Imidazenil: A low efficacy agonist at α1- but high efficacy at α5-GABAA receptors fail to show anticonvulsant cross tolerance to diazepam or zolpidem

Abstract

SUMMARYWhereas advances in the molecular biology of GABA A receptor complex using knock-out and knockin mice have been valuable in unveiling the structure, composition, receptor assembly, and several functions of different GABA A receptor subtypes, the mechanism(s) underlying benzodiazepine (BZ) tolerance and withdrawal remain poorly understood. Studies using specific GABA A receptor subunit knock-in mice suggest that tolerance to sedative action of diazepam requires long-term activation of α1 and α5 GABA A receptor subunits. We investigated the role of long-term activation of these GABA A receptor subunits during anticonvulsant tolerance using high affinity and high intrinsic efficacy ligands for GABA A receptors expressing the α5 subunit (imidazenil) or α1 subunit (Zolpidem), and a non-selective BZ recognition site ligand (diazepam). We report here that longterm activation of GABA A receptors by zolpidem and diazepam but not by imidazenil elicits anticonvulsant tolerance. Although anticonvulsant cross-tolerance occurs between diazepam and zolpidem, there is no cross-tolerance between imidazenil and diazepam or zolpidem. Furthermore, diazepam or zolpidem long-term treatment decreased the expression of mRNA encoding the α1 GABA A receptor subunit in prefrontal cortex by 43% and 20% respectively. In addition, diazepam but not zolpidem long-term treatment produced a 30% increase in the expression of the α5 GABA A receptor subunit mRNA in prefrontal cortex. In contrast, imidazenil which is devoid of anticonvulsant tolerance does not elicit significant changes in the expression of α1 or α5 GABA A receptor subunit. These findings suggest that long-term activation of GABA A receptors containing the α1 or other subunits but not the α5 receptor subunit is essential for the induction of anticonvulsant tolerance.

Differential effects of short- and long-term zolpidem treatment on recombinant α1β2γ2s subtype of GABAA receptors in vitro

“…Vlainić and Peričić (2009) [10] demonstrated development of anticonvulsant and sedative tolerance after repeated (10 days) zolpidem treatment in mice. Similar results were obtained in rats [11] . Several studies have also suggested that zolpidem has a significant risk of abuse and dependence in humans [12] .…”

“…Previous studies on mice [10] and rats [11] suggested that, upon repeated treatment, zolpidem produced tolerance to its anticonvulsive and sedative effects. Therefore, zolpidem has a higher abuse potential than previously suggested [12] .…”

Hooked on benzodiazepines: GABAA receptor subtypes and addiction

“…Therefore α1-sparing compounds will certainly not be suitable for all indications. However, imidazo-BDZ carboxamide derivatives (e.g., imidazenil) are α1-sparing compounds that have been shown to have anxiolytic and anticonvulsant actions without (at least so far) demonstrating tolerance and dependence liabilities in monkeys [87] and in rodents [88,89] (Table 1). As such, it may therefore be possible to dissociate anxiolysis from addictive liability, which would have important clinical ramifications for the effective treatment of anxiety-related disorders.…”

The effects of zolpidem treatment on GABAA receptors in cultured cerebellar granule cells: Changes in functional coupling

“…However, mice treated repeatedly with zolpidem, similar to those treated repeatedly with diazepam, have been found to develop tolerance to its sedative and anticonvulsant effects (Vlainić and Peričić, 2009). Similar results were obtained in rats (Auta et al, 2008). In addition, the World Health Organization reports that the frequency of zolpidem abuse and dependence is similar to that of benzodiazepines.…”

“…In contrast, Holt et al (1997), who studied the effects of zolpidem treatment in rats, reported that the effects on GABA A receptor gene expression in the cortex depended on the exposure time: the effect obtained after 7 days (increased level of α4 mRNA) markedly differed from that observed after 14 days (decreased level of α1 mRNA). Decreased expression of α1 GABA A receptor subunit mRNA was also observed in the prefrontal cortex after treatment of rats with zolpidem for 14 days (Auta et al, 2008).…”