The Kindling Model of Alcohol Dependence: Similar Persistent Reduction in Seizure Threshold to Pentylenetetrazol in Animals Receiving Chronic Ethanol or Chronic Pentylenetetrazol

Rats on a chronic intermittent ethanol (CIE) regimen showed a persistent reduction in seizure threshold to the convulsant drug pentylenetetrazol (PTZ). CIE rats were given ethanol by intubation on an alternate day schedule and tested at selected intervals for seizure threshold with PTZ. A significant reduction in seizure threshold, a sign of withdrawal, was observed 20 hr after the first dose. The severity of withdrawal intensified on repetition of the ethanol administration and depression‐hyperexcitability cycle, with the seizure threshold reaching a maximum decrease after 12 doses and remaining reduced up to 60 doses. The reduction in seizure threshold persisted for at least 40 days of no alcohol following the 60th dose. The long‐lasting decrease in seizure threshold following CIE treatment resembled the “kindling” phenomenon produced by chronic administration of PTZ (25 mg/kg, 3 times/week). The CIE rats developed, in addition, a tolerance to the anticonvulsant action of ethanol, which occurred well after the decrease in PTZ seizure threshold, and a tolerance to the hypothermic effect of ethanol, which developed rapidly. PTZ kindled rats that had never been exposed to ethanol also exhibited tolerance to the hypothermic effect of ethanol. We propose that kindling contributes to the mechanism of the development of dependence on central nervous system depressants like benzodiazepines, barbiturates, and alcohol, drugs that act on the γ‐aminobutyric acid‐A receptor chloride ion channel complex. Repeated episodes of depression and withdrawal hyperexcitability are postulated to produce kindling during the repeated withdrawal episodes. In chronic ethanol abuse, the withdrawal stress/hyperexcitability would be repeated many times and lead to the development of dependence as measured by the persistent increase in withdrawal severity, manifested as heightened sensitivity to seizures (kindling). The long‐lasting decreases in seizure threshold following both chronic pentylenetetrazol and chronic intermittent ethanol suggest the possibility that some common mechanisms, such as the involvement of γ‐aminobutyric acid‐A receptors, may underlie the two kindling phenomena.