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

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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 non-selective 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 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 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.

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Acknowledgements

The research was supported by the National Institutes of Health grants R01 NS070715 (SSN) and NS076517 and MH096463 (JMC). Additional support was provided by the Shimadzu Analytical Facility of Southeastern Wisconsin. All authors have made significant contributions to the research and manuscript, and all authors have read and approved the final manuscript.

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Authors and Affiliations

  1. Department of Pharmacology and Toxicology, Virginia Commonwealth University, 410 North 12th Street, PO Box 980613, Richmond, VA, 23298, USA

    Kathryn L. Schwienteck, Matthew L. Banks & S. Stevens Negus

  2. Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, Milwaukee, WI, USA

    Guanguan Li, Michael M. Poe & James M. Cook

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  1. Kathryn L. Schwienteck
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  2. Guanguan Li
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  3. Michael M. Poe
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  4. James M. Cook
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  5. Matthew L. Banks
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  6. S. Stevens Negus
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Correspondence to S. Stevens Negus.

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Experiments were performed with the approval of the Virginia Commonwealth University Institutional Animal Care and Use Committee in accordance with the National Institutes of Health Guidelines for the Care and Use of Laboratory Animals 8th edition (National Research Council 2011).

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The authors declare that they have no conflict of interest.

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Schwienteck, K.L., Li, G., Poe, M.M. et al. Abuse-related effects of subtype-selective GABAA receptor positive allosteric modulators in an assay of intracranial self-stimulation in rats. Psychopharmacology 234, 2091–2101 (2017). https://doi.org/10.1007/s00213-017-4615-8

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