The ?5 subunit regulates the expression and function of ?4*-containing neuronal nicotinic acetylcholine receptors in the ventral-tegmental area.

ABSTRACT: Human genetic association studies have shown gene variants in the ?5 subunit of the neuronal nicotinic receptor (nAChR) influence both ethanol and nicotine dependence. The ?5 subunit is an accessory subunit that facilitates ?4* nAChRs assembly in vitro. However, it is unknown whether this occurs in the brain, as there are few research tools to adequately address this question. As the ?4*-containing nAChRs are highly expressed in the ventral tegmental area (VTA) we assessed the molecular, functional and pharmacological roles of ?5 in ?4*-containing nAChRs in the VTA. We utilized transgenic mice ?5+/+(?4YFP) and ?5-/-(?4YFP) that allow the direct visualization and measurement of ?4-YFP expression and the effect of the presence (?5+/+) and absence of ?5 (-/-) subunit, as the antibodies for detecting the ?4* subunits of the nAChR are not specific. We performed voltage clamp electrophysiological experiments to study baseline nicotinic currents in VTA dopaminergic neurons. We show that in the presence of the ?5 subunit, the overall expression of ?4 subunit is increased significantly by 60% in the VTA. Furthermore, the ?5 subunit strengthens baseline nAChR currents, suggesting the increased expression of ?4* nAChRs to be likely on the cell surface. While the presence of the ?5 subunit blunts the desensitization of nAChRs following nicotine exposure, it does not alter the amount of ethanol potentiation of VTA dopaminergic neurons. Our data demonstrates a major regulatory role for the ?5 subunit in both the maintenance of ?4*-containing nAChRs expression and in modulating nicotinic currents in VTA dopaminergic neurons. Additionally, the ?5?4* nAChR in VTA dopaminergic neurons regulates the effect of nicotine but not ethanol on currents. Together, the data suggest that the ?5 subunit is critical for controlling the expression and functional role of a population of ?4*-containing nAChRs in the VTA.

SUBMITTER: Chatterjee S 

PROVIDER: S-EPMC3712017 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature