Negative allosteric modulation of GABAA receptors inhibits facilitation of brain stimulation reward by drugs of abuse in C57BL6/J mice
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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.
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.
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.
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.
KeywordsBenzodiazepine D-methamphetamine Ro15-4513 Intracranial self-stimulation (ICSS) Toluene Inhalant abuse GABA Brain stimulation reward (BSR) Flumazenil Negative allosteric modulation
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.
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).
- Chan M-H, Chung S-S, Stoker AK et al (2012) Sarcosine attenuates toluene-induced motor incoordination, memory impairment, and hypothermia but not brain stimulation reward enhancement in mice. Toxicol Appl Pharmacol 265:158–165. doi: 10.1016/j.taap.2012.10.004 PubMedCentralCrossRefPubMedGoogle Scholar
- Chan M-H, Tsai Y-L, Lee M-Y, et al. (2015) The group II metabotropic glutamate receptor agonist LY379268 reduces toluene-induced enhancement of brain-stimulation reward and behavioral disturbances. Psychopharmacology (Berl). doi: 10.1007/s00213-015-3973-3Google Scholar
- D’Souza D (2015) Ability of partial inverse agonist, iomazenil, to block ethanol effects in humans. NCT01590277.Google Scholar
- National Drug Intelligence Center (2011) The economic impact of illicit drug use on American society. Washington D.C, United States Department of JusticeGoogle Scholar
- National Research Council (2011) Guide for the care and use of laboratory animals, 8th edn. National Academies Press, Washington, D.CGoogle Scholar
- Paxinos G, Franklin KBJ (2007) The mouse brain in stereotaxic coordinates, 3rd edn. Academic, San DiegoGoogle Scholar
- Riegel AC, Zapata A, Shippenberg TS, French ED (2007) The abused inhalant toluene increases dopamine release in the nucleus accumbens by directly stimulating ventral tegmental area neurons. Neuropsychopharmacol Off Publ Am Coll Neuropsychopharmacol 32:1558–1569. doi: 10.1038/sj.npp.1301273 CrossRefGoogle Scholar
- Stanton A. Glantz (2006) Primer of Biostatistics, 6th Edition. McGraw-Hill Education/MedicalGoogle Scholar
- Taylor SR, Badurek S, Dileone RJ, et al. (2014) GABAergic and Glutamatergic Efferents of the Mouse Ventral Tegmental Area. J Comp Neurol. doi: 10.1002/cne.23603Google Scholar