title: Neural basis of benzodiazepine reward: requirement for α2 containing GABAA receptors in the nucleus accumbens.
abstract: Despite long-standing concerns regarding the abuse liability of benzodiazepines, the mechanisms underlying properties of benzodiazepines that may be relevant to abuse are still poorly understood. Earlier studies showed that compounds selective for α1-containing GABAA receptors (α1GABAARs) are abused by humans and self-administered by animals, and that these receptors may underlie a preference for benzodiazepines as well as neuroplastic changes observed in the ventral tegmental area following benzodiazepine administration. There is some evidence, however, that even L-838, 417, a compound with antagonistic properties at α1GABAARs and agonistic properties at the other three benzodiazepine-sensitive GABAA receptor subtypes, is self-administered, and that the α2GABAARs may have a role in benzodiazepine-induced reward enhancement. Using a two-bottle choice drinking paradigm to evaluate midazolam preference and an intracranial self-stimulation (ICSS) paradigm to evaluate the impact of midazolam on reward enhancement, we demonstrated that mice carrying a histidine-to-arginine point mutation in the α2 subunit which renders it insensitive to benzodiazepines (α2(H101R) mice) did not prefer midazolam and did not show midazolam-induced reward enhancement in ICSS, in contrast to wild-type controls, suggesting that α2GABAARs are necessary for the reward enhancing effects and preference for oral benzodiazepines. Through a viral-mediated knockdown of α2GABAARs in the nucleus accumbens (NAc), we demonstrated that α2 in the NAc is necessary for the preference for midazolam. Findings imply that α2GABAARs in the NAc are involved in at least some reward-related properties of benzodiazepines, which might partially underlie repeated drug-taking behavior.
authors.affiliation: 1] Laboratory of Genetic Neuropharmacology, McLean Hospital, Belmont, MA, USA [2] Department of Psychiatry, Harvard Medical School, Boston, MA, USA.
authors.forename: Elif
authors.initials: E
authors.lastname: Engin
authors.affiliation: 1] Laboratory of Genetic Neuropharmacology, McLean Hospital, Belmont, MA, USA [2] Department of Psychiatry, Harvard Medical School, Boston, MA, USA.
authors.forename: Konstantin I
authors.initials: KI
authors.lastname: Bakhurin
authors.affiliation: 1] Laboratory of Genetic Neuropharmacology, McLean Hospital, Belmont, MA, USA [2] Department of Psychiatry, Harvard Medical School, Boston, MA, USA.
authors.forename: Kiersten S
authors.initials: KS
authors.lastname: Smith
authors.affiliation: Tufts University School of Medicine, Department of Neuroscience, Boston, MA, USA.
authors.forename: Rochelle M
authors.initials: RM
authors.lastname: Hines
authors.affiliation: 1] Laboratory of Genetic Neuropharmacology, McLean Hospital, Belmont, MA, USA [2] Department of Psychiatry, Harvard Medical School, Boston, MA, USA.
authors.forename: Lauren M
authors.initials: LM
authors.lastname: Reynolds
authors.affiliation: Department of Molecular Neurobiology, Max Planck Institute for Medical Research, Heidelberg, Germany.
authors.forename: Wannan
authors.initials: W
authors.lastname: Tang
authors.affiliation: Department of Molecular Neurobiology, Max Planck Institute for Medical Research, Heidelberg, Germany.
authors.forename: Rolf
authors.initials: R
authors.lastname: Sprengel
authors.affiliation: Tufts University School of Medicine, Department of Neuroscience, Boston, MA, USA.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Moss
authors.affiliation: 1] Laboratory of Genetic Neuropharmacology, McLean Hospital, Belmont, MA, USA [2] Department of Psychiatry, Harvard Medical School, Boston, MA, USA.
authors.forename: Uwe
authors.initials: U
authors.lastname: Rudolph
mesh_terms: D000818:Animals; D002755:Choice Behavior / Q000187:drug effects*; D018757:GABA Modulators / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008874:Midazolam / Q000494:pharmacology*; D009714:Nucleus Accumbens / Q000187:drug effects*; D011963:Receptors, GABA-A / Q000502:physiology*; D012201:Reward
chemical_list: D018757:GABA Modulators; C493920:Gabra2 protein, mouse; D011963:Receptors, GABA-A; D008874:Midazolam