Synaptic GABAergic and glutamatergic mechanisms underlying alcohol sensitivity in mouse hippocampal neurons.
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 GABAA receptor-mediated inhibitory postsynaptic currents (GABAA 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, GABAB activity and presynaptic and postsynaptic actions of ethanol were investigated. Inhibition of GABAB receptor function enhances ethanol-mediated potentiation of distal GABAA IPSCs in ILS but not ISS mice, and this blockade of GABAB receptor function has no effect on the action of ethanol on NMDA EPSCs in either mouse strain. Thus, subregional differences in GABAB 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.
Proctor
W R
WR
VA Eastern Colorado Health Care System, Denver, CO80220, USA. bill.proctor@uchsc.edu
Diao
Lihong
L
Freund
R K
RK
Browning
M D
MD
Wu
P H
PH
D000818:Animals; D001596:Benzylamines / Q000494:pharmacology; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000494:pharmacology*; D019706:Excitatory Postsynaptic Potentials; D018756:GABA Antagonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000494:pharmacology*; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D016202:N-Methylaspartate / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010721:Phosphinic Acids / Q000494:pharmacology; D011963:Receptors, GABA-A / Q000187:drug effects / Q000378:metabolism; D018080:Receptors, GABA-B / Q000187:drug effects / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000378:metabolism; D012890:Sleep / Q000235:genetics; D009435:Synaptic Transmission; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology*
D001596:Benzylamines; D002492:Central Nervous System Depressants; D018756:GABA Antagonists; D010721:Phosphinic Acids; D011963:Receptors, GABA-A; D018080:Receptors, GABA-B; D016194:Receptors, N-Methyl-D-Aspartate; C083008:CGP 52432; D000431:Ethanol; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D016202:N-Methylaspartate