The cAMP-protein kinase A signal transduction pathway modulates ethanol consumption and sedative effects of ethanol.
Ethanol and other drugs of abuse modulate cAMP-PKA signaling within the mesolimbic reward pathway. To understand the role of the cAMP-PKA signal transduction in mediating the effects of ethanol, we have studied ethanol consumption and the sedative effects of ethanol in three lines of genetically modified mice. We report that mice with the targeted disruption of one Gsalpha allele as well as mice with reduced neuronal PKA activity have decreased alcohol consumption compared with their wild-type littermates. Genetic reduction of cAMP-PKA signaling also makes mice more sensitive to the sedative effects of ethanol, although plasma ethanol concentrations are unaffected. In contrast, mice with increased adenylyl cyclase activity resulting from the transgenic expression of a constitutively active form of Gsalpha in neurons within the forebrain are less sensitive to the sedative effects of ethanol. Thus, the cAMP-PKA signal transduction pathway is critical in modulating sensitivity to the sedative effects of ethanol as well as influencing alcohol consumption.
Wand
G
G
Departments of Medicine, Psychiatry, and Pediatrics, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. gwand@welch.jhu.edu
Levine
M
M
Zweifel
L
L
Schwindinger
W
W
Abel
T
T
D000262:Adenylyl Cyclases / Q000378:metabolism; D000428:Alcohol Drinking / Q000235:genetics / Q000378:metabolism*; D000483:Alleles; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002492:Central Nervous System Depressants / Q000008:administration & dosage*; D002678:Chimera; D002755:Choice Behavior / Q000187:drug effects / Q000502:physiology; D002864:Chromogranins; D003433:Crosses, Genetic; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism*; D004351:Drug Resistance / Q000235:genetics; D000431:Ethanol / Q000008:administration & dosage* / Q000097:blood; D005260:Female; D019205:GTP-Binding Protein alpha Subunits, Gs; D020022:Genetic Predisposition to Disease; D020962:Heterotrimeric GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D006579:Heterozygote; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins; D012646:Self Administration; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D012890:Sleep / Q000187:drug effects
D002492:Central Nervous System Depressants; D002864:Chromogranins; D009419:Nerve Tissue Proteins; D000431:Ethanol; D017868:Cyclic AMP-Dependent Protein Kinases; C498642:Gnas protein, mouse; D019205:GTP-Binding Protein alpha Subunits, Gs; D020962:Heterotrimeric GTP-Binding Proteins; D000262:Adenylyl Cyclases