Recent reports consistently indicate that 3H-nicotine binding, but not 125I-D-bungarotoxin binding, is upregulated in human postmortem prefrontal cortex, hippocampus, entorhinal cortex, and, to a lesser extent, striatum of smokers when compared with age-matched controls (60-62). Interestingly, nicotine binding is normalized in ex-smokers, confirming the reversibility of the upregulation of 3H-nicotine-binding sites observed in rodent brain following chronic passive nicotine administration (63,64). These results indicate that smoking and nicotine exposure produces upregulation of nAChR, most likely D4H2, but does not directly support receptor hypersensitivity, that is, increased effects of nicotine on postsynaptic target cells. Recent unpublished results obtained in rats self-administering nicotine (0.03 mg/kg/injection) for at least 3 wk (Tessari and Mugnaini, personal communication) indicate that 3H-nicotine-binding sites are upregulated in the parieto-frontal cortex, but not the VTA, suggesting a potential relevant role of the cerebral cortex in maintenance of self-administration. This interpretation is highly speculative, since it is not clear yet if this receptor upregulation stands for functional hypersensitivity (similar to denervation hypersensitivity) or reduced membrane turnover of inactivated receptors. Pharmacological and electro-physiological experiments show that prolonged exposures to nicotine produces desen-sitization of nAChR into a high-affinity binding state (53,65,66), suggesting the latter case. Finally, recent experiments in a cell line carrying heterologous D3H2 showed that a fraction of the upregulated receptor is still active (67), suggesting that a similar phenomenon may apply to in vivo receptor upregulations.
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