α2-containing GABA(A) receptors: A requirement for midazolam-escalated aggression and social approach in mice

Rationale: 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 GABA_A receptors. Objectives: Point-mutated mice rendered selectively insensitive to BZDs at α1-, α2-, or α3-containing GABA_A 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 GABA_A receptors in order to escalate aggression and α2- and α3-containing receptors to reduce social anxiety-like behavior. GABA_A receptors containing the α1-subunit are crucial for BZD-induced sedation, while α2-containing GABA_A receptors may be a shared site of action for the pro-aggressive and anxiolytic effects of BZDs.