Molecular and physiological diversity of nicotinic acetylcholine receptors in the midbrain dopaminergic nuclei

Abstract

Nicotinic acetylcholine receptors (nAChRs) on dopaminergic (DA) and GABAergic (Gaba) projection neurons of the substantia nigra (SN) and ventral tegmental area (VTA) are characterized by single-cell RT-PCR and patch-clamp recordings in slices of rat and wild-type, β2-/-, α4-/-, and α7-/- mice. The eight nAChR subunits expressed in these nuclei, α3-7 and β2-4, contribute to four different types of nAChR-mediated currents. Most DA neurons in the SN and VTA express two nAChR subtypes. One is inhibited by dihydro-β-erythroidine (2 μM), α-conotoxin MII (10 nM) and methyllycaconitine (1 nM) but does not contain the α7 subunit; it possesses a putative α4α6α5(β2)2 composition. The other subtype is inhibited by dihydro-β-erythroidine (2 μM) and has a putative α4α5(β2)2 composition. Gaba neurons in the VTA exhibit a third subtype with a putative (α4)2(β2)3 composition, whereas Gaba neurons in the SN have either the putative (α4)2(β2)3 oligomer or the putative α4α6α5(β2)2 oligomer. The fourth subtype, a putative (α7)5 homomer, is encountered in less than half of DA and Gaba neurons, in the SN as well as in the VTA. Neurons in the DA nuclei thus exhibit a diversity of nAChRs that might differentially modulate reinforcement and motor behavior.