PT  - JOURNAL ARTICLE
AU  - Lei Ke
AU  - Cynthia M. Eisenhour
AU  - Merouane Bencherif
AU  - Ronald J. Lukas
TI  - Effects of Chronic Nicotine Treatment on Expression of Diverse Nicotinic Acetylcholine Receptor Subtypes. I. Dose- and Time-Dependent Effects of Nicotine Treatment
DP  - 1998 Aug 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 825--840
VI  - 286
IP  - 2
4099  - http://jpet.aspetjournals.org/content/286/2/825.short
4100  - http://jpet.aspetjournals.org/content/286/2/825.full
SO  - J Pharmacol Exp Ther1998 Aug 01; 286
AB  - Nicotinic acetylcholine receptors (nAChRs) exist as a diverse family of physiologically important ligand-gated ion channels active in classic, excitatory neurotransmission and perhaps in more novel forms of neurochemical signaling. Because of their critical functional roles centrally and peripherally, nAChRs are ideal targets for the regulation of nervous system function. nAChRs also are targets of nicotine, which acts acutely like acetylcholine to stimulate nAChR function. Here, we report studies using model cell culture systems testing the general hypothesis that more chronic nicotine exposure has unique effects on nAChRs. Chronic nicotine treatment induces increases in numbers of human muscle-type nAChRs containing alpha-1,beta-1, gamma and deltasubunits, a human ganglionic nAChR subtype containingalpha-3 and beta-4 subunits and a human ganglionic nAChR containing alpha-7 subunits in intracellular and (except for alpha-7 nAChRs) in cell surface pools. However, the half-maximal potency with which nicotine has these effects differs across these nAChR subtypes, as do rates and magnitudes of the “nicotine-induced nAChR up-regulation.” These changes in nAChR numbers are not attributable to either transient or sustained changes in nAChR subunit mRNA levels. Nicotine exposure more potently, more rapidly, and with nAChR-subtype specificity, induces two phases of losses in functional responsiveness of muscle-type nAChRs andalpha-3 beta-4 nAChRs, including a “persistent inactivation” that is distinct from classicly defined “desensitization.” Based on these results, we hypothesize that chronic nicotine treatment induces persistent functional inactivation and numerical up-regulation of all nAChR subtypes viadistinct post-transcriptional mechanisms and with potencies, at rates and with magnitudes that are nAChR-subtype specific. We also hypothesize that chronic nicotine exposure produces long-lasting changes in nervous system function, at least in part, by disabling rather than activating nicotinic cholinergic signaling. The American Society for Pharmacology and Experimental Therapeutics