Differential adaptations in GABAergic and glutamatergic systems during ethanol withdrawal in male and female rats.
BACKGROUND
There are significant and consistent sex differences in recovery from ethanol withdrawal in our animal model of ethanol dependence. We have also observed significant and varied sex differences in subunit protein levels of gamma-aminobutyric acid A (GABAA) and the N-metheyl-D-aspartate subtype of glutamate receptors occurring with ethanol dependence and withdrawal. Considering the major role of these two systems as targets of ethanol, we wanted to explore additional possible mechanisms underlying changes in GABAergic and glutamatergic responses after chronic ethanol exposure. Therefore, the objective of the present study was to examine GABAergic- and glutamatergic-associated proteins at three days of ethanol withdrawal, when female rats appear to have largely recovered but male rats still display robust signs of withdrawal.


METHODS
Male and female rats were fed 6% ethanol in a nutritionally complete liquid diet for 14 days according to a pair-fed design; withdrawal was initiated by replacement of the diet with chow. At three days of withdrawal, the cerebral cortex and hippocampus were dissected for use in Western blot analysis. The paired design was maintained throughout all experimental procedures.


RESULTS
At three days of ethanol withdrawal, we found region-specific and sex-selective alterations in levels of GAD (glutamic acid decarboxylase, GABA synthetic enzyme), GABA and glutamate transporters, and the synapse-associated proteins HSP70, PSD-95, and synaptophysin. There were also several significant differences in transporter function at this time that varied between males and females.


CONCLUSIONS
Taken together, these findings show differential adaptations of GABAergic and glutamatergic neurotransmission between female and male rats that are associated with withdrawal recovery. This suggests that selective withdrawal-induced neuroadaptations in regulation of these systems' activities underlie, at least in part, sex differences in withdrawal recovery between male and female rats.
Department of Pharmaceutical Sciences, Idaho State University, Pocatello, Idaho 83209, USA.
P E
PE
Alele
L L
LL
Devaud
D000437:Alcoholism / Q000378:metabolism*; D027322:Amino Acid Transport System X-AG / Q000378:metabolism; D000818:Animals; D002540:Cerebral Cortex / Q000201:enzymology / Q000378:metabolism; D004195:Disease Models, Animal; D000431:Ethanol / Q000009:adverse effects*; D005260:Female; D050485:GABA Plasma Membrane Transport Proteins; D005968:Glutamate Decarboxylase / Q000378:metabolism; D005971:Glutamates / Q000378:metabolism*; D006624:Hippocampus / Q000201:enzymology / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D026901:Membrane Transport Proteins / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D012737:Sex Factors; D013375:Substance Withdrawal Syndrome / Q000209:etiology / Q000378:metabolism*; D009435:Synaptic Transmission / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D027322:Amino Acid Transport System X-AG; D050485:GABA Plasma Membrane Transport Proteins; D005971:Glutamates; D007527:Isoenzymes; D026901:Membrane Transport Proteins; D016194:Receptors, N-Methyl-D-Aspartate; D000431:Ethanol; D005680:gamma-Aminobutyric Acid; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2