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Psychopharmacology

, Volume 233, Issue 4, pp 715–725 | Cite as

Negative allosteric modulation of GABAA receptors inhibits facilitation of brain stimulation reward by drugs of abuse in C57BL6/J mice

  • Matthew E. Tracy
  • Matthew L. Banks
  • Keith L. SheltonEmail author
Original Investigation

Abstract

Rationale

There is an emerging body of evidence that implicates a crucial role of γ-aminobutyric acid subtype A (GABAA) receptors in modulating the rewarding effects of a number of abused drugs. Modulation of GABAA receptors may therefore represent a novel drug-class independent mechanism for the development of abuse treatment pharmacotherapeutics.

Objectives

We tested the hypothesis that the GABAA receptor benzodiazepine-site (BDZ) negative modulator Ro15-4513 would reduce the reward-related effects of three pharmacologically dissimilar drugs; toluene vapor, d-methamphetamine, and diazepam using intracranial self-stimulation (ICSS) in mice. We also examined whether Ro15-4513 attenuated dopamine release produced by d-methamphetamine in an in vivo microdialysis procedure.

Results

Ro15-4513 abolished ICSS reward facilitation produced by all three abused drugs at Ro15-4513 doses which had no effect on ICSS when administered alone. In contrast, the BDZ antagonist flumazenil only attenuated the ICSS-facilitating effects of diazepam. Administration of the same dose of Ro15-4513 which abolished drug-facilitated ICSS produced a 58 % decrease in d-methamphetamine-stimulated dopamine in the nucleus accumbens of mice relative to d-methamphetamine alone.

Conclusions

These results demonstrate that negative modulation of GABAA receptors can produce profound reductions in reward-related effects of a diverse group of drugs that activate the mesolimbic reward pathway through different mechanisms. These data suggest that pharmacological modulation of GABAA receptors may represent a viable pathway for the development of drug abuse pharmacotherapies.

Keywords

Benzodiazepine D-methamphetamine Ro15-4513 Intracranial self-stimulation (ICSS) Toluene Inhalant abuse GABA Brain stimulation reward (BSR) Flumazenil Negative allosteric modulation 

Notes

Acknowledgments

Dr. Shelton and Matt Tracy declare that the NIH has funded their research under R01DA-020553 and F31DA-034469, respectively. Dr. Banks declares that NIH has funded his research. During the past 3 years, he has received compensation as a collaborator with Perdue Pharmaceuticals for projects related to opioid pharmacology and drug development.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethics approval

All procedures were approved by the Institutional Animal Care and Use Committee of Virginia Commonwealth University and were in accordance with NIH guidelines (National Research Council 2011).

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Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Matthew E. Tracy
    • 1
  • Matthew L. Banks
    • 1
  • Keith L. Shelton
    • 1
    Email author
  1. 1.Department of Pharmacology and ToxicologyVirginia Commonwealth UniversityRichmondUSA

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