Title |
Negative allosteric modulation of GABAA receptors inhibits facilitation of brain stimulation reward by drugs of abuse in C57BL6/J mice
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Published in |
Psychopharmacology, November 2015
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DOI | 10.1007/s00213-015-4155-z |
Pubmed ID | |
Authors |
Matthew E. Tracy, Matthew L. Banks, Keith L. Shelton |
Abstract |
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. |
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Geographical breakdown
Country | Count | As % |
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United States | 1 | 3% |
Unknown | 30 | 97% |
Demographic breakdown
Readers by professional status | Count | As % |
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Student > Ph. D. Student | 5 | 16% |
Student > Bachelor | 5 | 16% |
Unspecified | 3 | 10% |
Student > Doctoral Student | 2 | 6% |
Student > Master | 2 | 6% |
Other | 6 | 19% |
Unknown | 8 | 26% |
Readers by discipline | Count | As % |
---|---|---|
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Agricultural and Biological Sciences | 5 | 16% |
Neuroscience | 5 | 16% |
Unspecified | 3 | 10% |
Psychology | 2 | 6% |
Other | 0 | 0% |
Unknown | 9 | 29% |