ERK regulation in chronic ethanol exposure and withdrawal.
The extracellular signal regulated protein kinases (ERKs), also known as mitogen-activated protein kinases (MAPK) of 42 and 44 kd, play a crucial role in the induction of various forms of neural plasticity. Ethanol induces long-lasting functional changes that are more severe following repeated exposure and may involve intracellular signal transduction mechanisms. Therefore, we investigated the regulation of the ERK signal transduction pathway in models of continuous and intermittent ethanol exposure and withdrawal. Moderate blood alcohol levels (BALs) reduced ERK activation in most of the brain regions studied. Conversely, during withdrawal, activation of ERK was increased in most areas with some regional variations in the levels and kinetics of induction. The most dramatic effects were observed in the amygdala, the cerebellum, the striatum and the hippocampus. In the amygdala and the cerebellum, the activation of ERK observed during withdrawal was significantly higher after intermittent ethanol exposure than after continuous exposure, suggesting the establishment of a form of sensitization to the effects of withdrawal on ERK regulation. Thus the dysregulation of the ERK pathway could contribute to escalation of withdrawal symptoms induced by repeated withdrawal and possibly to the neuroadaptative changes believed to underlie progression towards addiction.
Sanna
Pietro Paolo
PP
Department of Neuropharmacology, The Scripps Research Institute, 10550 N Torrey Pines Road, La Jolla, CA 92037, USA. psanna@scripps.edu
Simpson
Cindy
C
Lutjens
Robert
R
Koob
George
G
D020270:Alcohol Withdrawal Seizures / Q000097:blood / Q000139:chemically induced / Q000201:enzymology; D019973:Alcohol-Related Disorders / Q000097:blood / Q000201:enzymology*; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000201:enzymology*; D001923:Brain Chemistry; D002908:Chronic Disease; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D000431:Ethanol / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009928:Organ Specificity; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
D000431:Ethanol; D020928:Mitogen-Activated Protein Kinases