Pro-inflammatory immune-to-brain signaling is involved in neuroendocrine responses to acute emotional stress.
Activation of the hypothalamo-pituitary-adrenal (HPA) axis by inflammatory stressors (e.g., bacterial lipopolysaccharide) is thought to involve vascular transduction of circulating cytokines, with perivascular macrophages (PVMs) along with endothelia, effecting activation of HPA control circuitry via inducible (cyclooxygenase-2- or COX-2-dependent) prostaglandin synthesis. To test the stressor-specificity of this mechanism, we examined whether ablation of PVMs or pharmacologic blockade of COX activity affected HPA responses to a representative emotional stressor, restraint. Exposing rats to a single 30min acute restraint episode provoked increased plasma levels of at least one proinflammatory cytokine, IL-6, microglial activation and multiple indices of cerebrovascular activation, including COX-2 expression and increased brain prostaglandin E2levels at 0-2h after stress. Pretreatment with the nonselective COX inhibitor, indomethacin, either icv (10μg in 5μl) or iv (1mg/kg) significantly reduced restraint-induced Fos expression in the paraventricular hypothalamic nucleus (PVH) by 45%, relative to vehicle-injected controls. A 75% reduction of the PVH activational response was seen in rats exposed to acute restraint 5-7days after ablation of brain PVMs by icv injection of liposomes encapsulating the bisphosphonate drug, clodronate. Basal plasma levels of ACTH and corticosterone were not altered in clodronate liposome-injected rats, but the peak magnitude of restraint-induced HPA secretory responses was substantially reduced, relative to animals pretreated with saline-filled liposomes. These findings support an unexpectedly prominent role for inducible prostaglandin synthesis by PVMs in HPA responses to acute restraint, a prototypic emotional stressor.
Laboratory of Neuronal Structure and Function, The Salk Institute for Biological Studies and the Clayton Medical Research Foundation, La Jolla, CA 92037, United States.
Jordi
J
Serrats
Laboratory of Neuronal Structure and Function, The Salk Institute for Biological Studies and the Clayton Medical Research Foundation, La Jolla, CA 92037, United States.
Jan-Sebastian
JS
Grigoleit
Laboratory of Neuronal Structure and Function, The Salk Institute for Biological Studies and the Clayton Medical Research Foundation, La Jolla, CA 92037, United States.
Elena
E
Alvarez-Salas
Laboratory of Neuronal Structure and Function, The Salk Institute for Biological Studies and the Clayton Medical Research Foundation, La Jolla, CA 92037, United States. Electronic address: sawchenko@salk.edu.
Paul E
PE
Sawchenko
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004644:Emotions / Q000502:physiology; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D007213:Indomethacin / Q000494:pharmacology; D007249:Inflammation / Q000378:metabolism*; D008297:Male; D010913:Pituitary-Adrenal System / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012149:Restraint, Physical; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013312:Stress, Physiological / Q000502:physiology*; D013315:Stress, Psychological / Q000378:metabolism* / Q000503:physiopathology
D016861:Cyclooxygenase Inhibitors; D007213:Indomethacin
Clodronate liposomes; Cyclooxygenase; Hypothalamo-pituitary-adrenal axis; Paraventricular nucleus; Perivascular macrophage; Prostaglandin E2; Restraint; Stress