Both alpha2 and alpha3 GABAA receptor subtypes mediate the anxiolytic properties of benzodiazepine site ligands in the conditioned emotional response paradigm

Eur J Neurosci. 2006 May;23(9):2495-504. doi: 10.1111/j.1460-9568.2006.04775.x.


Mice with point-mutated alpha2 GABAA receptor subunits (rendering them diazepam insensitive) are resistant to the anxiolytic-like effects of benzodiazepines (BZs) in unconditioned models of anxiety. We investigated the role of the alpha2 GABAA subtype in a model of conditioned anxiety. alpha2(H101R) and wildtype mice were trained in a conditioned emotional response (CER) task, in which lever-pressing for food on a variable interval (VI) schedule was suppressed during the presentation of a conditioned stimulus (CS+) that predicted footshock. The ability of diazepam, ethanol and pentobarbital to reduce suppression during the CS+ was interpreted as an anxiolytic response. Diazepam (0, 0.5, 1, 2, 4 and 8 mg/kg) induced a dose-dependent anxiolytic-like effect in wildtype mice. At high doses, diazepam (2, 4 and 8 mg/kg) was sedative in alpha2(H101R) mice. Analysis of the anxiolytic properties of nonsedative diazepam doses (0.5 and 1 mg/kg), showed that alpha2(H101R) mice were resistant to the anxiolytic effects of diazepam. Equivalent anxiolytic properties of pentobarbital (20 mg/kg) and ethanol (1 and 2 g/kg) were seen in both genotypes. These findings confirm the critical importance of the alpha2 GABAA subtype in mediating BZ anxiolysis. However, as a compound, L-838417, with agonist properties at alpha2, alpha3 and alpha5-containing receptors, gave rise to anxiolytic-like activity in alpha2(H101R) mice in the CER test, alpha3-containing GABA receptors are also likely to contribute to anxiolysis. Observations that alpha2(H101R) mice were more active, and displayed a greater suppression of lever pressing in response to fear-conditioned stimuli than wildtype mice, suggests that the alpha2(H101R) mutation may not be behaviourally silent.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • Anti-Anxiety Agents / therapeutic use*
  • Anxiety / drug therapy*
  • Anxiety / genetics
  • Anxiety / physiopathology
  • Benzodiazepines / therapeutic use*
  • Central Nervous System Depressants / therapeutic use
  • Conditioning, Classical / drug effects*
  • Conditioning, Classical / physiology
  • Diazepam / therapeutic use
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Emotions / drug effects*
  • Emotions / physiology
  • Ethanol / therapeutic use
  • Female
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Receptors, GABA-A / genetics
  • Receptors, GABA-A / physiology*


  • Anti-Anxiety Agents
  • Central Nervous System Depressants
  • Receptors, GABA-A
  • Benzodiazepines
  • Ethanol
  • Diazepam