Cold Turkey and MAP Kinase

Abstract

Glial cell line-derived neurotrophic factor (GDNF) acts in the ventral tegmental area (VTA) of the brain, a brain region associated with drug-seeking behavior, to decrease self-administration of ethanol in mice. Its receptor is a complex that includes a glycosyl-phosphatidylinositol-linked GDNF family receptor and the receptor tyrosine kinase Ret. Carnicella et al . further explored the signaling mechanisms of GDNF and its effects on ethanol-drinking behavior. Administration of GDNF into the VTA, but not other nearby brain areas, reduced the frequency with which mice activated a lever that administered a dose of ethanol. After treatment of animals with GDNF or saline solution, initial rates of lever pressing for an ethanol reward were similar, but GDNF-treated animals repeated the ethanol-seeking behavior less often and terminated sessions of drinking earlier than did control animals. These effects were evident within 10 minutes after administration of GDNF and were associated with increased activity of the mitogen-activated protein kinases (MAPKs) ERK1 and 2 (ERK1/2). Pharmacological inhibition of the MAPK pathway prevented the effects of GDNF. Administration of GDNF also was effective in a mouse model of relapse of drinking behavior after a period of extinction of the behavior. The authors conclude that GDNF appears to reduce the incentive value of alcohol and the strength of behavioral reinforcement associated with alcohol consumption. Interestingly, GDNF did not alter self-administration of a "natural" reward such as sucrose. The effect in the relapse model suggests that GDNF’s effects extend to modification of ethanol-seeking behavior, as well as limiting ethanol consumption. Thus, the authors propose that GDNF signaling in the VTA might be a useful target for therapeutic intervention in alcoholism in humans. S. Carnicella, V. Kharazia, J. Jeanblanc, P. H. Janak, D. Ron, GDNF is a fast-acting potent inhibitor of alcohol consumption and relapse. Proc. Natl. Acad. Sci. U.S.A. 105 , 8114-8119 (2008). [Abstract] [Full Text]