The first major goal is to utilize chronic benzodiazepine (chlordiazepoxide CDP) dependence animal models developed in this lab for single-dose withdrawal (acute dependence), chronic high and low dose dependence and protracted withdrawal to test a GABA hypothesis for hypoeffectiveness associated with withdrawal. Rats undergoing maximal withdrawal will be treated with pro-GABAergic drugs to evaluate withdrawal expression; the status of the GABA system associated with single dose dependence, chronic low and high dose dependence and protracted withdrawal will be evaluated and compared by determining seizure thresholds for drugs that oppose GABA transmission. Maximal sub-convulsive doses of GABA blocking drugs will be evaluated in maximal CDP withdrawal to determine how withdrawal signs are changed. The second major goal is to test the specificity for a GABA mechanism by considering alternative specific neurochemical hypotheses, i.e., serotonergic, adrenergic and adenosinergic. Specific agonists, mimetics, antagonists and enzyme inhibitors will be evaluated in the withdrawal suppression model and by seizure thresholds to pro-convulsive neurochemically specific treatments. The third objective is to test the hypothesis that long-term (up to a year) low dose benzodiazepine exposure induces dependence that grows in magnitude progressively with time. Sub-clinical experimental studies are needed to answer this question since clinical case reports of patients are equivocal. The fourth objective is to test the hypotheses that the non-pharmacological organismal variables of gender and strain are significant determinants of benzodiazepine dependence. Epidemiology data suggest women might be at a greater risk of benzodiazepine dependence than man. Genetic/strain differences have not been explored, but are relevant for other CNS depressants including alcohol and barbiturate dependence.
