Protein Kinase C Epsilon Activity in the Nucleus Accumbens and Central Nucleus of the Amygdala Mediates Binge Alcohol Consumption

详细信息    查看全文

• 作者：Debra K. Cozzoli^a ; ^b ; Justin Courson^a ; Charlotte Rostock^a ; Rianne R. Campbell^a ; Melissa G. Wroten^a ; Hadley McGregor^a ; Amanda L. Caruana^a ; Bailey W. Miller^a ; Jia-Hua Hu^c ; Ping Wu Zhang^c ; Bo Xiao^c ; Paul F. Worley^c ; John C. Crabbe^b ; Deborah A. Finn^b ; Karen K. Szumlinski^a ; ^{szumlinski@psych.ucsb.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Alcohol use disorders ; Drinking in the dark ; Glutamate ; HDID-1 mice ; Homer ; Scheduled high alcohol consumption
• 刊名：Biological Psychiatry
• 出版年：2016
• 出版时间：15 March 2016
• 年：2016
• 卷：79
• 期：6
• 页码：443-451
• 全文大小：1354 K

文摘

Protein kinase C epsilon (PKCε) is emerging as a potential target for the development of pharmacotherapies to treat alcohol use disorders, yet little is known regarding how a history of a highly prevalent form of drinking, binge alcohol intake, influences enzyme priming or the functional relevance of kinase activity for excessive alcohol intake.

Methods

Immunoblotting was employed on tissue from subregions of the nucleus accumbens (NAc) and the amygdala to examine both idiopathic and binge drinking-induced changes in constitutive PKCε priming. The functional relevance of PKCε translocation for binge drinking and determination of potential upstream signaling pathways involved were investigated using neuropharmacologic approaches within the context of two distinct binge drinking procedures, drinking in the dark and scheduled high alcohol consumption.

Results

Binge alcohol drinking elevated p(Ser729)-PKCε levels in both the NAc and the central nucleus of the amygdala (CeA). Moreover, immunoblotting studies of selectively bred and transgenic mouse lines revealed a positive correlation between the propensity to binge drink alcohol and constitutive p(Ser729)-PKCε levels in the NAc and CeA. Finally, neuropharmacologic inhibition of PKCε translocation within both regions reduced binge alcohol consumption in a manner requiring intact group 1 metabotropic glutamate receptors, Homer2, phospholipase C, and/or phosphotidylinositide-3 kinase function.

Conclusions

Taken together, these data indicate that PKCε signaling in both the NAc and CeA is a major contributor to binge alcohol drinking and to the genetic propensity to consume excessive amounts of alcohol.