title: α2-containing GABA(A) receptors: a requirement for midazolam-escalated aggression and social approach in mice.
abstract: BACKGROUND
  Benzodiazepines (BZDs) are prescribed to reduce anxiety, agitation, and muscle spasms and for their sedative-hypnotic and anticonvulsant effects. Under specific conditions, BZDs escalate aggression in some individuals. Specific effects of BZDs have been linked to the α-subunit subtype composition of GABAA receptors.
  
  
  OBJECTIVE
  Point-mutated mice rendered selectively insensitive to BZDs at α1-, α2-, or α3-containing GABAA receptors were used to determine which α-subunit subtypes are necessary for BZDs to escalate aggression and social approach and to reduce fear-motivated behavior.
  
  
  METHODS
  During resident-intruder confrontations, male wild-type (WT) and point-mutated α1(H101R), α2(H101R), and α3(H126R) mice were treated with midazolam (0-1.7 mg/kg, i.p.) and evaluated for aggression in an unfamiliar environment. Separate midazolam-treated WT and point-mutated mice were assessed for social approach toward a female or investigated in a 6-day fear-potentiated startle procedure.
  
  
  RESULTS
  Moderate doses of midazolam (0.3-0.56 mg/kg, i.p.) escalated aggression in WT and α3(H126R) mutants and increased social approach in WT and α1(H101R) mice. The highest dose of midazolam (1.0 mg/kg) reduced fear-potentiated startle responding. All mice were sensitive to the sedative effect of midazolam (1.7 mg/kg) except α1(H101R) mutants.
  
  
  CONCLUSIONS
  Midazolam requires BZD-sensitive α1- and α2-containing GABAA receptors in order to escalate aggression and α2- and α3-containing receptors to reduce social anxiety-like behavior. GABAA receptors containing the α1-subunit are crucial for BZD-induced sedation, while α2-containing GABAA receptors may be a shared site of action for the pro-aggressive and anxiolytic effects of BZDs.
authors.affiliation: Department of Psychology, Tufts University, Medford, MA, 02144, USA. emily.newman@tufts.edu.
authors.forename: Emily L
authors.initials: EL
authors.lastname: Newman
authors.affiliation: Laboratory of Genetic Neuropharmacology, McLean Hospital, Belmont, MA, 02478, USA.|Department of Psychiatry, Harvard Medical School, Boston, MA, 02215, USA.
authors.forename: Kiersten S
authors.initials: KS
authors.lastname: Smith
authors.affiliation: Laboratory of Behavioral Neuroendocrinology, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba, Ibaraki, Japan.
authors.forename: Aki
authors.initials: A
authors.lastname: Takahashi
authors.affiliation: Department of Psychology, Tufts University, Medford, MA, 02144, USA.
authors.forename: Adam
authors.initials: A
authors.lastname: Chu
authors.affiliation: Department of Psychology, Tufts University, Medford, MA, 02144, USA.
authors.forename: Lara S
authors.initials: LS
authors.lastname: Hwa
authors.affiliation: Department of Psychology, Tufts University, Medford, MA, 02144, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Psychology, Tufts University, Medford, MA, 02144, USA.
authors.forename: Joseph F
authors.initials: JF
authors.lastname: DeBold
authors.affiliation: Laboratory of Genetic Neuropharmacology, McLean Hospital, Belmont, MA, 02478, USA.|Department of Psychiatry, Harvard Medical School, Boston, MA, 02215, USA.
authors.forename: Uwe
authors.initials: U
authors.lastname: Rudolph
authors.affiliation: Department of Psychology, Tufts University, Medford, MA, 02144, USA.|Department of Neuroscience, Tufts University, Boston, MA, 02111, USA.
authors.forename: Klaus A
authors.initials: KA
authors.lastname: Miczek
mesh_terms: D000374:Aggression / Q000187:drug effects* / Q000502:physiology / Q000523:psychology*; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology / Q000627:therapeutic use; D001007:Anxiety / Q000188:drug therapy / Q000523:psychology; D001569:Benzodiazepines / Q000494:pharmacology / Q000627:therapeutic use; D005239:Fear / Q000187:drug effects / Q000502:physiology / Q000523:psychology; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008874:Midazolam / Q000494:pharmacology* / Q000627:therapeutic use; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D011963:Receptors, GABA-A / Q000502:physiology*; D012919:Social Behavior
chemical_list: D014151:Anti-Anxiety Agents; C493920:Gabra2 protein, mouse; D011963:Receptors, GABA-A; D001569:Benzodiazepines; D008874:Midazolam
keywords: Aggression; Benzodiazepine; Fear-potentiated startle; GABAA receptor subunit; Gabra1; Gabra2; Gabra3; Midazolam; Social anxiety; Social approach