Chronic exposure to ethanol produces a latent state of CNS hyperexcitability which becomes evident upon removal from ethanol exposure. The occurrence of some of the symptoms of this hyperexcitability are serious enough medically to warrant pharmacological intervention. Benzodiazepines have for some time been the drugs of choice in the treatment of ethanol withdrawal, but the use of these drugs is not without controversy. Benzodiazepines are most effective in reducing the incidence of motor convulsions following ethanol withdrawal, but evidence relating to their ability to reduce or prevent electrophysiological signs of central seizure activity is incomplete. Investigations of withdrawing alcoholics indicate that some individuals may be resistant to the anticonvulsant effects of benzodiazepines, and some investigators have suggested that these drugs may actually increase the probability of withdrawal seizures during subsequent withdrawals from ethanol. Data are also available indicating a possible dissociation between the effects of benzodiazepines on motor convulsions and their effects on abnormal neuronal electrical discharge. Since electrical seizure discharge is sometimes associated with neuropathological changes and may result in a kindling-like increase in the severity of subsequent withdrawal episodes, it is of clinical relevance to determine the extent to which pharmacological agents suppress both motor convulsions and electrical discharge following withdrawal from chronic ethanol exposure. Studies proposed in this application will examine and compare the effects of several drug treatments on measurements of the ethanol withdrawal syndrome in rats chronicallY exposed to ethanol. These studies will include two drugs commonly used in the treatment of the ethanol withdrawal syndrome, the benzodiazepine diazepam and the anticonvulsant carbamazepine, and will also include four additional drugs representative of two drug classes of recent clinical interest, the voltage-dependent calcium channel inhibitors and the NMDA receptor antagonists. Measurements of convulsant withdrawal symptoms will be made along with observations of electrophysiological measures of CNS function. Drug treatment will include both single and multiple dosing schedules and the effects on subsequent withdrawal symptomatology will be evaluated. Since recent evidence suggests that the severity of ethanol withdrawal symptoms may depend more upon the history of withdrawal experiences than upon the actual length of ethanol exposure, studies are also proposed to examine the effectiveness of these drugs in suppressing withdrawal symptoms after multiple withdrawal episodes, as well as after a single period of ethanol exposure and withdrawal. These studies should provide important information about the effectiveness of these treatments for the ethanol withdrawal syndrome under different conditions of ethanol exposure and drug administration, and will permit an examination of effects on central neuronal functioning as well as on motor convulsions and behavioral measures of CNS hyperexcitability.
