The major goal of this proposal is to develop an approach for benzodiazepine behavioral toxicity assessment that measures operationally defined pharmacodynamic contributions to the side effects, particularly neuromotor-cognitive impairment, while controlling for pharmacokinetic parameters. To determine the factors contributing to alterations in pharmacodynamic profiles, we will compare several benzodiazepines of differing pharmacological properties in terms of the following aspects of the behavioral drug effect: (1) de novo sensitivity-potency; (2) acute tolerance; (3) characteristics of de novo sensitivity-potency and acute tolerance for different neuromotor-cognitive functions. An important underlying premise in this proposal is that our recent findings demonstrating comparative benzodiazepine differences in potency and acute tolerance are in part based on differential receptor kinetics. To delineate further the contribution of receptor kinetics to the development of acute tolerance for different benzodiazepines, we propose the following objectives: (1) To elucidate the pharmacodynamic nature of the potentially unique high affinity binding by benzodiazepines with ortho Cl- on the """"""""C"""""""" ring in both a young and an elderly sample. (2) To elucidate the contribution of Bz1 and Bz2 receptors to benzodiazepine impairment by assessing the differential effect of a Bz1 specific drug vs. a Bz1, Bz2 nonspecific drug for coordination tasks vs. cognitive or learning-memory tasks in a young and an old population. (3) To explore the relationship between acute and chronic benzodiazepine tolerance. A long-term goal of this project is to develop a neuromotor-cognitive task battery that can be used to evaluate different sedative-anxiolytic drugs for the type, intensity and time course of impairment in order to predict expected levels of clinical impairment. Such a battery could be utilized in a physician's office to facilitate more discriminating prescribing practices as well as in the research laboratory to assess more systematically sedative-anxiolytic behavioral toxicity, especially for predicting drugs with the greatest potential for facilitating fatal traffic accidents.
Showing the most recent 10 out of 11 publications
