The physical dependence liability associated with CNS depressant drugs such as barbiturates, benzodiazepines and ethanol has prompted investigations into the possible mechanisms which may underlie the establishment of the drug dependent state. The GABA-benzodiazepine chloride ion channel complex is thought to represent a fundamental site for the action of CNS depressant agents. The interactions between the separate components of this site has been of considerable interest for investigation of the mechanisms which may be involved in the establishment of dependence on these agents. The current proposal is designed to investigate the influence of benzodiazepine inverse agonists (i.e. agents which have an intrinsic effect opposite of that of the benzodiazepine agonist) on the expression of physical dependence on pentobarbital (Study 1). A second thrust of this proposal (Study 2) is to define the effect of chronic pentobarbital administration on GABA-dependent chloride ion flux in brain neuronal membranes. Again the effect of benzodiazepine agonists (diazepam), antagonists (R015-1788) and inverse agonists (R015-4513 and FG7142) on chloride ion flux in brain samples from pentobarbital treated and control rats will be assessed. Study 1 is divided into 4 separate experiments. In all experiments rats are made dependent on pentobarbital by continuous pentobarbital infusion, using an escalating dosage schedule, for 13 days. On Day 14 will begin a 72 hour withdrawal period. In experiment 1 pentobarbital-dependent rats will be administered either vehicle or R015-45213 in doses of 2.5, 5.0 or 10 mg/kg twice daily. In experiment 3 rats will be administered R015-4513 daily during the 13 day pentobarbital infusion period and in experiment 4 rats will be administered FG7142 daily during the pentobarbital infusion period. In all experiments body weight and water consumption will be monitored daily. During the withdrawal period rats will be monitored for signs of withdrawal from pentobarbital. In study 2 rats will be grouped into either saline-infused or pentobarbital infused groups and infused for 13 days followed by a 72 hour long withdrawal period. At 3, 6, 9 and 13 days and at 12, 24, 48 and 72 hours control and pentobarbital treated rats will be sacrificed and the whole brain (minus cerebellum) prepared for 36 Cl-flux studies. The effect of chronic pentobarbital administration on GABA-dependent Cl- uptake will be studied in the presence and absence of diazepam, R015-4513, FG-7142 and R015-1788 (antagonist) using a neuronal membrane """"""""microsac"""""""" preparation. These studies are designed to investigate the effect of benzodiazepine inverse agonists on the expression of the pentobarbital dependent state.
| Yutrzenka, G J; Stone, T; Anderson, S (1996) Ro 15-4513 alteration of pentobarbital dependence. Pharmacol Biochem Behav 55:379-86 |
