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NEUROPHARMACOLOGY

Chronic Nicotine Differentially Regulates 6- and β3-Containing Nicotinic Cholinergic Receptors in Rat Brain

Department of Pharmacology and Physiology, George Washington University, Washington, DC (D.C.P., A.B.G.); Department of Pharmacology, Georgetown University, Washington, DC (D.M., J.C.P., K.J.K.); and Department of Psychiatry, University of Utah, Salt Lake City, Utah (J.M.M.)

We investigated the effects of chronic nicotine on 6- and β3-containing nicotinic acetylcholine receptors (nAChRs) in two rat brain regions using three methodological approaches: radioligand binding, immunoprecipitation, and nicotine-stimulated synaptosomal release of dopamine. Nicotine was administered by osmotic minipumps for 2 weeks. Quantitative autoradiography with [¹²⁵I]-conotoxin MII to selectively label 6^* nAChRs showed a 28% decrease in binding in the striatum but no change in the superior colliculus. Immunoprecipitation of nAChRs labeled by [³H]epibatidine in these two regions showed that chronic nicotine increased 4- and β2-containing nAChRs by 39 to 67%. In contrast, chronic nicotine caused a 39% decrease in 6-containing nAChRs in striatum but no change in superior colliculus. No changes in β3-containing nAChRs were seen in either region after chronic nicotine. The decreased expression of 6-containing nAChRs persisted for at least 3 days, recovering to baseline by 7 days after removal of the pumps. There was a small but significant decrease in total nicotine-stimulated dopamine release in striatal synaptosomes after nicotine exposure. However, the component of dopamine release that was resistant to -conotoxin MII blockade was unaffected, whereas dopamine release that was sensitive to blockade by -conotoxin MII was decreased by 56%. These findings indicate that the 6^* nAChR is regulated differently from other nAChR subtypes, and they suggest that the inclusion of a β3 subunit with 6 may serve to inhibit nicotine-induced down-regulation of these receptors.

Address correspondence to: Kenneth J. Kellar, Department of Pharmacology, Georgetown University School of Medicine, 3900 Reservoir Road NW, Washington DC 20057. E-mail: kellark{at}georgetown.edu

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