γ-Aminobutyric Acid-Type A Receptor Deficits Cause Hypothalamic-Pituitary-Adrenal Axis Hyperactivity and Antidepressant Drug Sensitivity Reminiscent of Melancholic Forms of Depression

Abstract

BACKGROUND: GABA 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 HPA axis abnormalities and antidepressant drug responses.

Antidepressant effects of an inverse agonist selective for α5 GABA-A receptors in the rat forced swim test

“…The overall effect of L-655,708 may thus refl ect a better performance based on both cognition and motivational enhancements. The results of our study are consistent with previously published data, which demonstrate a role for GABA-A receptors in depressive-like behavior [20,21,28,29]. However, while α2-containing GABA-A receptors are known to be involved in regulating anxietylike behavior [30], our results suggest that α5-containing GABA-A receptors may be involved in depressive-like behavior.…”

“…Namely, modulation in GABAergic inhibition has been proposed to play an important role in the pathophysiology of depression [19][20][21]. Data from experimental models demonstrate that the forced swim test represents a reliable and valuable behavioral research model of depression in rodents and also an important tool to study neurobiological mechanisms involved in antidepressant activity.…”

Diabetes induces GABA receptor plasticity in murine vagal motor neurons

“…Alterations in THIP sensitivity of IPSC decay time constant are subtle in neurons from mice with diabetes, but even subtle changes in synaptic GABA A receptor responses can significantly affect overall rodent behavior (Crestani et al 1999;Shen et al 2010). Since THIP sensitivity of sIPSC frequency was unchanged, neither a sustained increase in activity of intact, upstream GABAergic neurons projecting to the DMV nor an increase in total number of GABAergic synapses seems likely to underlie the increase in decay time constant.…”

El papel del ácido gamma-aminobutírico en la depresión de la mujer

“…Otra de las relaciones importantes de la subunidad γ2 es aquella que comparte con el eje hipotalámi-co-hipofisiario-adrenal (HHA). Los estudios demuestran que los antidepresivos tricíclicos, al normalizar la subunidad γ2, estabilizan la hiperfunción del eje HHA, lo que se traduce en una mejoría de los síntomas de la depresión con características ansiosas 24 . En cuanto a la subunidad δ, se ha propuesto que desempeña un papel importante en la depresión posparto.…”

“…En cuanto a la subunidad δ, se ha propuesto que desempeña un papel importante en la depresión posparto. Se ha observado que el incremento de la progesterona (propio del embarazo) ejerce una disminución de la expresión de las subunidades γ 2 y δ, reflejándose en una depresión posparto de características ansiosas 24 . Sin embargo, se ha encontrado que las alteraciones en el equilibrio de los neuroesteroides alopregnanolona e isopregnanolona pueden ser corregidas con la administración de inhibidores selectivos de la recaptura de serotonina (ISRS) 25 .…”