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NEUROPHARMACOLOGY

Electrophysiological, Pharmacological, and Molecular Evidence for 7-Nicotinic Acetylcholine Receptors in Rat Midbrain Dopamine Neurons

Divisions of Neurology (J.W.) and Neurobiology (A.A.G., K.M.S., L.X., S.M.-M., L.L., R.J.L.), Barrow Neurological Institute, Phoenix, Arizona

Dopamine (DA) neurons located in the mammalian midbrain have been generally implicated in reward and drug reinforcement and more specifically in nicotine dependence. However, roles played by nicotinic acetylcholine receptors, including those composed of 7-subunits [7-nicotinic acetylcholine receptors (nAChRs)], in modulation of DA signaling and in nicotine dependence are not clearly understood. Although midbrain slice recording has been used previously to identify functional 7-nAChRs, these preparations are not optimally designed for extremely rapid and reproducible drug application, and rapidly desensitized, 7-nAChR-mediated currents may have been underestimated or not detected. Here, we use patch-clamp, whole-cell current recordings from single neurons acutely dissociated from midbrain nuclei and having features of DA neurons to characterize acetylcholine-induced, inward currents that rapidly activate and desensitize, are mimicked by the 7-nAChR-selective agonist, choline, blocked by the 7-nAChR-selective antagonists, methyllycaconitine and -bungarotoxin, and are similar to those of heterologously expressed, human 7-nAChRs. We also use reverse transcriptase-polymerase chain reaction, in situ hybridization, and immunocytochemical staining to demonstrate nAChR 7 subunit gene expression as message and protein in the rat substantia nigra pars compacta and ventral tegmental area. Expression of 7 subunit message and of 7-nAChR-mediated responses is developmentally regulated, with both being absent in samples taken from rats at postnatal day 7, but later becoming present and increasing over the next 2 weeks. Collectively, this electrophysiological, pharmacological, and molecular evidence indicates that nAChR 7 subunits and functional 7-nAChRs are expressed somatodendritically by midbrain DA neurons, where they may play important physiological roles and contribute to nicotine reinforcement and dependence.

Address correspondence to: Dr. Jie Wu, Division of Neurology, Barrow Neurological Institute, 350 West Thomas Road, Phoenix, AZ 85013-4496. E-mail: jwu2{at}chw.edu

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