N-methyl-D-aspartate-type receptors mediate striatal ³H-acetylcholine release evoked by excitatory amino acids

Abstract

Several lines of evidence suggest that striatal cholinergic inter-neurones receive an excitatory input from the cerebral cortex which utilizes an excitatory amino acid, L-glutamate or L-aspartate, as its neurotransmitter. Cortical ablation reduces striatal high-affinity glutamate uptake^1,2 and concomitantly decreases acetylcholine turnover³. The destruction of cholinergic, as well as other, neurones of the striatum by the rigid glutamate analogue kainic acid seems to require a functional excitatory amino acid innervation^4,5. Furthermore, electron microscopic studies⁶ suggest the existence of a cortical input to the aspiny dendrites of neurones morphologically similar to the presumed striatal cholinergic interneurones^7,8. The recent discovery of preferential antagonists of amino acid-induced excitation in the vertebrate central nervous system has led to the classification of excitatory amino acid receptors into three subtypes: the N-methyl-D-aspartate (NMDA), the quisqnalate-and the kainate-preferring receptors⁹. We have now attempted to characterize the receptor(s) mediating the excitatory amino acid influence on striatal cholinergic neurones by investigating the effects of specific excitatory amino acid receptor agonists and antagonists on the release of ³H-acetylcholine from slices of the rat corpus striatum. We find that excitatory amino acid analogues evoke a tetrodotoxin-sensitive release of ³H-acetylcholine from rat striatal slices superfused in Mg²⁺-free medium, NMDA and ibotenate being the most potent and kainate and quisqualate the least potent. This effect is antagonized by Mg²⁺ and by (−)2-amino-7-phosphonoheptanoate (−APHept) and (±)2-amino-5-phosphonopentanoate (±APPent) but not by glutamic acid diethyl ester (GDEE). These data suggest the involvement of a NMDA-type receptor in the excitatory amino acid influence on striatal acetylcholine release.