Up-regulation of nicotinic receptors by nicotine varies with receptor subtype

Recent evidence suggests that in addition to alpha 4 beta 2 and alpha 3-containing nicotinic receptors, alpha 6-containing receptors are present in midbrain dopaminergic neurons and involved in the nicotine reward pathway. Using heterologous expression, we found that alpha 6 beta 2, like alpha 3 beta 2 and alpha 4 beta 2 receptors, formed high affinity epibatidine binding complexes that are pentameric, trafficked to the cell surface, and produced acetylcholine-evoked currents. Chronic nicotine exposure up-regulated alpha 6 beta 2 receptors with differences in up-regulation time course and concentration dependence compared with alpha 4 beta 2 receptors, the predominant high affinity nicotine binding site in brain. The alpha 6 beta 2 receptor up-regulation required higher nicotine concentrations than for alpha 4 beta 2 but lower than for alpha 3 beta 2 receptors. The alpha 6 beta 2 up-regulation occurred 10-fold faster than for alpha 4 beta 2 and slightly faster than for alpha 3 beta 2. Our data suggest that nicotinic receptor up-regulation is subtype-specific such that alpha 6-containing receptors up-regulate in response to transient, high nicotine exposures, whereas sustained, low nicotine exposures up-regulate alpha 4 beta 2 receptors.