Benzodiazepines are very useful and safe drugs when used alone in the treatment anxieties, sleep disorders, muscle pain, convulsions and alcohol withdrawal. They however can be very toxic when used with other central nervous system depressants and produce physical dependence when used chronically. Physical dependence on benzodiazepines is complex and involves many systems of the brain and results in many signs when they are withdrawn. Different benzodiazepines produce different therapeutic effects and different types of physical dependencies. It is also known that the recently found that diazepam and halazepam in large doses produce a dose related liver toxicity while other benzodiazepines (eg alprazolam) do not. The general aims of this proposal are to (1) find which parts of the brain and (2) which benzodiazepine receptors are responsible for the different signs of the abstinence syndrome. (3) Which administering benzodiazepines chronic increase the number of responsible receptors. (5) The benzodiazepine abstinence syndrome is thought to increase the need for benzodiazepines. The parts of the brain and the receptors responsible for this increased need will be identified. (6) Efforts will be made to find out if the hepatotoxicity seen in the dog is of importance in humans by studying liver function and free plasma levels of diazepam, alprazolam and their metabolites in patients being treated with these drugs chronically. To identify those parts of the brain and the receptor that are responsible for abstinence signs and symptoms, small amounts of specific agonist and antagonists will be injected into different brain sites of benzodiazepine abstinent and stabilized dependent rats and see if the different sign are decreased or increased. To help identify receptor characteristics responsible for dependencies, abstinence will be produced with graded doses of the antagonist, flumazenil, in dogs and rats dependent on graded doses of diazepam and its metabolites. Free brain levels of diazepam, its metabolites and flumazenil will be determined. These data and abstinence scores will be used to calculate the number and the affinity of the receptors. These studies may provide a rational basis for designing new and selective benzodiazepines which are safer and do not produce dependence.

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Drug Abuse Biomedical Research Review Committee (DABR)
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University of Kentucky
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Jing, X; Wala, E P; Sloan, J W (1998) The effect of chronic benzodiazepines exposure on body weight in rats. Pharmacol Res 37:179-89
Sloan, J W; Wala, E; Jing, X et al. (1998) Diazepam-treated female rats: flumazenil- and PK 11195-induced withdrawal in the hippocampus CA1. Pharmacol Biochem Behav 61:121-30
Wala, E P; Sloan, J W; Jing, X (1997) Dorsal raphe and substantia nigra response to flumazenil in diazepam-dependent rats. Pharmacol Biochem Behav 58:221-9
Wala, E P; Sloan, J W; Jing, X (1997) Comparison of abstinence syndromes precipitated by flumazenil and PK 11195 in female diazepam-dependent rats. Psychopharmacology (Berl) 133:214-23
Wala, E P; Sloan, J W; Jing, X et al. (1996) Intrathecally administered flumazenil and PK 11195 precipitate abstinence syndrome in freely moving diazepam dependent rats. Drug Alcohol Depend 43:169-77
Wala, E P; Sloan, J W (1995) Flumazenil, diazepam, nordiazepam and oxazepam interactions on plasma protein binding. Pharmacol Res 32:299-304
Wala, E P; Martin, W R; Sloan, J W (1995) Brain-plasma distribution of free and total benzodiazepines in dogs physically dependent on different doses of diazepam. Pharmacol Biochem Behav 52:707-13
Jing, X; Wala, E P; Sloan, J W (1995) Flunitrazepam and nordiazepam slowly released from silastic capsules induce physical dependence in rat. Drug Alcohol Depend 39:63-70
Sloan, J W; Martin, W R; Wala, E (1993) Effect of the chronic dose of diazepam on the intensity and characteristics of the precipitated abstinence syndrome in the dog. J Pharmacol Exp Ther 265:1152-62
Wala, E P; Martin, W R; Sloan, J W (1993) Pharmacokinetics of nordiazepam in physical dependence and precipitated abstinence in dogs. Pharmacol Biochem Behav 44:857-64

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