Abuse-related effects of subtype-selective GABAA receptor positive allosteric modulators in an assay of intracranial self-stimulation in rats

Abstract

Rationale GABAA Positive Allosteric Modulators (GABAA PAMs), such as diazepam and zolpidem, are used clinically for anxiety and insomnia, but abuse-liability is a concern. Novel GABAA PAMS may have lower abuse-liability while retaining clinical utility. Objective The present study compared abuse-related effects of the nonselective GABAA PAM diazepam, the α1-selective GABAA PAM zolpidem, and three novel GABAA PAMs (JY-XHe-053, XHe-II-053, and HZ-166) using intracranial self-stimulation (ICSS) in rats. These novel compounds have relatively low efficacy at α1, α2, and α3-containing GABAA receptors, putative in vivo selectivity at α2/α3-containing GABAA receptors, and produce anxiolytic-like effects with limited sedation in nonhuman primates. Methods Adult, male Sprague-Dawley rats (n=17) were each implanted with a bipolar electrode in the medial forebrain bundle and trained to respond under a fixed-ratio 1 schedule of reinforcement for electrical brain stimulation. The potency and time course of effects were compared for diazepam (0.1–10 mg/kg), zolpidem (0.032–3.2 mg/kg), and the three novel compounds (JY-XHe-053, XHe-II-053, and HZ-166; all 3.2–32 mg/kg). Results Zolpidem and diazepam produced transient facilitation of ICSS at small doses and more sustained rate-decreasing effects at larger doses. JY-XHe-053 and HZ-166 produced weak and inconsistent ICSS facilitation, whereas XHe-II-053 had no effect on ICSS. Conclusions These results support a key role for α1-containing GABAA receptors in mediating GABAA PAM-induced ICSS facilitation. These results are concordant with drug self-administration studies in monkeys in suggesting that GABAA PAMs with low α1 efficacy and putative α2/α3 selectivity have lower abuse-liability than high-efficacy non-selective or α1-selective GABAA PAMs.

Evaluation of the anti-conflict, reinforcing, and sedative effects of YT-III-31, a ligand functionally selective for α3 subunit-containing GABAA receptors

“…This observation raises the possibility that compounds with zero or relatively lower α1GABA A intrinsic efficacy may have reduced reinforcing effects. Importantly, these findings are consistent with a recent report by Schwienteck et al (2017) using ICSS procedures in rats, in which compounds with differing degrees of functional selectivity for α2/3GABA A receptors produced less facilitation of ICSS thresholds than diazepam, suggesting lower abuse liability than associated with a conventional benzodiazepine.…”

Role of mu opioid receptor (MOR) agonist efficacy as a determinant of opioid antinociception in a novel assay of pain-depressed behavior in female and male mice

“…Consistent with its effectiveness to treat many types of clinical pain and to alleviate other examples of IP acid-induced behavioral depression in rodents, the positive control NSAID analgesic ketoprofen fully blocked IP acid-induced depression of both crosses and movement at doses that had no effect on these endpoints when ketoprofen was administered alone (35,46,47,51). By contrast, the negative controls diazepam, U69593, and psilocybin produced dose-dependent behavioral depression when administered alone consistent with other evidence for their motor effects (51)(52)(53)(54)(55)(56), and lower doses that did not impair motor function failed to alleviate IP acid-induced behavioral depression. These findings imply that diazepam, U69593, and psilocybin either do not produce analgesia or do so only at doses equal to or above those that produce motor impairment.…”

No Abuse Potential of Silexan in Healthy Recreational Drug Users: A Randomized Controlled Trial

“…According to currently applicable clinical practice guidelines (e.g., National Collaborating Centre for Mental Health, 2011 ; Bandelow et al, 2012 ; Baldwin et al, 2014 ), recommended pharmacological treatments for anxiety disorders include antidepressant drugs such as selective serotonin reuptake inhibitors and selective norepinephrine reuptake inhibitors, sedative-hypnotic drugs such as benzodiazepines, and pregabalin. Benzodiazepines and pregabalin in particular have been associated with abuse potential and dependence based on clinical observations and through their mechanisms of action (e.g., Nothdurfter et al, 2012 ; Baldwin et al, 2013 ; Engin et al, 2014 ; Schjerning et al, 2016 ; Schwienteck et al, 2017 ). Silexan may thus be an interesting therapeutic option for the pharmacotherapy of anxiety-related disorders.…”