gamma-Aminobutyric acid-type A receptor deficits cause hypothalamic-pituitary-adrenal axis hyperactivity and antidepressant drug sensitivity reminiscent of melancholic forms of depression

Biol Psychiatry. 2010 Sep 15;68(6):512-20. doi: 10.1016/j.biopsych.2010.04.024. Epub 2010 Jul 1.

Abstract

Background: The gamma-aminobutyric acid (GABA) Type A receptor deficits that are induced by global or forebrain-specific heterozygous inactivation of the gamma2 subunit gene in mouse embryos result in behavior indicative of trait anxiety and depressive states. By contrast, a comparable deficit that is delayed to adolescence is without these behavioral consequences. Here we characterized gamma2-deficient mice with respect to hypothalamic-pituitary-adrenal (HPA) axis abnormalities and antidepressant drug responses.

Methods: We analyzed the behavioral responses of gamma2(+/-) mice to desipramine and fluoxetine in novelty suppressed feeding, forced swim, tail suspension, and sucrose consumption tests as well as GABA(A) receptor deficit- and antidepressant drug treatment-induced alterations in serum corticosterone.

Results: Baseline corticosterone concentrations in adult gamma2-deficient mice were elevated independent of whether the genetic lesion was induced during embryogenesis or delayed to adolescence. However, the manifestation of anxious-depressive behavior in different gamma2-deficient mouse lines was correlated with early onset HPA axis hyperactivity during postnatal development. Chronic but not subchronic treatment of gamma2(+/-) mice with fluoxetine or desipramine normalized anxiety-like behavior in the novelty suppressed feeding test. Moreover, desipramine had antidepressant-like effects in that it normalized HPA axis function and depression-related behavior of gamma2(+/-) mice in the forced swim, tail suspension, and sucrose consumption tests. By contrast, fluoxetine was ineffective as an antidepressant and failed to normalize HPA axis function.

Conclusions: Developmental deficits in GABAergic inhibition in the forebrain cause behavioral and endocrine abnormalities and selective antidepressant drug responsiveness indicative of anxious-depressive disorders such as melancholic depression, which are frequently characterized by HPA axis hyperactivity and greater efficacy of desipramine versus fluoxetine.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic Uptake Inhibitors / administration & dosage
  • Adrenergic Uptake Inhibitors / pharmacology
  • Animals
  • Antidepressive Agents / administration & dosage
  • Antidepressive Agents / pharmacology*
  • Behavior, Animal / drug effects
  • Corticosterone / blood
  • Depressive Disorder / blood
  • Depressive Disorder / drug therapy*
  • Depressive Disorder / genetics
  • Desipramine / administration & dosage
  • Desipramine / pharmacology*
  • Disease Models, Animal
  • Female
  • Fluoxetine / administration & dosage
  • Fluoxetine / pharmacology*
  • Hypothalamo-Hypophyseal System / drug effects
  • Hypothalamo-Hypophyseal System / metabolism*
  • Mice
  • Mice, Knockout
  • Pituitary-Adrenal System / drug effects
  • Pituitary-Adrenal System / metabolism*
  • Receptors, GABA-A / genetics
  • Receptors, GABA-A / metabolism*
  • Serotonin Uptake Inhibitors / administration & dosage
  • Serotonin Uptake Inhibitors / pharmacology

Substances

  • Adrenergic Uptake Inhibitors
  • Antidepressive Agents
  • Receptors, GABA-A
  • Serotonin Uptake Inhibitors
  • Fluoxetine
  • Desipramine
  • Corticosterone