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

Abstract

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

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

Keywords: Abuse liability; Diazepam; GABAA positive allosteric modulators; ICSS; Intracranial self-stimulation; Rats; Zolpidem.

Fig. 1

Effects of diazepam (0.1–10 mg/kg) on ICSS in rats. Left panels (a,c,e) show drug effects on frequency-rate curves. Abscissae: frequency of electrical brain stimulation in log hertz. Ordinates: ICSS rate expressed as percent maximum control rate (%MCR). Filled symbols indicate frequencies at which ICSS rates after diazepam were different than those observed after vehicle (a) or at baseline (c,e) as determined by the Holm-Sidak post-hoc test following a significant two-way ANOVA. Right panels (b,d,f) show summary data expressed as percent baseline total stimulations delivered across all frequencies of brain stimulation per test component. Abscissae: drug dose (mg/kg) or time (min or H) after drug administration. Ordinates: % Baseline Total Stimulations per Component. Upward/downward arrows indicate significant drug-induced increases/decreases, respectively, in ICSS relative to vehicle or baseline for at least one brain stimulation frequency as determined by analysis of full-frequency rate curves in the left panels. All points show mean ± SEM for 5 rats

Fig. 2

Effects of zolpidem (0.032–3.2 mg/kg) on ICSS in rats. Left panels (a,c,e) show drug effects on frequency-rate curves. Filled symbols indicate frequencies at which ICSS rates after zolpidem were different than those observed after vehicle (a) or at baseline (c,e) as determined by the Holm-Sidak post-hoc test following a significant two-way ANOVA. Right panels (b,d,f) show summary data expressed as percent baseline total stimulations delivered across all frequencies of brain stimulation per test component. Upward/downward arrows indicate significant drug-induced increases/decreases, respectively, in ICSS relative to vehicle or baseline for at least one brain stimulation frequency as determined by analysis of full-frequency rate curves in the left panels. All points show mean ± SEM for four to eight rats (dose effect curve: 0.032–3.2 mg/kg n=5, 3.2 mg/kg n=4; time courses: n=8). The asterisk in panel b indicates that results with 3.2 mg/kg zolpidem were not included in statistical analysis because one rat lost its headcap before this dose was tested. Other details as in Fig. 1

Fig. 3

Effects of JY-XHe-053 (3.2–32 mg/kg), XHe-II-053 (3.2–32 mg/kg) and HZ-166 (3.2–32 mg/kg) on ICSS in rats. Left panels (a,c,e) show drug effects on frequency-rate curves. Filled symbols indicate frequencies at which ICSS rates after test drug were different than those observed after vehicle as determined by the Holm-Sidak post-hoc test following a significant two-way ANOVA. Right panels (b,d,f) show summary data expressed as percent baseline total stimulations delivered across all frequencies of brain stimulation per test component. Upward/downward arrows indicate significant drug-induced increases/decreases, respectively, in ICSS relative to vehicle or baseline for at least one brain stimulation frequency as determined by analysis of full-frequency rate curves in the left panels. All points show mean ± SEM for five to six rats (JY-XHe-053 and XHe-II-053: n=5; HZ-166: n=6). Other details as in Fig. 1

Fig. 4

Effects of GABA_A PAMs on ICSS thresholds. Abscissa: Compound and dose (mg/kg) that was most effective to facilitate ICSS. Ordinate: Δθ₀ in log Hz. $ indicates a significant difference between effects of drug and vehicle as indicated by t-test