FUNCTIONAL ANALYSIS OF GABAERGIC SEDATIVE/ANXIOLYTICS

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Anxiolytics and sedative-hypnotics are among the most widely prescribed of all psychoactive medications. Misuse, abuse, and physiological dependence associated with their use are of continuing concern. Over the past 20 years, drug discrimination analysis has provided an animal model for classification of the subjective effects of psychoactive drugs relevant to preclinical drug abuse liability assessments. It also has proven uniquely sensitive and selective as a behavioral assay for examining functional in vivo relevance of novel chemical structures, novel receptor binding profiles, and novel cellular activity for centrally acting drugs. The aims of the present application are predicated on the evidence from our previous work that drug discrimination analysis is uniquely powerful for analyzing the relationship between the biochemical and behavioral effects of psychoactive drugs. Specific Aim 1 is to characterize the relation between in vitro profiles for GABAA modulators that bind the benzodiazepine (Bz) site and their in vivo profiles of discriminative stimulus effects. Advances in understanding the structure of the GABAA-receptor complex have led to development of novel compounds that preferentially bind GABAA receptor subtypes, have lower efficacy in modulating GABA, or both. The hope is that such compounds will be better treatments for anxiety and sleep disorders, produce less tolerance with chronic use, and have less abuse liability and dependence potential. The in vitro work on these compounds provides a platform for making predictions about specific behavioral effects, which we will test. Specific Aim 2 is to test predictions about the relation between chronic Bz administration and the effects of glutamatergic ligands administered during and after the chronic Bz. In vitro data and data from studies of convulsant thresholds in mice strongly suggest that the withdrawal syndrome that emerges after discontinuation of chronic Bz use may be due less to reduced GABAergic functioning as to overfunctioning of the ionotropic glutamatergic system. The proposed studies will exploit the sensitivity of drug discrimination training for neuronal substrates of drug action to explore the predictions of the glutamate hypothesis of the Bz withdrawal syndrome. These data will be critical to our understanding of mechanisms of Bz dependence and their relation to Bz tolerance. One of the studies under Specific Aim 2 will extend our work on physiological dependence on Bz ligands to provide a direct test of the use of non-competitive antagonists for the N-methyl-D-aspartate receptor to ameliorate Bz withdrawal.