Sensitization of the Hypothalamic-Pituitary-Adrenal Axis in a Male Rat Chronic Stress Model

Abstract

Stress activation of the hypothalamic-pituitary-adrenal (HPA) axis is regulated by rapid glucocorticoid negative feedback. Chronic unpredictable stress animal models recapitulate certain aspects of major depression in humans, which have been attributed to impaired glucocorticoid negative feedback. We tested for an attenuated HPA sensitivity to fast glucocorticoid feedback inhibition in male rats exposed to a chronic variable stress (CVS) paradigm. In vitro, parvocellular neuroendocrine cells of the hypothalamic paraventricular nucleus recorded in slices from CVS rats showed an increase in basal excitatory synaptic inputs and a decrease in basal inhibitory synaptic inputs compared with neurons from control rats. There was no difference between control and CVS-treated rats in the rapid glucocorticoid suppression of excitatory synaptic inputs, a fast feedback mechanism. In vivo, CVS-treated rats showed an increase in ACTH secretion at baseline and after both iv CRH and acute stress and no impairment of the corticosterone suppression of the ACTH response, compared with controls. In an in vitro pituitary preparation, an increase in basal ACTH release, a small increase in CRH-induced ACTH release, and no decrement in the glucocorticoid suppression of ACTH release were seen in pituitaries from CVS rats. Thus, CVS does not suppress rapid glucocorticoid negative feedback at the hypothalamus or pituitary, but increases the synaptic excitability of paraventricular nucleus CRH neurons and the CRH sensitivity of the pituitary. Therefore, increased HPA activity in chronically stressed male rats is due to sensitization of the HPA axis, rather than to desensitization to rapid glucocorticoid feedback.

Paraventricular Hypothalamic Mechanisms of Chronic Stress Adaptation

“…Chronic variable stress reduces mIPSC frequency (but not amplitude) in putative CRH neurons, indicative of loss of inhibitory inputs (55, 56). Chronic variable stress exposure also decreases the expression of GABA A receptor α5, β1, β2, and δ subunits (55, 57), consistent with reduced GABAergic inhibition.…”

“…Baseline excitatory drive of parvocellular PVN neurons is enhanced by chronic stress exposure, manifest as increased mEPSC frequency (56). In addition, ionotrophic N -methyl- d -aspartate receptor subunits are modulated by chronic variable stress in a manner consistent with enhanced postsynaptic glutamate receptivity.…”

“…Thus, chronic restraint stress likely produces a loss of presynaptic cannabinoid inhibition, effectively blocking endocannabinoid-mediated glucocorticoid-dependent fast feedback inhibition of the HPA axis (62). However, it is important to note that glucocorticoid-induced endocannabinoid signaling is not affected following chronic variable stress (56), indicating that different mechanisms may regulate PVN responses under conditions of predictable vs. unpredictable stress exposure.…”

“…The lower cfos mRNA/Fos response may also be associated with the relative (low) intensity of the evocative stimuli with respect to other stimuli occuring in the unpredictable stress or social stress paradigms. Of course, it is important to consider that the magnitude of the Fos response may not be an accurate reporter of cellular activation in the context of repeated drive, given that other intracellular changes [e.g., increased CRH expression (68), enhanced excitability (56)] may compensate for habituation in the AP1 pathway.…”

“…Work from our group suggests that chronic variable stress increases glutamatergic inputs to CRH neurons, as determined by elevations in the number of vesicular glutamate transporter 2 (VGluT2) appositions onto both dendrites and somata (46) and increases in excitatory synaptic inputs to PVN neurons (56). Both observations suggest that the enhanced drive is mediated by additional synaptic contacts.…”