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, 21 (14), 5297-303

The cAMP-protein Kinase A Signal Transduction Pathway Modulates Ethanol Consumption and Sedative Effects of Ethanol

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The cAMP-protein Kinase A Signal Transduction Pathway Modulates Ethanol Consumption and Sedative Effects of Ethanol

G Wand et al. J Neurosci.

Abstract

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.

Figures

Fig. 1.
Fig. 1.
Comparison of nucleus accumbens Gsα protein levels and adenylyl cyclase activity in Gnas (−/+) and wild-type littermates in C57BL/6J background. Antisera to Gsα recognizes 52 and 45 kDa forms of the protein (top panel). The 52 and 45 kDa signals were summed for densitometric analysis (middle panel). The filter was stripped and reprobed with Goα antisera for normalization of Gsα levels. Goα levels did not differ by genotype. Each lane represents membranes from one mouse (40 μg/lane). AlF- and GTP-stimulated adenylyl cyclase activity in nucleus accumbens membranes (*p < 0.05) (bottom panel).
Fig. 2.
Fig. 2.
Sleep time as a measurement of sensitivity to the sedative hypnotic effects of ethanol (3.5 g/kg). a, Gnas (−/+) versus wild-type, *p < 0.001.c, R(AB) versus wild-type, *p < 0.001. e, Q227L versus wild-type, *p< 0.001. b, d, f, Blood ethanol concentrations at the indicated time points (n = 6–12 per genotype). Values are mean ± SEM.
Fig. 3.
Fig. 3.
Consumption of ethanol by Gnas (−/+) mice and wild-type littermates in C57BL/6J background. a,Consumption (in grams per kilogram) of 6% ethanol solution (genotype, F(1,14) = 7.28,p = 0.019). b, Consumption (in grams per kilogram per day) of each ethanol solution, 3 d average, (genotype, F(1,14) = 19.37,p = 0.001). c, Ethanol-preference ratios (volume of ethanol consumed per total volume of fluid consumed) as a measure of relative ethanol preference (genotype,F(1,14) = 27.48, p= 0.0001). d, Total fluid consumption (ethanol plus water, in milliliters). e, f, Preference ratios for sucrose and quinine (volume of solution consumed per total volume of fluid consumed). g, h, Average total food intake per day over trial period and average body weight at the start of trials. Values are mean ± SEM (n = 6 per genotype and concentration). Groups were compared by two-way repeated measures ANOVAs. *p < 0.05 relative to wild-type littermates, post hoc Tukey.
Fig. 4.
Fig. 4.
Consumption of ethanol by R(AB) mice and wild-type littermates in C57BL/6J background. a, Consumption (in grams per kilogram) of 6% ethanol solution (genotype,F(1,12) = 6.0, p = 0.034). b, Consumption (in grams per kilogram per day) of each ethanol solution, 3 d average (genotype,F(1,12) = 12.17, p= 0.006). c, Ethanol-preference ratios (volume of ethanol consumed per total volume of fluid consumed) as a measure of relative ethanol preference (genotype,F(1,12) = 20.55, p= 0.001). d, Total fluid consumption (ethanol plus water, in milliliters). e, f, Preference ratios for sucrose and quinine (volume of solution consumed per total volume of fluid consumed). g, h, Average total food intake per day over trial period and average body weight at the start of trials. Values are mean ± SEM (n = 6 per genotype and concentration). Groups were compared by two-way repeated measures ANOVAs. *p < 0.05 relative to wild-type littermates, post hoc Tukey test.
Fig. 5.
Fig. 5.
Regional distribution of GsαQ227L transgene. To determine the distribution of transgene expression in the brain, we performed in situ hybridization studies using a transgene-specific oligonucleotide as described (Abel et al., 1997b). In coronal sections taken from a GsαQ227L transgenic mouse, expression of the transgene can be observed in the cortex and striatum (rostral section, left) and in the hippocampus (caudal section, right). No transgene expression is observed in the cerebellum, hypothalamus, thalamus, or brainstem. No expression is seen in wild-type control animals (data not shown).
Fig. 6.
Fig. 6.
Consumption of ethanol by GsαQ227L transgenic mice and wild-type littermates in C57BL/6J background.a, Consumption (in grams per kilogram per day) of each ethanol solution, 3 d average. b,Ethanol-preference ratios [volume of ethanol consumed (in milliliters) per total volume of fluid consumed (in milliliters)]) as a measure of relative ethanol preference.

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