Functional role of local GABAergic influences on the HPA axis

Abstract

Neuronatomical and pharmacological studies have established GABA-mediated inhibition of the HPA axis at the level of the PVN. The origin of this innervation is a series of local hypothalamic and adjacent forebrain regions that project to stress-integrative hypophysiotropic CRH neurons. While a role in tonic inhibition of the stress axis is likely, this system of inhibitory loci is also capable of producing a dynamic braking capacity in the context of the neuroendocrine stress response. The latter function is mediated in large part by glutamatergic forebrain afferents that increase GABA release at the level of the PVN. In addition, this local GABA system can be inhibited by upstream GABAergic projection neurons, producing activation of the HPA axis via removal of GABAergic tone. This PVN projecting GABA network interfaces with a wide range of homeostatic mechanisms, and is capable of biochemical plasticity in response to chronic stress. Collectively, the elements of this system provide for exquisite control of neuroendocrine activation in the face of stressful stimuli, and loss of this regulatory capacity may underlie many stress-related disorders.

Baseline ‘state anxiety’ influences HPA-axis sensitivity to one sham-controlled HF-rTMS session applied to the right dorsolateral prefrontal cortex

“…Our findings of a higher HPA-system sensitivity in more anxious individuals after HF-rTMS applied over the right DLPFC might be especially germane in light of the therapeutic applications of rTMS as a treatment for anxiety disorders and/or posttraumatic stress disorder (PTSD) (Cohen et al, 2004;Pallanti and Bernardi, 2009;Zwanzger et al, 2009;Handwerger, 2009;Yue et al, in press). Because of the overwhelming evidence that GABAergic mechanisms regulate neuroendocrine stress responses (Herman et al, 2002;Herman et al, 2004;Kovács et al, 2004;Cullinan et al 2008;Radley et al, 2009) and the importance of GABA receptor involvement in the pathophysiology and treatment of anxiety disorders (Lydiard, 2003;Nemeroff, 2003;Kalueff and Nutt., 2007), it is tempting to assume that in our study the observed HPA-axis sensitivity to one HF-rTMS session in more anxious females was mediated by the GABA system.…”

Effect of Manganese Chloride on the Neurochemical Profile of the Rat Hypothalamus

“…However, GABA and myo-Ins concentrations were also lower relative to the rat hippocampus, whereas these metabolites had significantly higher levels in the mouse hypothalamus relative to the hippocampus (Lei et al, 2010). g-Aminobutyric acid is known to have an important inhibitory role in the regulation of the hypothalamic-pituitary-adrenocortical axis (Cullinan et al, 2008) and especially at the level of the paraventricular nucleus (Cullinan et al, 2008). No GABAergic neurons are located within the PVN itself (Cullinan et al, 2008), which may explain the lower GABA levels measured compared with the hippocampus in healthy rats.…”

“…g-Aminobutyric acid is known to have an important inhibitory role in the regulation of the hypothalamic-pituitary-adrenocortical axis (Cullinan et al, 2008) and especially at the level of the paraventricular nucleus (Cullinan et al, 2008). No GABAergic neurons are located within the PVN itself (Cullinan et al, 2008), which may explain the lower GABA levels measured compared with the hippocampus in healthy rats. In response to changes in brain homeostasis, metabolite concentrations in the hippocampus and the hypothalamus increased.…”

CRH: The link between hormonal-, metabolic- and behavioral responses to stress

“…Furthermore One other important aspect of the negative feedback on HPA axis is the effect of glucocorticoids on limbic areas, which is mediated by local GABAergic inputs to the CRH neurons (Bali & Kovacs 2003, Cole & Sawchenko 2002, Cullinan et al 2008, Miklos & Kovacs 2002). …”