EFFECTS ON ETHANOL WITHDRAWAL HYPEREXCITABILITY OF CHRONIC TREATMENT WITH A COMPETITIVE N-METHYL-D-ASPARTATE RECEPTOR ANTAGONIST

The effects of the competitive N-methyl-D-aspartate receptor antagonis t DL-(E)-2-amino-4-methyl-5-phosphonopentanoate carboxy-ethylester (CG P39551) on the hyperexcitability produced by withdrawal from chronic e thanol treatment were studied in mice, to which CGP39551 was given chr onically with the ethanol. When an interval of 72 or 96 hr was left be tween the last of the repeated CGP39551 injections and withdrawal from ethanol, the severity of the ethanol withdrawal syndrome was increase d. When shorter time intervals were left between the end of the CGP395 51 treatment and the ethanol withdrawal, the chronic CGP39551 treatmen t protected against the withdrawal hyperexcitability. When a single lo w dose of CGP39551 was given immediately after ethanol withdrawal, the compound protected against the withdrawal hyperexcitability. It is th erefore suggested that the protective effects of concurrent chronic tr eatment with CGP39551, seen when the shorter intervals were allowed, w ere caused by residual compound. The increased severity of withdrawal, when sufficient time was left for washout of CGP39551, suggests that chronic administration of CGP39551 increased the adaptive changes that cause or contribute to ethanol withdrawal hyperexcitability. The resu lts differ from the previously reported effects of N-methyl-D-aspartat e antagonists on ethanol tolerance, because this was reduced by concur rent chronic treatment. They are also in contrast with the effects of chronic dihydropyridine calcium channel antagonists, which decreased b oth the development of tolerance and the ethanol withdrawal syndrome, when given chronically, concurrently with the ethanol. Cessation of pr olonged ethanol intake results in a period of neuronal hyperexcitabili ty, described as the withdrawal or abstinence syndrome. In humans, thi s takes the form of tremor, agitation, delirium and confusion; full co nvulsions can occur. The syndrome can be decreased by some anticonvuls ant drugs, such as benzodiazepines or chlormethiazole, but the effects of these drugs are not selective, and the neuronal changes that lead to the symptoms are not yet fully understood.