Benzodiazepine derivatives, and other GABA-benzodiazepine receptor agonist ligands, continue to be extensively prescribed for the treatment of anxiety, insomnia, and panic disorder. Despite their generally favorable profile of safety and efficacy, the propensity of benzodiazepine agonists to produce tolerance and dependence during chronic administration, and a discontinuation syndrome on withdrawal, continues to be of concern. We have used experimental models to characterize the behavioral and pharmacodynamic features of benzodiazepine tolerance and withdrawal, as well as the neurochemical and molecular mechanisms of these phenomena, and strategies or interventions that may eliminate or minimize the problems. The model consists principally of a rodent species (male CD-1 mice) to which medications can be delivered continuously over periods of days or weeks via subcutaneously-implanted osmotic pumps. At varying times during and after medication infusion, animals are evaluated to determine: behavioral measures of motor activity; chemically-induced seizure threshold; in vivo benzodiazepine receptor occupancy, in vitro measures of receptor number, affinity, function, and coupling; expression of mRNA including several benzodiazepine receptor subunits; plasma and brain concentrations of drugs being infused. Using this well-validated model, as well as two newer models under development (cultured cortical neurons; EEG responses in rats with implanted electrodes), the project proposes to focus on the following research questions: a. The role of benzodiazepine receptor subtypes (BZ-1 vs BZ-2) in the development of tolerance and withdrawal, to be studied by chronic administration and discontinuation of a ligand (zolpidem) that is relatively BZ-1 selective; b. The role of the excitatory amino acid (EAA) receptor system in coregulation of benzodiazepine tolerance and withdrawal, studied by concurrent infusion of putative EAA antagonists; c. Age-dependent differences in response to chronic benzodiazepine administration and withdrawal, and the possible role of EAA coregulation, studied using matched cohorts of young and old animals.
| Fahey, Jeanne M; Pritchard, Gary A; Reddi, Jyoti M et al. (2006) The effect of chronic lorazepam administration in aging mice. Brain Res 1118:13-24 |
