Initial activation of nACh receptors by agonists results in a downregulation and desensitization of the receptor, followed by receptor inactivation and a paradoxical upregulation with chronic agonist exposure.201 Postmortem studies show that smokers have increased nicotinic receptor binding in the brain compared with nonsmokers.202 This nACh receptor upregulation may contribute to the reinforcing effects of nicotine.203 PKC appears to play an important role in nACh receptor cycling. The high-affinity α4β2 nACh receptor is upregulated by chronic nicotine treatment in rats,204 and receptors containing the β2 subunit are implicated in the reinforcing properties of nicotine as mice lacking the β2 subunit show attenuated nicotine self-administration.205 Acute nicotine treatment desensitizes α4β2 nACh receptors, which can recover from desensitization if nicotine treatment is stopped.206 Inhibition of PKC with calphostin C slows recovery, whereas activation of PKC with phorbol esters enhances it.206 In addition, the α4 nicotinic subunit contains a PKC phosphorylation site at Ser-366, and mutation of this site produces receptors that show little recovery from desensitization.206 Interestingly, ethanol can also downregulate nACh receptors, an effect that is attenuated by chelerythrine.207 Chronic nicotine
