Up-Regulation of Brain Nicotinic Acetylcholine Receptors in the Rat during Long-Term Self-Administration of Nicotine: Disproportionate Increase of the α6 Subunit

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Abstract
In male rats continually self-administering nicotine (approximately 1.5 mg free base/kg/day), we found a significant increase of nicotinic acetylcholine receptors (nAChRs) labeled by epibatidine (Epb) in 11 brain areas. A large increase of high-affinity Epb binding sites was apparent in the ventral tegmentum/substantia nigra, nucleus tractus solitarii, nucleus accumbens, thalamus/subthalamus, parietal cortex, hypothalamus, and amygdala. A smaller but significant up-regulation of high-affinity Epb sites was seen in the piriform cortex, hippocampus, caudate/putamen, and cerebellar cortex. The up-regulation of nAChRs, shown by immunoadsorption and Western blotting, involved α4, α6, and β2 subunits. As a consequence of long-term self-administration of nicotine, the α6 immunoreactive (IR) binding of either labeled Epb or 125I-α-conotoxin MII increased to a much greater extent than did α4 or β2 IR binding of Epb. In addition, the β2 IR binding of Epb was consistently enhanced to a greater extent than was α4. These findings may reflect a larger surface membrane retention of α6-containing and, to some degree, β2-containing nAChRs compared with α4-containing nAChRs during long-term self-administration of nicotine.