CHRONIC NICOTINE EXPOSURE DIFFERENTIALLY AFFECTS THE FUNCTION OF HUMAN ALPHA-3, ALPHA-4, AND ALPHA-7 NEURONAL NICOTINIC RECEPTOR SUBTYPES

Because chronic exposure to nicotine and nicotinic drugs might both ac tivate and desensitize nicotinic acetylcholine receptors (AChRs), we s ought to determine whether prolonged exposure to nicotine concentratio ns encountered in tobacco users differentially affects electrophysiolo gical properties of major subtypes of human neuronal nicotinic AChRs. Xenopus laevis oocytes were injected with subunit cRNAs encoding (1) h omomeric alpha 7 AChRs, (2) heteromeric alpha 4 beta 2 AChRs and (3) h eteromeric alpha 3 AChRs formed from combinations of alpha 3, beta 2, beta 4 and alpha 5 cRNAs. Acute activation required micromolar concent rations of nicotine. Chronic exposure to submicromolar concentrations of nicotine irreversibly inactivated many alpha 4 beta 2 AChRs and alp ha 7 AChRs but inhibited alpha 3 AChRs much less. Thus, although alpha 3 AChRs are present in the brain in much smaller amounts than are alp ha 4 beta 2 AChRs or alpha 7 AChRs, alpha 3 AChRs in brain and autonom ic ganglia may be able to play a relatively large role in acute respon ses to endogenous ACh or subsequent doses of nicotine after chronic ex posure to nicotine. The behavioral effects of nicotine may typically r eflect the sustained inhibition of alpha 4 beta 2 AChRs and alpha 7 AC hRs in combination with the residual susceptibility of alpha 3 AChRs a nd perhaps some other AChR subtypes for acute activation. Tolerance fo r nicotine exhibited by tobacco users may reflect the long-term irreve rsible functional inactivation of alpha 4 beta 2 AChRs and alpha 7 ACh Rs produced by chronic exposure to nicotine.