Effect of CGP39551 administration on the kindling of ethanol-withdrawal seizures.
BACKGROUND
It has previously been shown that drugs, such as benzodiazepines, that inhibit seizure activity during ethanol withdrawal, fail to alleviate the potentiated withdrawal seen following repeated episodes of withdrawal when administered during each withdrawal episode. Acute administration of the N-methyl- D-aspartate (NMDA) receptor competitive antagonist, CGP39551, has been shown to inhibit seizure activity during ethanol withdrawal, and, when administered during the periods of repeated diazepam withdrawal, it blocked the reduction in pentylenetetrazol (PTZ) seizure threshold seen following a final, untreated withdrawal.


OBJECTIVE
The aim of the current study was to determine if CGP39551 could alter final ethanol-withdrawal symptoms when administered during the acute intermittent withdrawal periods.


METHODS
Mice were chronically treated with ethanol-containing liquid diet for either 30 days continuously (single withdrawal) or with 8-h withdrawal periods on day 16 and day 23 of treatment (repeated withdrawal). Control animals received a control diet for the same period of time. On the final withdrawal animals were tested for behavioural signs of withdrawal. The effect of CGP39551 administered acutely on withdrawal [up to 5 mg/kg, intraperitoneally (i.p.)] or during the intermittent withdrawal periods (10 mg/kg, i.p.) was examined.


RESULTS
Acute administration of CGP39551 failed to inhibit handling-induced convulsions in the single-withdrawal or repeated-withdrawal group and had no effect on either decreased exploration or increased sensitivity to PTZ seen in withdrawal. Surprisingly, when CGP39551 was administered during periods of repeated ethanol withdrawal a potentiation of seizure activity was seen in the final, untreated withdrawal. This potentiation of seizure activity, compared with vehicle-treated animals, was not seen when CGP39551 was given whilst animals had access to ethanol (single-withdrawal group and repeated-withdrawal group where CGP39551 treatment was non-contingent with withdrawal episodes). However, the decrease in exploration seen during withdrawal was potentiated in repeated-withdrawal animals treated with CGP39551 irrespective of the time at which the CGP39551 was administered.


CONCLUSIONS
Treatment with an NMDA receptor-competitive antagonist potentiated the ethanol-withdrawal syndrome in animals with previous experience of ethanol withdrawal.
Sussex Centre for Research in Alcohol, Alcoholism and Drug Dependence, School of Biological Sciences, University of Sussex, Falmer, Brighton BN1 9QG, UK.
Tamzin L
TL
Ripley
Sarah J
SJ
Dunworth
David N
DN
Stephens
D015763:2-Amino-5-phosphonovalerate / Q000008:administration & dosage* / Q000031:analogs & derivatives*; D020270:Alcohol Withdrawal Seizures / Q000139:chemically induced* / Q000503:physiopathology; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D000431:Ethanol / Q000009:adverse effects / Q000494:pharmacology; D007696:Kindling, Neurologic / Q000187:drug effects* / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology
C064540:CGP 39551; D000431:Ethanol; D015763:2-Amino-5-phosphonovalerate