Journal
JOURNAL OF PHYSIOLOGY-LONDON
Volume 575, Issue 1, Pages 145-159Publisher
WILEY
DOI: 10.1113/jphysiol.2006.112730
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Funding
- NIAAA NIH HHS [R01 AA014691, AA015086, R03 AA015086, AA014691] Funding Source: Medline
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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.
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