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

Abstract

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 α7 nAChRs can be inhibited non-competitively by naltrexone (IC 50∼25 μM). The voltage dependence of the effect suggested that naltrexone acts as an open-channel blocker of α7 nAChRs. Naltrexone also inhibited activation of α4β2 nAChRs in hippocampal neurons; however its IC 50 was higher (∼141 μM). At a concentration as high as 300 μM (which is sufficient to block by 100% and 70% the activity of α7 and α4β2 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 μM) or nicotine (10 μM, a concentration that fully desensitized α7 nAChRs) resulted in a 2-fold increase in the average amplitude of α7 nAChR-subserved currents. Naltrexone did not augment the maximal up-regulation of α7 nAChRs induced by nicotine, indicating that both drugs act via a common mechanism. In addition to increasing α7 nAChRs-mediated responses per neuron, nicotine increased the number of neurons expressing functional non-α7 nAChRs (probably α4β2 nAChRs); this effect was blocked by naltrexone (0.3 and 30 μM). Therefore, naltrexone may affect dependence on cigarette smoking by differentially altering function and expression of α7 and α4β2 nAChRs in the central nervous system.