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 α7-subunits [α7-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 α7-nAChRs, these preparations are not optimally designed for extremely rapid and reproducible drug application, and rapidly desensitized, α7-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 α7-nAChR-selective agonist, choline, blocked by the α7-nAChR- selective antagonists, methyllycaconitine and α-bungarotoxin, and are similar to those of heterologously expressed, human α7-nAChRs. We also use reverse transcriptase-polymerase chain reaction, in situ hybridization, and immunocytochemical staining to demonstrate nAChR α7 subunit gene expression as message and protein in the rat substantia nigra pars compacta and ventral tegmental area. Expression of α7 subunit message and of α7-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 α7 subunits and functional α7-nAChRs are expressed somatodendritically by midbrain DA neurons, where they may play important physiological roles and contribute to nicotine reinforcement and dependence.
|Number of pages
|Journal of Pharmacology and Experimental Therapeutics
|Published - Oct 2004
ASJC Scopus subject areas
- Molecular Medicine