Ventral tegmental area (VTA) GABA neurons appear to be critical substrates underlying the acute and chronic effects of ethanol on dopamine (DA) neurotransmission in the mesocorticolimbic system implicated in alcohol reward.
The aim of this study was to examine the role of midbrain connexin-36 (Cx36) gap junctions (GJs) in ethanol's rewarding effects.
Using behavioral, molecular and electrophysiological methods we compared the effects of ethanol in mature Cx36 knockout (KO) mice and age-matched wild-type (WT) controls.
Cx36 KO mice exhibited significantly more ethanol-induced ataxia in the open field test, but less disruption in motor coordination than their WT controls in the rotarod paradigm.
Cx36 KO mice and WT mice treated with the Cx36 antagonist mefloquine (MFQ) consumed significantly less ethanol than their vehicle-treated WT controls in the drink-in-the-dark procedure.
The firing rate of VTA GABA neurons in WT mice was inhibited by ethanol with an IC50 of 0.25 g/kg, while VTA GABA neurons in KO mice were significantly less sensitive to ethanol.
Dopamine neuron sIPSC frequency was reduced by ethanol (30 mM) in WT mice, but not affected in KO mice
Cx36 KO mice evinced a significant up-regulation in DAT and D2 receptors in the VTA, as assessed by quantitative RT-PCR.
These findings demonstrate the behavioral relevance of Cx36 GJ-mediated electrical coupling between GABA neurons in mature animals, and suggest that loss of coupling between VTA GABA neurons results in disinhibition of DA neurons, a hyper-DAergic state and lowered hedonic valence for ethanol consumption.
Request Reprint E-Mail: scott_steffensen@byu.edu
