DILTIAZEM ALTERS SOME WITHDRAWAL SIGNS IN PENTOBARBITAL-DEPENDENT RATS

Male, Sprague-Dawley rats were made dependent on pentobarbital sodium (PB) by continuous, IP infusion of PB for 13 days. On Day 14, a 72-hour PB-free period began during which body weight, 24-hour water consumption and withdrawal scores were noted. In Study 1, rats were placed into one of four treatment groups at the start of the PB-free period. Groups included saline-infused control rats with twice daily administration of either vehicle or diltiazem and PB-dependent rats treated twice daily with either diltiazem or vehicle. In Study 2, rats were placed into one of the four treatment groups at the start of the 13-day PB-infusion period. In Study 1, PB-dependent rats treated with diltiazem exhibited approximately 10% loss of body weight at both 12 and 48 hours of the PB-free period while PB-dependent rats treated with vehicle exhibited only about a 5% loss of body weight. PB-dependent rats treated with either diltiazem or vehicle both exhibited about a 40% decline in water consumption and were noted to have significant increases in withdrawal scores by the fifth hour of the PB-free period. As compared to the scores of PB-dependent rats treated with vehicle, diltiazem did not significantly alter the withdrawal scores of PB-dependent rats at any time point during the PB-free period. In Study 2, the chronic administration of diltiazem to PB-infused rats produced both a significant decrease in water consumption at 48 and 72 hours and a significant increase in withdrawal scores from 3-48 hours. Mortality, which occurred only during the PB-free period and involved only PB-dependent rats treated with diltiazem, reached 50% by the end of the PB-free period. It appears that the chronic administration of diltiazem for 13 days led to an exacerbation of some of the typical withdrawal symptoms in PB-dependent rats.