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

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

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1
Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, 16801, USA.

Erratum in

  • Biol Psychiatry. 2012 Dec 1;72(11):978. Dosage error in article text.

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.

PMID:
20579975
PMCID:
PMC2930197
DOI:
10.1016/j.biopsych.2010.04.024
[Indexed for MEDLINE]
Free PMC Article

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