The cyclic AMP/protein kinase A signal transduction pathway modulates tolerance to sedative and hypothermic effects of ethanol.
BACKGROUND
An expanding body of literature indicates the important role of the cAMP/PKA signaling pathway in establishing initial sensitivity to alcohol as well as being involved in certain forms of tolerance to ethanol. The use of mice with heterozygous inactivation of the Gnas gene encoding Gsalpha allowed us to explore the relationship between tolerance to ethanol and cAMP/PKA signaling.


METHODS
Mice with the targeted disruption of one Gsalpha allele were compared with wild-type littermates in their initial sensitivity to ethanol-induced sedation and hypothermia and then monitored for the development of tolerance during two subsequent bouts of intoxication. Components of the cAMP/PKA signaling pathway were analyzed in ethanol-naïve mice and again following the development of tolerance to ethanol to better understand the contribution of this signaling pathway to the acquisition of tolerance.


RESULTS
During the initial exposure to ethanol, mice with the targeted disruption of one Gsalpha allele (Gnas) were more sensitive to the sedative effects of ethanol compared with wild-type littermates. Wild-type mice developed within-session tolerance to ethanol-induced hypothermia whereas Gnas mice did not. Following the subsequent ethanol treatments, wild-type mice developed between-session tolerance to the sedative effects of ethanol to a greater degree than mice with heterozygous inactivation of the Gnas gene. The development of tolerance to the sedative effects of ethanol was accompanied by increased expression of phospho-CREB in the cerebellum, hippocampus, and frontal cortex. No changes in phospho-CREB expression were detected in these brain regions in mice with heterozygous inactivation of the Gnas gene.


CONCLUSIONS
The results show that cAMP/PKA signal transduction modulates sensitivity to sedative and hypothermic effects of ethanol. This signal transduction system also influences the acquisition of within-session and between-session tolerance. The mechanism through which cAMP/PKA signaling modulates the development of tolerance remains to be elucidated but may involve changes in phospho-CREB expression.
Yang
Xioaju
X
Departments of Medicine and Psychiatry, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Oswald
Lynn
L
Wand
Gary
G
D000818:Animals; D002864:Chromogranins; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology*; D004361:Drug Tolerance / Q000235:genetics; D000431:Ethanol / Q000494:pharmacology*; D005260:Female; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000172:deficiency / Q000235:genetics; D006993:Hypnotics and Sedatives / Q000494:pharmacology*; D007035:Hypothermia / Q000139:chemically induced* / Q000201:enzymology* / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*
D002864:Chromogranins; D006993:Hypnotics and Sedatives; D000431:Ethanol; D017868:Cyclic AMP-Dependent Protein Kinases; C498642:Gnas protein, mouse; D019205:GTP-Binding Protein alpha Subunits, Gs