CONTRIBUTION OF NICOTINIC RECEPTORS TO THE FUNCTION OF SYNAPSES IN THE CENTRAL-NERVOUS-SYSTEM - THE ACTION OF CHOLINE AS A SELECTIVE AGONIST OF ALPHA-7 RECEPTORS

The alpha 7-nicotinic receptor (nAChR)-selective agonist choline and n AChR-subtype-selective antagonists led to the discovery that activatio n of both alpha 7 and alpha 4 beta 2 nAChRs located in CA1 interneuron s in slices taken from the rat hippocampus facilitates the tetrodotoxi n (TTX)-sensitive release of gamma-aminobutyric acid (GABA). Experimen ts carried out in cultured hippocampal neurons not only confirmed that preterminal alpha 7 and alpha 4 beta 2 nAChRs modulate the TTX-sensit ive release of GABA, bur also demonstrated that evoked release of GABA is reduced by rapid exposure of the neurons to acetylcholine (ACh, 10 mu M-1 mM) in the presence of the muscarinic receptor antagonist atro pine (1 mu M). This effect of ACh, which is fully reversible and conce ntration-dependent, is partially blocked by superfusion of the culture d neurons with external solution containing either the alpha 7-nAChR-s elective antagonist methyllycaconitine (MLA, 1 nM) or the alpha 4 beta 2-nAChR-selective antagonist dihydro-beta-erythroidine (DH beta E, 10 0 nM). A complete blockade of ACh-induced reduction of evoked release of GABA was achieved only when the neurons were perfused with external solution containing both MLA and DH beta E, suggesting that activatio n of both alpha 7 and alpha 4 beta 2 nAChRs modulates the evoked relea se of GABA from hippocampal neurons. Such mechanisms may account for t he apparent involvement of nAChRs in the psychological effects of toba cco smoking, in brain disorders (e.g., schizophrenia and epilepsy), an d in physiological processes, including cognition and nociception. ((C )Elsevier, Paris).