Abuse-related Effects of Subtype-selective GABA Receptor Positive Allosteric Modulators in an Assay of Intracranial Self-stimulation in Rats

Rationale: GABA positive allosteric modulators (GABA PAMs), such as diazepam and zolpidem, are used clinically for anxiety and insomnia, but abuse liability is a concern. Novel GABA PAMS may have lower abuse liability while retaining clinical utility.

Objective: The present study compared abuse-related effects of the non-selective GABA PAM diazepam, the α1-selective GABA PAM zolpidem, and three novel GABA 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 GABA receptors, putative in vivo selectivity at α2/α3-containing GABA receptors, and produce anxiolytic-like effects with limited sedation in non-human 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 GABA receptors in mediating GABA PAM-induced ICSS facilitation. These results are concordant with drug self-administration studies in monkeys in suggesting that GABA PAMs with low α1 efficacy and putative α2/α3 selectivity have lower abuse liability than high-efficacy non-selective or α1-selective GABA PAMs.