Chronic ethanol inhalation produced no change in the number or affinity of flunitrazepam binding sites on well-washed synaptic membranes prepared from male Quackenbush mice, but produced a significant decrease in the capacity of GABA to enhance flunitrazepam binding. This decrease was characterized by a higher EC50 (1.4 microM compared to 0.6 microM) and a lower maximal level of enhancement (162% compared to 172%) for tissue from the chronically treated animals compared to tissue from control animals. Acute ethanol treatment or ethanol incubated in vitro with the brain membranes did not produce changes in any of the flunitrazepam binding parameters. These results support other findings that chronic ethanol may affect the coupling of various sites on GABA-A receptor-ionophore complexes in brain.
The phenomenon of ethanol withdrawal kindling was examined using two different paradigms of ethanol treatment in rats and mice. In the first protocol, male Wistar rats were treated by ethanol inhalation for 14 days before withdrawal. Ethanol exposure was repeated three times with two days abstinence between treatments. In the second protocol, male C57BL/6 mice were fed liquid diet (Lieber DeCarli) containing 6.5%(v/v) ethanol for ten days. Feeding was repeated five times separated by 24 hr intervals. After both treatments, either spontaneous or handling-induced withdrawal behaviours were significantly intensified by sequential withdrawals. These results support the kindling hypothesis of ethanol withdrawal and provide models to develop potential pharmacological tools to attenuate enhanced withdrawal severity and to study the molecular mechanisms underlying this phenomenon.
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