Synaptic and extrasynaptic GABAA receptors in benzodiazepine withdrawal: effects of pregnanolone and gaboxadol in benzodiazepine‐dependent monkeys

Abstract

Benzodiazepines and neuroactive steroids positively modulate GABAA receptors through different binding sites. These drugs share many behavioral effects including the ability to reverse benzodiazepine withdrawal; however during chronic benzodiazepine treatment, tolerance develops to benzodiazepines and not to neuroactive steroids. This difference might be related to actions of neuroactive steroids at benzodiazepine‐insensitive extrasynaptic GABAA receptors. This study examined the ability of gaboxadol, an orthosteric agonist at extrasynaptic GABAA receptors, to attenuate flumazenil‐lever responding, a sign of benzodiazepine withdrawal. Four rhesus monkeys received 5.6 mg/kg/day diazepam and discriminated 0.1 mg/kg flumazenil. Gaboxadol (1.78–5.6 mg/kg) did not produce flumazenil‐lever responding or shift flumazenil dose‐response curves whereas pregnanolone, a neuroactive steroid, shifted the curves rightward. Because pregnanolone attenuated withdrawal whereas agonist action only at extrasynaptic GABAA receptors (gaboxadol) did not, it is unlikely that those receptors account for the difference between benzodiazepines and neuroactive steroids in benzodiazepine‐treated monkeys. This difference is more likely due to changes in synaptic GABAA receptors, such as subunit composition or coupling of binding sites. Supported by USPHS grants R01DA09157 and K05DA017918 (CPF).