The Role on Neuronal Nicotinic Acetylcholine Receptors nAChR in Nicotine Self Administration

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When nicotine enters the brain, it binds to neuronal nicotinic acetylcholine receptors (nAChR), heterogenously expressed in central nervous system neurons (53). Much like their cousins in the neuromuscular junction, brain nAChR are probably pentameric complexes arranged around a central pore that is permeable to K+, Na+, and Ca2+ (54). In the mammalian brain, eight □ subunits (D2-D7 and □9-D10) and three □ subunits (□2-D4) are differently combined to define two principal subfamilies of receptors: the □-bungarotoxin-sensitive subfamily, consisting of homopentametic D7 nAChR sub-units, and the hetero-oligomeric subfamily, made of different combinations of the other □ subunits and the □(2-4) subunits (53,55). Experiments performed in mutant mice lacking the D7-subunit nAChR receptors indicate that practically all the high-affinity □-bungarotoxin binding found in the mouse brain is due to D7-subunit-containing nAChR (56). Similar experiments performed in mutant mice lacking the H2 (51,57) and D4 subunits (58) indicate that almost all of the high-affinity 3H-nicotine-binding sites of the mouse brain are represented by an D4H2 nAChR. However, persistence of high-affinity binding sites for other nicotinic ligands with high affinity for D4II2 receptors, such as 3H-cytisine or 3H-epibatidine, were still found in restricted brain regions of both mutant mice, in particular the medial habenula and the interpeduncular nucleus, structures known to selectively express D2W and D3^4 nAChR (59).

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