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

Qiuying Shen, Rachnanjali Lal, Beth A. Luellen, John C. Earnheart, Anne Milasincic Andrews, Bernhard Luscher

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Abstract

Background: The γ-aminobutyric acid (GABA) Type A receptor deficits that are induced by global or forebrain-specific heterozygous inactivation of the γ2 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 γ2-deficient mice with respect to hypothalamic-pituitary- adrenal (HPA) axis abnormalities and antidepressant drug responses. Methods: We analyzed the behavioral responses of γ2+/- mice to desipramine and fluoxetine in novelty suppressed feeding, forced swim, tail suspension, and sucrose consumption tests as well as GABAA receptor deficit- and antidepressant drug treatment-induced alterations in serum corticosterone. Results: Baseline corticosterone concentrations in adult γ2-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 γ2-deficient mouse lines was correlated with early onset HPA axis hyperactivity during postnatal development. Chronic but not subchronic treatment of γ2+/- 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 γ2+/- 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.

Original languageEnglish (US)
Pages (from-to)512-520
Number of pages9
JournalBiological Psychiatry
Volume68
Issue number6
DOIs
Publication statusPublished - Sep 15 2010

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All Science Journal Classification (ASJC) codes

  • Biological Psychiatry

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