PRESYNAPTIC NICOTINIC ACETYLCHOLINE-RECEPTORS IN THE BRAIN

Nicotine, acting through nicotinic acetylcholine receptors (nAChR) loc ated on nerve terminals, can evoke the release of various neurotransmi tters in the brain. The presynaptic nicotinic stimulation of acetylcho line release, demonstrated in cortical and hippocampal preparations, m ay reflect a positive feedback mechanism via autoreceptors. This site is a target for novel nicotinic agonists in the symptomatic treatment of Alzheimer's disease. Nicotinic heteroreceptors can modulate the rel ease of catecholamines and amino acid transmitters in diverse brain re gions. Differences in agonist potency and efficacy and in antagonist s ensitivities between different transmitter pathways suggests heterogen eity of subtypes of presynaptic nAChR (notably between alpha 3- and al pha 4-containing nAChR). While neurochemical studies have failed to fi nd any evidence for the involvement of alpha 7-type nAChR in the presy naptic modulation of transmitter release, recent electrophysiological studies have disclosed this as a possibility with respect to glutamate transmission. Investigation of the mechanisms coupling nAChR activati on to exocytosis suggests that despite their high relative permeabilit y to Ca2+, nAChR on striatal terminals promote dopamine release by ope ning voltage-sensitive Ca2+ channels, principally N-type channels. Com parison of in vitro preparations with in vivo studies confirms that ni cotine (administered via a microdialysis probe) can elicit dopamine re lease from the terminal fields of the three major dopamine pathways: T his is dose dependent and mecamylamine sensitive. However, release fro m striatum and accumbens (but not frontal cortex) is completely blocke d by tetrodotoxin, compared with a partial block (40%) of release from synaptosomes. In vivo, nicotine may be able to influence dopamine rel ease by acting on 1) ''pre-terminal'' nAChR, 2) presynaptic nAChR on a djacent glutamatergic terminals, or 3) local interneurones bearing nAC hR, in addition to a direct action th rough presynaptic nAChR on dopam inergic terminals. Thus, a complex picture is emerging of various loci at which nicotine and other agonists can act through a variety of nAC hR subtypes to influence neurotransmitter release: The significance of this phenomenon for synaptic transmission is discussed. (C) 1996 Wile y-Liss, Inc.