Changes in benzodiazepine/GABA receptor complex function in benzodiazepine-tolerant mice

Abstract

Mice were given flurazepam, 40 mg k-1, IP, once daily for 7 consecutive days. Twenty-four and forty-eight hours after the last injection measurements were made of the effects on convulsion threshold, body temperature and locomotor activity, of drugs acting on the GABA receptor complex. Significant decreases were seen in the hypothermic and hypomobility effects of progabide at 48 h, but no significant changes were seen in the effects of pentylenetetrazol or pentobarbitone. The actions of picrotoxin in all three types of test and the convulsant action of bicuculline (IP) were significantly decreased at 24 h but not at 48 h. The convulsive, but not the hypothermic, effects of picrotoxin were increased at the 48 h interval. These results may suggest that the chronic benzodiazepine treatment decreased some aspects of GABA receptor function at 48 h after the last dose; however, such an effect probably does not explain the previously reported increases in the effects of inverse agonists following chronic agonist treatment.

Lorazepam discontinuation promotes ‘inverse agonist’ effects of benzodiazepines

“…We have used the term 'discontinuation syndrome' rather than 'withdrawal syndrome' to avoid connotations associated with opiate withdrawal (Miller, 1988). Discontinuation syndromes have not been observed in all systems or for some behavioural effects (Nutt et al, 1988). This may be due in part to use of various benzodiazepines and to choice of time points for testing.…”

“…Thus, assessment of symptoms soon after discontinuation of these agents may fail to detect behavioural or neurochemical alterations. For example, few alterations in seizure susceptibility were observed in mice 24 and 48 h after discontinuation of chronic flurazepam (Nutt et al, 1988). However, the metabolite n-desalkyl flurazepam has high receptor occupancy (low Kj) and a prolonged half-life, so that symptons may not occur until days after drug discontinuation (Miller et al, 1988a).…”

“…However, the mechanism of benzodiazepine discontinuation syndromes remains uncertain. Studies in animal models have reproduced a behavioural discontinuation syndrome (File, 1982;Miller et al, 1988c), in some cases indicating an increase in sensitivity to benzodiazepine 'inverse agonists' after discontinuation of flurazepam (Little et al, 1987a,b;Nutt et al, 1988). Indeed, one group suggested the presence of a 'withdrawal shift' in the direction of inverse agonist effects associated with benzodiazepine discontinuation .…”

Molecular mechanisms of benzodiazepine‐induced down‐regulation of GABAA receptor α1 subunit protein in rat cerebellar granule cells

“…Potentially, the benzodiazepines may simply enhance the GABA-mediated receptor desensitization effect or they may act by an entirely different mechanism. GABAA receptor function is diminished after chronic GABA or benzodiazepine treatment (Gallagher et al, 1984;Nutt et al, 1988). However, the mechanisms responsible are still unknown.…”

Drug treatment of chronic insomnia — dawn at the end of a long night?

“…Benzodiazepine tolerance and withdrawal are thought to be due to adaptive alterations in endogenous GABA function as a result of chronic agonist stimulation of the receptor, which leads to profound changes in receptor function, especially a shift in the direction of enhanced inverse agonist function (Nutt, et al, 1988). These are probably because of altered GABA-A/benzodiazepine receptor subunit expression (Holt, et al, 1996).…”