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 affected by a smoker's level of nicotine (50-500 nM) remain unclear. Thus, the objective of this study was to determine the concentration- and time-dependent 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 currents (EC50=158 muM) in stratum radiatum interneurons that express alpha7 nAChRs. 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 choline (10 mM). Nicotine (greater than or equal to0.125 muM) applied to the neurons for 1-5 min induced slowly desensitizing whole-cell currents (EC50=3.2 muM) in stratum lacunosum moleculare interneurons; this effect was mediated by alpha4 beta2 nAChRs. Also via activation of alpha4 beta2 nAChRs, nicotine (0.125-0.5 muM) increased the frequency and amplitude of GABAergic postsynaptic currents (PSCs) in stratum radiatum interneurons. However, exposure of the neurons for 10-15 min to nicotine (0.25-0.5 muM) resulted in desensitization of alpha4 beta2 nAChRs. It is suggested that nanomolar concentrations of nicotine after acute intake suppress inhibitory inputs to pyramidal cells through a disinhibitory mechanism involving activation of alpha4 beta2 nAChRs and desensitization of alpha7 nAChRs, and after chronic intake leads to up-regulation of both receptor subtypes via desensitization. These findings have direct implications to the actions of nicotine in cigarette smokers. (C) 2000 Elsevier Science Ltd. All rights reserved.