Time course of the development of barbiturate tolerance and dependence

Adult male Sprague-Dawley rats were made barbiturate dependent by the forced consumption of increasing concentrations of barbital (0.2-0.5 percent by weight) in powdered food. Manifestations characteristic of barbiturate dependence, i.e. weight loss, susceptibility to pentylenetetrazol (PTZ)-induced convulsions and susceptibility to spontaneous convulsions, were examined following the abrupt withdrawal of barbital at the end of each week of the barbital regimen. A statistically significant decrease in weight gain was observed during a 40 hour period following barbital withdrawal at the end of the first week of the barbital regimen. Progressively more severe weight losses were observed following the withdrawal of barbital from the chronically treated rats at the end of each subsequent week of the regimen. An increased susceptibility to PTZ-induced convulsions was also evident following the withdrawal of barbital from rats at the end of the first week of the drug regimen. At the end of subsequent weeks 60-100 percent of the barbital treated rats had convulsions following PTZ administration. The convulsions were severe and many rats died. Spontaneous convulsions were observed in increasing numbers following the withdrawal of barbital from drug-treated rats beginning with the third week of the barbital regimen. Barbiturate tolerance as evidenced by high brain and serum levels of barbital at awakening from an anesthetic dosage was evident by the end of the first week of barbital consumption. The results show that barbiturate tolerance and dependence develops rapidly within 1 to 2 weeks of the administration of barbital in powdered food.