Supersensitivity to allosteric GABAA receptor modulators and alcohol in mice lacking PKCε
Copyright policy )Supersensitivity to allosteric GABAA receptor modulators and alcohol in mice lacking PKCε
Several of the actions of ethanol are mediated by gamma-aminobutyrate type A (GABA(A)) receptors. Here we demonstrated that mutant mice lacking protein kinase C epsilon (PKCepsilon) were more sensitive than wild-type littermates to the acute behavioral effects of ethanol and other drugs that allosterically activate GABA(A) receptors. GABA(A) receptors in membranes isolated from the frontal cortex of PKCepsilon null mice were also supersensitive to allosteric activation by ethanol and flunitrazepam. In addition, these mutant mice showed markedly reduced ethanol self-administration. These findings indicate that inhibition of PKCepsilon increases sensitivity of GABA(A) receptors to ethanol and allosteric modulators. Pharmacological agents that inhibit PKCepsilon may be useful for treatment of alcoholism and may provide a non-sedating alternative for enhancing GABA(A) receptor function to treat other disorders such as anxiety and epilepsy.
- University of California System United States
- University of California, San Francisco United States
- University of Kent United Kingdom
Male, RM, Self Administration, Flunitrazepam, Protein Kinase C-epsilon, Mice, Radioligand Assay, Allosteric Regulation, Cerebellum, Animals, GABA Modulators, QH426, Protein Kinase C, Cerebral Cortex, Behavior, Animal, Ethanol, Receptors, GABA-A, QP, Corpus Striatum, Isoenzymes, Mice, Inbred C57BL, Mutation, Female
Male, RM, Self Administration, Flunitrazepam, Protein Kinase C-epsilon, Mice, Radioligand Assay, Allosteric Regulation, Cerebellum, Animals, GABA Modulators, QH426, Protein Kinase C, Cerebral Cortex, Behavior, Animal, Ethanol, Receptors, GABA-A, QP, Corpus Striatum, Isoenzymes, Mice, Inbred C57BL, Mutation, Female
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