The opioid antagonist naltrexone inhibits activity and alters expression of α7 and α4β2 nicotinic receptors in hippocampal neurons:: implications for smoking cessation programs

This study was designed to investigate whether naltrexone, an opioid antagonist that has been evaluated clinically as a co-adjuvant in smoking cessation programs, affects function and expression of neuronal nicotinic receptors (nAChRs). Whole-cell current recordings from rat hippocampal neurons in culture and in slices demonstrated that alpha7 nAChRs can be inhibited non-competitively by naltrexone (IC(50)similar to 25 muM). The voltage dependence of the effect suggested that naltrexone acts as an open-channel blocker of alpha7 nAChRs. Naltrexone also inhibited activation of alpha4 beta2 nAChRs in hippocampal neurons; however its IC50 was higher (similar to 141 muM). At a concentration as high as 300 muM (which is sufficient to block by 100% and 70% the activity of alpha7 and alpha4 beta2 nAChRs, respectively), naltrexone had no effect on kainate and AMPA receptors, blocked by no more than 20% the activity of NMDA and glycine receptors, and reduced by 35% the activity of GABA(A) receptors. A 3-day exposure of cultured hippocampal neurons to naltrexone (30 muM) or nicotine (10 muM, a concentration that fully desensitized alpha7 nAChRs) resulted in a 2-fold increase in the average amplitude of alpha7 nAChR-subserved currents. Naltrexone did not augment the maximal up-regulation of alpha7 nAChRs induced by nicotine, indicating that both drugs act via a common mechanism. In addition to increasing alpha7 nAChRs-mediated responses per neuron, nicotine increased the number of neurons expressing functional non-alpha7 nAChRs (probably alpha4 beta2 nAChRs); this effect was blocked by naltrexone (0.3 and 30 muM). Therefore, naltrexone may affect dependence on cigarette smoking by differentially altering function and expression of alpha7 and alpha4 beta2 nAChRs in the central nervous system. (C) 2000 Elsevier Science Ltd. All rights reserved.