Chronic stress induces both functional and structural adaptations within the hypothalamo-pituitary-adrenocortical (HPA) axis, suggestive of long-term alterations in neuroendocrine reactivity to subsequent stressors. We hypothesized that prior chronic stress would produce persistent enhancement of HPA axis reactivity to novel stressors. Adult male rats were exposed to chronic variable stress (CVS) for 1 wk and allowed to recover. Plasma ACTH and corticosterone levels were measured in control or CVS rats exposed to novel psychogenic (novel environment or restraint) or systemic (hypoxia) stressors at 16 h, 4 d, 7 d, or 30 d after CVS cessation. Plasma ACTH and corticosterone responses to psychogenic stressors were attenuated at 4 d (novel environment and restraint) and 7 d (novel environment only) recovery from CVS, whereas hormonal responses to the systemic stressor were largely unaffected by CVS. CRH mRNA expression was up-regulated in the paraventricular nucleus of the hypothalamus (PVN) at 16 h after cessation of CVS, but no other alterations in PVN CRH or arginine vasopressin mRNA expression were observed. Thus, in contrast to our hypothesis, reductions of HPA axis sensitivity to psychogenic stressors manifested at delayed recovery time points after CVS. The capacity of the HPA axis to respond to a systemic stressor appeared largely intact during recovery from CVS. These data suggest that chronic stress selectively targets brain circuits responsible for integration of psychogenic stimuli, resulting in decreased HPA axis responsiveness, possibly mediated in part by transitory alterations in PVN CRH expression.
Previous studies have observed significant abnormalities in the fatty acid composition of peripheral tissues from drug-naïve first-episode schizophrenic (SZ) patients relative to normal controls, including deficits in omega-3 and omega-6 polyunsaturated fatty acids, which are partially normalized following chronic antipsychotic treatment. We hypothesized that postmortem cortical tissue from patients with SZ would also exhibit deficits in cortical docosahexaenoic acid (DHA, 22:6n-3) and arachidonic acid (AA; 20:4n-6) relative to normal controls, and that these deficits would be greater in drug-free SZ patients. We determined the total fatty acid composition of postmortem orbitofrontal cortex (OFC) (Brodmann area 10) from drug-free and antipsychotic-treated SZ patients (n=21) and age-matched normal controls (n=26) by gas chromatography. After correction for multiple comparisons, significantly lower DHA (-20%) concentrations, and significantly greater vaccenic acid (VA) (+12.5) concentrations, were found in the OFC of SZ patients relative to normal controls. Relative to age-matched same-gender controls, OFC DHA deficits, and elevated AA:DHA, oleic acid:DHA and docosapentaenoic acid (22:5n-6):DHA ratios, were found in male but not female SZ patients. SZ patients that died of cardiovascular-related disease exhibited lower DHA (-31%) and AA (-19%) concentrations, and greater OA (+20%) and VA (+17%) concentrations, relative to normal controls that also died of cardiovascular-related disease. OFC DHA and AA deficits, and elevations in oleic acid and vaccenic acid, were numerically greater in drug-free SZ patients and were partially normalized in SZ patients treated with antipsychotic medications (atypical>typical). Fatty acid abnormalities could not be wholly attributed to lifestyle or postmortem tissue variables. These findings add to a growing body of evidence implicating omega-3 fatty acid deficiency as well as the OFC in the pathoaetiology of SZ, and suggest that abnormalities in OFC fatty acid composition may be gender-specific and partially normalized by antipsychotic medications.
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