Similar effects of ethanol and flumazenil on acquisition of a shuttle-box avoidance response during withdrawal from chronic ethanol treatment.
1. Acquisition of a two-way shuttle-box avoidance response is facilitated by ethanol. This facilitated acquisition of an avoidance response to ethanol was attenuated during withdrawal from chronic-ethanol diet intake (i.e. tolerance developed by ethanol). The deficit in the avoidance task after chronic ethanol treatment could be overcome by increasing the dose of ethanol. 2. Flumazenil, a benzodiazepine antagonist, also facilitated acquisition of the avoidance response in control rats. This response to flumazenil was significantly reduced during withdrawal from chronic-ethanol treatment. This reduced avoidance responding during withdrawal also could be overcome by increasing the dose of flumazenil. 3. The benzodiazepine-inverse agonist, RO 15-4513, produced a deficit in avoidance responding that was antagonized by both ethanol and flumazenil in a dose-related manner. 4. To determine whether flumazenil has the properties of a benzodiazepine agonist, it was established that, unlike the benzodiazepine chlordiazepoxide, flumazenil did not enhance the ethanol-induced deficit in the aerial righting reflex. Additionally, flumazenil blocked the action of chlordiazepoxide in this procedure, consistent with the benzodiazepine antagonist action of flumazenil. 5. Data collected are consistent with the hypothesis that an endogenous substance with the properties of a benzodiazepine-inverse agonist antagonizes the anticonflict actions of acutely administered ethanol during withdrawal from chronic-ethanol exposure.
Criswell
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Brain and Development Research Center, University of North Carolina School of Medicine, Chapel Hill 27599-7250.
Breese
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GR
D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects*; D001386:Azides / Q000494:pharmacology; D001569:Benzodiazepines / Q000494:pharmacology; D002707:Chlordiazepoxide / Q000494:pharmacology; D003220:Conflict, Psychological; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000494:pharmacology*; D005442:Flumazenil / Q000494:pharmacology*; D008297:Male; D004856:Postural Balance / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013375:Substance Withdrawal Syndrome / Q000523:psychology*
D001386:Azides; D001569:Benzodiazepines; D000431:Ethanol; D005442:Flumazenil; D002707:Chlordiazepoxide; C042957:Ro 15-4513