GABAA receptor mechanisms in benzodiazepine physical dependence and tolerance

Benzodiazepines (BZs) are widely used in the treatment of anxiety and sleep disorders. However, unwanted side effects, such as sedation, motor impairment, and the potential for physical dependence and tolerance, can hinder their use in the clinic. Elucidating the GABAA receptor subtypes underlying these behavioral effects can facilitate the development of an anxiolytic pharmacotherapy with enhanced clinical utility and reduced unwanted side effects. Subtype selective compounds were used to investigate the underlying receptor mechanisms involved in the observable behavioral effects of BZs. In addition, the receptor mechanisms involved in BZ physical dependence and tolerance were also investigated. In addition to observable behavioral effects and motor impairment (MAP and FRR) of BZs, novel categories of observable sedation (sleep posture, moderate sedation, and deep sedation) have been included. Acutely, sleep posture is likely mediated by α2/3GABAA receptors while α1GABA A receptors may mediate deep sedation associated with BZs. The motor impairing effects observed with the MAP and FRR tasks likely involve an interaction of GABAA receptors containing α1, α2, and α3 subunits. The receptor mechanisms underlying tolerance and physical dependence associated with chronic alprazolam administration were investigated. Tolerance developed rapidly to deep sedation, which is likely mediated by α1GABA A receptors, while sleep posture, which is thought to be mediated by α2/3GABAA receptors, persisted throughout chronic treatment. Motor impairment measured by the MAP and FRR tasks also developed tolerance at a similar rate as deep sedation, further suggesting a role for α1GABA A receptors in these behaviors. Substitution tests were conducted to investigate physical dependence and cross-tolerance. Results suggest physical dependence developed following chronic alprazolam treatment. In addition, α1GABAA receptors likely play a role in physical dependence. Withdrawal effects following substitution tests with zolpidem and NEP-581 precluded the determination of cross-tolerance