Diazepam during prior ethanol withdrawals does not alter seizure susceptibility during a subsequent withdrawal

• Published in: Pharmacology, biochemistry and behavior Vol. 68; no. 2; pp. 339 - 346
• Main Authors: Mhatre, Molina C., McKenzie, Stephanie E., Gonzalez, Larry P.
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01-02-2001; Elsevier Science
• Subjects: Affinity Labels - adverse effects; Alcohol; Alcohol Withdrawal Seizures - blood; Alcohol Withdrawal Seizures - chemically induced; Alcohol Withdrawal Seizures - drug therapy; Alcoholism and acute alcohol poisoning; Animals; Anticonvulsants - therapeutic use; Azides - adverse effects; Benzodiazepines - adverse effects; Biological and medical sciences; Brain - drug effects; Brain - physiopathology; Central Nervous System Depressants - adverse effects; Central Nervous System Depressants - blood; Diazepam; Diazepam - therapeutic use; EEG; Electroencephalography; Ethanol; Ethanol - adverse effects; Ethanol - blood; Male; Medical sciences; Multiple withdrawal; Rats; Rats, Sprague-Dawley; Repeated withdrawal; Ro15-4513; Seizures; Toxicology; Withdrawal; γ-Aminobutyric acid receptor complex; Multiple withdrawal; Ethanol; Withdrawal; EEG; Repeated withdrawal; Alcohol; Ro15-4513; Diazepam; Seizures; Agonist; Intraperitoneal administration; Antialcohol drug; Rat; Toxicity; Central nervous system; Action potential; Benzodiazepine receptor; Prevention; Benzodiazepine derivatives; Neurological disorder; Mechanism of action; Withdrawal syndrome; Nervous system diseases; Alcoholism; Rodentia; Detoxification; Biological activity; Cerebral disorder; Vertebrata; Chemotherapy; Mammalia; Convulsion; Inverse agonist; Animal; Central nervous system disease; Gabaergic receptor A; Brain (vertebrata)
• ISSN: 0091-3057; 1873-5177
• DOI: 10.1016/S0091-3057(00)00481-0

The number of cycles of alcohol detoxification is suggested to be an important variable in the predisposition to severe withdrawal seizures in alcohol-dependent individuals. Several clinical studies have suggested that exposure to repeated alcohol withdrawals may lead to increased severity of subsequent withdrawal episodes. Consistent with these observations, exposure to multiple cycles of ethanol withdrawal in our previous study significantly increased sensitivity to the convulsive effects of the GABA
A receptor inverse agonist, Ro15-4513, in comparison to continuous ethanol exposure with no intermittent withdrawals. There was also a selective increase in the occurrence of spontaneous spike and sharp wave (SSW) activity in the EEG recorded from hippocampal area CA
3 in proportion to the number of withdrawal episodes experienced. It is hypothesized that during such repeated episodes of ethanol intoxication and withdrawal, changes in neuronal excitation during prior withdrawals could serve as initially subconvulsive kindling stimuli that might eventually result in the increased severity of the withdrawal syndrome. There is some evidence of the successful suppression of such neuronal excitation during acute ethanol withdrawal by positive modulators of the GABA
A receptor. In the present study, the benzodiazepine agonist, diazepam, at a dose (4.0 mg/kg) that suppresses acute withdrawal symptoms, when administered during intermittent withdrawals, did not alter seizure sensitivity during a subsequent nonmedicated withdrawal. Diazepam treatment during prior withdrawals also did not have any effect on the multiple withdrawal-associated increase in SSW activity in hippocampal area CA
3 during an untreated withdrawal. This finding suggests that suppression of acute withdrawal symptoms by diazepam does not prevent long-lasting changes in CNS function resulting from repeated exposures to ethanol withdrawal.