title: The role of connexin-36 gap junctions in alcohol intoxication and consumption.
abstract: 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 intoxication and consumption. 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. Compared to WT mice, Cx36 KO mice exhibited significantly more ethanol-induced motor impairment in the open field test, but less disruption in motor coordination in the rotarod paradigm. Cx36 KO mice, and WT mice treated with the Cx36 antagonist mefloquine (MFQ), consumed significantly less ethanol than their 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 GABA-mediated 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.
authors.affiliation: Department of Psychology and Physiology and Developmental Biology, Brigham Young University, Provo, Utah 84602, USA. scott_steffensen@byu.edu
authors.forename: Scott C
authors.initials: SC
authors.lastname: Steffensen
authors.forename: Katie D
authors.initials: KD
authors.lastname: Bradley
authors.forename: David M
authors.initials: DM
authors.lastname: Hansen
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Wilcox
authors.forename: Rebecca S
authors.initials: RS
authors.lastname: Wilcox
authors.forename: David W
authors.initials: DW
authors.lastname: Allison
authors.forename: Collin B
authors.initials: CB
authors.lastname: Merrill
authors.forename: Jeffrey G
authors.initials: JG
authors.lastname: Edwards
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000428:Alcohol Drinking / Q000378:metabolism*; D000435:Alcoholic Intoxication / Q000378:metabolism*; D000818:Animals; D002492:Central Nervous System Depressants / Q000633:toxicity*; D017630:Connexins / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism; D000431:Ethanol / Q000633:toxicity*; D017629:Gap Junctions / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects; D009474:Neurons / Q000187:drug effects; D018408:Patch-Clamp Techniques; D011597:Psychomotor Performance / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D009435:Synaptic Transmission / Q000187:drug effects; D017557:Ventral Tegmental Area / Q000187:drug effects / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism; D000097004:Gap Junction delta-2 Protein
chemical_list: D002492:Central Nervous System Depressants; D017630:Connexins; D004298:Dopamine; D000431:Ethanol; D005680:gamma-Aminobutyric Acid; D000097004:Gap Junction delta-2 Protein