CGS 9896 blocks the pentylenetetrazol‐like effect of withdrawal from chronic ethanol

AbstractTermination of chronic ethanol produces a withdrawal syndrome characterized not only by physical signs but also by subjective symptoms. One such subjective effect is an interoceptive discriminative stimulus similar to that of the anxiogenic drug pentylenetetrazol (PTZ). In the present study, the pyrazoloquinoline CGS 9896, a nonsedating anxiolytic of low abuse liability, was tested for its ability to reduce the PTZ‐like stimulus effect of ethanol withdrawal. Rats were trained with food reward in a two‐lever choice task to discriminate between PTZ, 20 mg/kg, and saline. Training was then suspended, and the rats were given ethanol for 4–6 days in a nutritionally complete liquid diet (dose consumed 11–13 g/kg/day). At selected times after a final dose of ethanol (3 g/kg), given by gavage, they were tested for lever selection. In contrast to their saline‐lever selection in tests with saline prior to chronic ethanol, rats selected the PTZ lever in tests with saline during withdrawal. Although CGS 9896 transiently impaired performance of the lever‐selection task, it decreased the percentage of rats selecting the PTZ lever during withdrawal. Blockade by CGS 9896 of the PTZ‐like withdrawal stimulus was dose‐dependent over the range 5–20 mg/kg and was more effective after orally than after intraperitoneally administered CGS 9896. These data suggest that CGS 9896 may ameliorate some of the unpleasant subjective sequelae of ethanol withdrawal and may be of clinical value in the treatment of alcoholism.