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This Article Full Text Full Text (PDF) All Versions of this Article: 100/6/3417    most recent 90970.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Kelm, M. K. Articles by Breese, G. R. Search for Related Content PubMed PubMed Citation Articles by Kelm, M. K. Articles by Breese, G. R.

The Role of Protein Kinase A in the Ethanol-Induced Increase in Spontaneous GABA Release Onto Cerebellar Purkinje Neurons

¹Departments of Pharmacology and ²Psychiatry, Bowles Center for Alcohol Studies, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina ³Departments of Pharmacology and Psychiatry, Bowles Center for Alcohol Studies, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina

Submitted 27 August 2008; accepted in final form 14 October 2008

Ethanol increases miniature inhibitory postsynaptic current frequency and decreases the paired-pulse ratio, which suggests that ethanol increases both spontaneous and evoked GABA release, respectively. We have shown previously that ethanol increases GABA release at the rat interneuron–Purkinje cell synapse and that this ethanol effect involves calcium release from internal stores; however, further exploration of the mechanism responsible for ethanol-enhanced GABA release was needed. We found that a cannabinoid receptor 1 (CB1) agonist, WIN-55212, and a GABA_B receptor agonist, baclofen, decreased baseline spontaneous GABA release and prevented ethanol from increasing spontaneous GABA release. The CB1 receptor and GABA_B receptor are G i–linked G protein–coupled receptors with common downstream messengers that include adenylate cyclase and protein kinase A (PKA). Adenylate cyclase and PKA antagonists blocked ethanol from increasing spontaneous GABA release, whereas a PKA antagonist limited to the postsynaptic neuron did not block ethanol from increasing spontaneous GABA release. These results suggest that presynaptic PKA plays an essential role in ethanol-enhanced spontaneous GABA release. Similar to ethanol, we found that the mechanism of the cannabinoid-mediated decrease in spontaneous GABA release involves internal calcium stores and PKA. A PKA antagonist decreased baseline spontaneous GABA release. This effect was reduced after incubating the slice with a calcium chelator, BAPTA-AM, but was unaffected when BAPTA was limited to the postsynaptic neuron. This suggests that the PKA antagonist is acting through a presynaptic, calcium-dependent mechanism to decrease spontaneous GABA release. Overall, these results suggest that PKA activation is necessary for ethanol to increase spontaneous GABA release.