A primary mechanism underlying long-lasting synaptic plasticity is a change in the number or expression of membrane-bound receptors. Long-term exposure to nicotine induces an up-regulation of specific subtypes of nAChRs and increases the number of high-affinity nicotinic binding sites across multiple brain regions in the brains of postmortem human smokers (Perry et al., 1999) and nicotine-treated rodents (Schwartz and Kellar, 1983; Flores et al., 1992; Marks et al., 1992; Gentry and Lukas, 2002). The concept of up-regulation of nAChRs is somewhat unexpected and contradictory to what the homeostatic model would predict. Following chronic drug use, receptors are usually down regulated in response to excessive stimulation as an adaptive mechanism to adjust the neural network to a pre-exposure point. Evidence suggests that nicotine causes a rapid desensitization of nAChRs, and this loss in receptor function would promote up-regulation to compensate for the diminished signaling of inactivated receptors over prolonged periods of time (Fenster et al., 1999a,b). These changes result in higher sensitivity to nicotine and have been correlated with nicotine addiction [see review, Govind et al. (2009)].
