title: gamma-Aminobutyric acid-type A receptor deficits cause hypothalamic-pituitary-adrenal axis hyperactivity and antidepressant drug sensitivity reminiscent of melancholic forms of depression.
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.
authors.affiliation: Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, 16801, USA.
authors.forename: Qiuying
authors.initials: Q
authors.lastname: Shen
authors.forename: Rachnanjali
authors.initials: R
authors.lastname: Lal
authors.forename: Beth A
authors.initials: BA
authors.lastname: Luellen
authors.forename: John C
authors.initials: JC
authors.lastname: Earnheart
authors.forename: Anne Milasincic
authors.initials: AM
authors.lastname: Andrews
authors.forename: Bernhard
authors.initials: B
authors.lastname: Luscher
mesh_terms: D018759:Adrenergic Uptake Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D000928:Antidepressive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D003345:Corticosterone / Q000097:blood; D003866:Depressive Disorder / Q000097:blood / Q000188:drug therapy* / Q000235:genetics; D003891:Desipramine / Q000008:administration & dosage / Q000494:pharmacology*; D004195:Disease Models, Animal; D005260:Female; D005473:Fluoxetine / Q000008:administration & dosage / Q000494:pharmacology*; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D010913:Pituitary-Adrenal System / Q000187:drug effects / Q000378:metabolism*; D011963:Receptors, GABA-A / Q000235:genetics / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage / Q000494:pharmacology
chemical_list: D018759:Adrenergic Uptake Inhibitors; D000928:Antidepressive Agents; D003345:Corticosterone; D003891:Desipramine; D005473:Fluoxetine; D011963:Receptors, GABA-A; D017367:Selective Serotonin Reuptake Inhibitors