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Up-Regulation of Brain Nicotinic Acetylcholine Receptors in the Rat during Long-Term Self-Administration of Nicotine: Disproportionate Increase of the 6 Subunit

Department of Pharmacology, University of Tennessee Health Science Center, Memphis, Tennessee (S.L.P.,Y.F., K.M., B.M.S.); Department of Pharmacology, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania (J.L., J.M.L.); and Departments of Psychiatry and Biology, University of Utah, Salt Lake City, Utah (J.M.M.)

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 4, 6, and 2 subunits. As a consequence of long-term self-administration of nicotine, the 6 immunoreactive (IR) binding of either labeled Epb or ¹²⁵I--conotoxin MII increased to a much greater extent than did 4 or 2 IR binding of Epb. In addition, the 2 IR binding of Epb was consistently enhanced to a greater extent than was 4. These findings may reflect a larger surface membrane retention of 6-containing and, to some degree, 2-containing nAChRs compared with 4-containing nAChRs during long-term self-administration of nicotine.

Address correspondence to: Dr. Burt M. Sharp, Department of Pharmacology, University of Tennessee College of Medicine, 874 Union Avenue, Memphis, TN 38163. E-mail: bsharp{at}utmem.edu

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