Up-regulation of Nicotinic Receptors by Nicotine Varies with Receptor Subtype

Abstract Recent evidence suggests that in addition to α4β2 and α3-containing nicotinic receptors, α6-containing receptors are present in midbrain dopaminergic neurons and involved in the nicotine reward pathway. Using heterologous expression, we found that α6β2, like α3β2 and α4β2 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 α6β2 receptors with differences in up-regulation time course and concentration dependence compared with α4β2 receptors, the predominant high affinity nicotine binding site in brain. The α6β2 receptor up-regulation required higher nicotine concentrations than for α4β2 but lower than for α3β2 receptors. The α6β2 up-regulation occurred 10-fold faster than for α4β2 and slightly faster than for α3β2. Our data suggest that nicotinic receptor up-regulation is subtype-specific such that α6-containing receptors up-regulate in response to transient, high nicotine exposures, whereas sustained, low nicotine exposures up-regulate α4β2 receptors.