Acute ethanol challenge inhibits glycogen synthase kinase-3beta in the rat prefrontal cortex.
Intracellular signalling pathways emerge as key mediators of the molecular and behavioural effects of addictive drugs including ethanol. Previously, we demonstrated that the innate high ethanol preference in AA rats is driven by dysfunctional endocannabinoid signalling in the medial prefrontal cortex (mPFC). Here, we report that acute ethanol challenge, at a dose commonly regarded as reinforcing, strongly phosphorylates glycogen synthase kinase-3beta (GSK-3beta) in this region with corresponding increased phosphorylation of AKT, a major regulator of GSK-3beta. In the non-preferring counterpart ANA line we found a weaker, AKT-independent phosphorylation of GSK-3beta by ethanol. Furthermore, AA rats showed rapid and transient dephosphorylation of ERK1/2 upon acute ethanol challenge in the medial prefrontal cortex (mPFC) and to a lesser degree in the nucleus accumbens; ANA rats were completely non-responsive for this mechanism. Together, these results identify candidate pathways for mediating high ethanol preference and emphasize the importance of the mPFC in controlling this behaviour.
Neznanova
Olga
O
Laboratory of Clinical and Translational Studies, NIAAA, National Institutes of Health, Bethesda, MD, USA.
Björk
Karl
K
Rimondini
Roberto
R
Hansson
Anita C
AC
Hyytiä
Petri
P
Heilig
Markus
M
Sommer
Wolfgang H
WH
D000818:Animals; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D000431:Ethanol / Q000008:administration & dosage*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009714:Nucleus Accumbens / Q000187:drug effects / Q000201:enzymology; D051058:Oncogene Protein v-akt / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D017397:Prefrontal Cortex / Q000187:drug effects*; D051381:Rats; D012694:Serine / Q000378:metabolism; D013912:Threonine / Q000378:metabolism
D002492:Central Nervous System Depressants; D013912:Threonine; D000431:Ethanol; D012694:Serine; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D051058:Oncogene Protein v-akt; D048052:Mitogen-Activated Protein Kinase 3; D038362:Glycogen Synthase Kinase 3