The behavioural and neuronal effects of the chronic administration of benzodiazepine anxiolytic and hypnotic drugs.

Benzodiazepine anxiolytic and hypnotic drugs are some of the most widely prescribed drugs in the Western world. Despite this fact, the mechanisms that underlie the development of tolerance to, and dependence upon, benzodiazepines are poorly understood. The aim of this review is to summarize and critically evaluate the experimental evidence relating to the chronic behavioural and neuronal effects of benzodiazepines. Behavioural studies in animals generally indicate that tolerance gradually develops to the muscle relaxant, ataxic, locomotor and anticonvulsant effects of benzodiazepines. The evidence relating to the development of tolerance to the anxiolytic effects of benzodiazepines is less clear. The literature on the possible mechanisms of benzodiazepine tolerance and dependence is large, highly complex and difficult to interpret. The effect of chronic benzodiazepine treatment varies enormously as a function of the benzodiazepine used and the treatment schedule employed. Many studies have demonstrated a down-regulation of benzodiazepine binding sites, although affinity is usually unchanged. The evidence relating to the number and affinity of GABAA binding sites is unclear. Some studies suggest that chronic benzodiazepine administration results in a reduction in the number of Cl- channels associated with the GABAA receptor complex, although it is not clear that the efficacy of the GABA binding site in operating the Cl- channel necessarily changes. There is, however, substantial evidence to support the hypothesis that chronic benzodiazepine treatment results in a reduction in the coupling between the GABAA and benzodiazepine binding sites (the "functional uncoupling hypothesis"). Although some electrophysiological studies suggest that chronic benzodiazepine treatment results in a subsensitivity to GABA, this effect seems to be highly area-specific.