Withdrawal seizure prone (WSP) and withdrawal seizure resistant (WRS) mice were genetically selected to express severe or mild handling-induced convulsions (HIC), respectively, after cessation of chronic ethanol (EtOH) vapor inhalation. The studies reported here tested WSP and WSR mice to determine whether elevated HIC were seen after administration of acute doses of several drugs that depress central nervous system activity. The drugs tested were EtOH, pentobarbital, t-butanol, acetaldehyde, and diazepam. All drugs initially suppressed HIC in WSP mice. This suppression was followed by an exacerbation of HIC, suggestive of a state of rebound central nervous system hyperexcitability during acute withdrawal. Susceptibility to acute withdrawal seizures was clearly under genetic control, since WSR mice did not display acute withdrawal HIC to any appreciable extent. Acute EtOH withdrawal seizures did not require testing WSP mice repeatedly, as they could be seen upon a single HIC test 8 hr after EtOH injection. Results with acetaldehyde and t-butanol suggest that the formation of acetaldehyde may be sufficient, but is not necessary for the elicitation of acute EtOH withdrawal. Earlier studies had found that WSP mice displayed more severe withdrawal HIC than WSR mice after chronic treatment with t-butanol, phenobarbital, nitrous oxide, or diazepam. The genetic predisposition to chronic EtOH withdrawal HIC in WSP mice generalized to all central nervous system depressants acutely tested, suggesting that acute and chronic withdrawal to all these drugs is largely under the control of a common group of genes.