UP-REGULATION OF NICOTINIC ACETYLCHOLINE-RECEPTORS FOLLOWING CHRONIC EXPOSURE OF RATS TO MAINSTREAM CIGARETTE-SMOKE OR ALPHA-4-BETA-2 RECEPTORS TO NICOTINE

Smokers are reported to have a higher density of central nicotinic ace tylcholine receptors (nAChRs) that non-smokers at autopsy. Whether thi s increased receptor density is a response to smoking or a result of g enetic variability is not known. While sub-chronic treatment of rats a nd mice with nicotine results in up-regulation of central nAChRs, chan ges in receptor density in response to cigarette smoke have not been s tudied previously. In this study, male Sprague-Dawley rats were expose d nose-only for 13 weeks to mainstream cigarette smoke followed by ass essment of [H-3]nicotine binding in five brain regions of smoke- and s ham-exposed animals. In smoke-exposed animals, there was a significant increase in nAChR density in the cortex, striatum, and cerebellum (35 , 25, and 31% increases, respectively), while there was no significant change in receptor density in the thalamus and hippocampus. Smoke exp osure did not alter markedly the affinity of the receptor for nicotine in these brain regions. Furthermore, up-regulation of nAChRs did not alter the biphasic binding properties by which nicotine binds to its r eceptor. There were no changes in the association (fast phase) or isom erization (slow phase) rate constants, and the percent contribution of slow and fast phase binding to nAChRs was not altered in the up-regul ated receptor population compared with control. Similar results were o bserved following chronic nicotine exposure of cultured cortical cells from fetal rat brain or cells transfected with the alpha 4 beta 2 nAC hR subtype. These results show that the up-regulation following smoke exposure in the rat is phenomenologically similar to that observed in vitro. These data provide preliminary evidence for a relationship betw een cigarette smoking and nAChR up-regulation in vivo and suggest that similar mechanisms of upregulation may underlie chronic smoke exposur e of live animals and nicotine exposure of artificially expressed alph a 4 beta 2 receptors in vitro.