title: Negative allosteric modulation of GABAA receptors inhibits facilitation of brain stimulation reward by drugs of abuse in C57BL6/J mice.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  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.
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, 410 North 12th Street, Room 746, P.O. Box 980613, Richmond, VA, 23298-0613, USA.
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Tracy
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, 410 North 12th Street, Room 746, P.O. Box 980613, Richmond, VA, 23298-0613, USA.
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Banks
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, 410 North 12th Street, Room 746, P.O. Box 980613, Richmond, VA, 23298-0613, USA. klshelto@vcu.edu.
authors.forename: Keith L
authors.initials: KL
authors.lastname: Shelton
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects / Q000502:physiology; D000818:Animals; D001386:Azides / Q000008:administration & dosage; D001569:Benzodiazepines / Q000008:administration & dosage; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D003975:Diazepam / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D005442:Flumazenil / Q000008:administration & dosage; D018757:GABA Modulators / Q000008:administration & dosage*; D013287:Illicit Drugs / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017551:Microdialysis; D011963:Receptors, GABA-A / Q000502:physiology*; D012201:Reward; D012653:Self Stimulation / Q000187:drug effects* / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000008:administration & dosage
chemical_list: D001386:Azides; D018757:GABA Modulators; D013287:Illicit Drugs; D011963:Receptors, GABA-A; D001569:Benzodiazepines; D005442:Flumazenil; D005680:gamma-Aminobutyric Acid; C042957:Ro 15-4513; D003975:Diazepam
keywords: Benzodiazepine; Brain stimulation reward (BSR); D-methamphetamine; Flumazenil; GABA; Inhalant abuse; Intracranial self-stimulation (ICSS); Negative allosteric modulation; Ro15-4513; Toluene