adult male rat striata. The GabaA a gonist, muscimol, immediately stimulated release maximally similar to 300% with EC50 = similar to 1 mu M. This action was enhanced by the al losteric GabaA receptor modulators, diazepam and secobarbital, and inh ibited by the GabaA antagonist, bicuculline, by ligands for D2 or musc arinic cholinergic receptors or by low calcium buffer, tetrodotoxin or vesamicol. Membrane depolarization inversely regulated muscimol-stimu lated secretion. Release of endogenous and newly synthesized ACh was s timulated in parallel by muscimol without changing choline release. Mu scimol pretreatment inhibited release evoked by K+ depolarization or b y receptor-mediated stimulation with glutamate. Thus, GabaA receptors on adult striatal cholinergic interneurons directly stimulate voltage- and calcium-dependent exocytosis of ACh stored in vesamicol-sensitive synaptic vesicles. The action depends on the state of membrane polariz ation and apparently depolarizes the membrane in turn. This functional assay demonstrates that excitatory GabaA actions are not limited to n eonatal tissues. GabaA-stimulated ACh release may be prevented in situ by normal tonic dopaminergic and muscarinic input to cholinergic neur ons. (C) 1998 Elsevier Science B.V.