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This Article Full Text Full Text (PDF) All Versions of this Article: 575/1/145    most recent jphysiol.2006.112730v1 Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Proctor, W. R. Articles by Wu, P. H. Search for Related Content PubMed PubMed Citation Articles by Proctor, W. R. Articles by Wu, P. H. Related Collections Neuroscience

¹ VA Eastern Colorado Health Care System, Denver, CO 80220, USA
² Department of Psychiatry
³ Departments of Neurology and Pediatrics
⁴ Department of Pharmacology
⁵ Neuroscience Program, University of Colorado at Denver and Health Sciences Center, Denver, CO 80262, USA

This study was designed to examine the neuronal mechanisms of ethanol sensitivity by utilizing inbred short sleep (ISS) and inbred long sleep (ILS) mouse strains that display large differences in sensitivity to the behavioural effects of ethanol. Comparisons of whole-cell electrophysiological recordings from CA1 pyramidal neurons in hippocampal slices of ISS and ILS mice indicate that ethanol enhances GABA_A receptor-mediated inhibitory postsynaptic currents (GABA_A IPSCs) and reduces NMDA receptor-mediated excitatory postsynaptic currents (NMDA EPSCs) in a concentration- and strain-dependent manner. In ILS neurons, these receptor systems are significantly more sensitive to ethanol than those in ISS neurons. To further examine the underlying mechanisms of differential ethanol sensitivities in these mice, GABA_B activity and presynaptic and postsynaptic actions of ethanol were investigated. Inhibition of GABA_B receptor function enhances ethanol-mediated potentiation of distal GABA_A IPSCs in ILS but not ISS mice, and this blockade of GABA_B receptor function has no effect on the action of ethanol on NMDA EPSCs in either mouse strain. Thus, subregional differences in GABA_B activity may contribute to the differential ethanol sensitivity of ISS and ILS mice. Moreover, analysis of the effects of ethanol on paired-pulse stimulation, spontaneous IPSC events, and brief local GABA or glutamate application suggest that postsynaptic rather than presynaptic mechanisms underlie the differential ethanol sensitivity of these mice. Furthermore, these results provide essential information to focus better on appropriate target sites for more effective drug development for the treatment of alcohol abuse.

(Received 3 May 2006; accepted after revision 6 June 2006; first published online 8 June 2006)
Corresponding author W. R. Proctor: Department of Psychiatry (Campus Box C-261), University of Colorado at Denver and Health Sciences Center, 4200 E. 9th Avenue, Denver, CO 80262, USA. Email: bill.proctor{at}uchsc.edu

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