Nicotine at concentrations found in cigarette smokers activates and desensitizes nicotinic acetylcholine receptors in CA1 interneurons of rat hippocampus

Behavioral effects of cigarette smoking are attributed to the interactions of nicotine with brain nicotinic acetylcholine receptors (nAChRs). However, the mechanisms by which nAChR function in developing and mature brain is a ffected by a smoker's level of nicotine (50-500 nM) remain unclear. Thus, t he objective of this study was to determine the concentration- and time-dep endent effects of nicotine on alpha7 and alpha4 beta2 nAChRs, the two major brain subtypes, natively expressed in CA1 interneurons of rat hippocampal slices. Only at concentrations greater than or equal to5 muM did nicotine ( applied for 6-60 s) elicit action potentials or measurable whole-cell curre nts (EC50=158 muM) in stratum radiatum interneurons that express alpha7 nAC hRs. Continuous exposure for 10-15 min of the neurons to nicotine (0.5-2.5 muM) inhibited alpha7 nAChR-mediated currents (IC50=640 nM) evoked by choli ne (10 mM). Nicotine (greater than or equal to0.125 muM) applied to the neu rons for 1-5 min induced slowly desensitizing whole-cell currents (EC50=3.2 muM) in stratum lacunosum moleculare interneurons; this effect was mediate d by alpha4 beta2 nAChRs. Also via activation of alpha4 beta2 nAChRs, nicot ine (0.125-0.5 muM) increased the frequency and amplitude of GABAergic post synaptic currents (PSCs) in stratum radiatum interneurons. However, exposur e of the neurons for 10-15 min to nicotine (0.25-0.5 muM) resulted in desen sitization of alpha4 beta2 nAChRs. It is suggested that nanomolar concentra tions of nicotine after acute intake suppress inhibitory inputs to pyramida l cells through a disinhibitory mechanism involving activation of alpha4 be ta2 nAChRs and desensitization of alpha7 nAChRs, and after chronic intake l eads to up-regulation of both receptor subtypes via desensitization. These findings have direct implications to the actions of nicotine in cigarette s mokers. (C) 2000 Elsevier Science Ltd. All rights reserved.