title: Restoration of neuroendocrine stress response by glucocorticoid receptor or GABA(A) receptor antagonists after experimental traumatic brain injury.
abstract: We previously reported that traumatic brain injury (TBI) produced by moderate controlled cortical impact (CCI) attenuates the stress response of the hypothalamic-pituitary-adrenal (HPA) axis between 21 and 70 days postinjury and enhances the sensitivity of the stress response to glucocorticoid negative feedback. In the current study, we investigated two possible mechanisms for the CCI-induced attenuation of the HPA stress response-i.e, glucocorticoid receptor (GR) and GABA-mediated inhibition of the HPA axis, with the GR antagonist, mifepristone (RU486), or the GABA(A)-receptor antagonist, bicuculline. In addition, we examined the effect of moderate CCI on GR and inhibitory neurons histologically in subfields of the hippocampus, medial prefrontal cortex, and amygdala. We show that at 30-min after onset of restraint stress, GR as well as GABA antagonism with MIFE or BIC, respectively, reversed the attenuating effects of moderate CCI on the stress-induced HPA response. Our histological results demonstrate that moderate CCI led to a loss of glutamic acid decarboxylase 67 or parvalbumin-positive inhibitory neurons within regions of the hippocampus and amygdala but did not lead to significant increases in GR in these regions. These findings indicate that suppression of the stress-induced HPA response after moderate CCI is mediated by the inhibitory actions of both GR and GABA, with a corresponding loss of inhibitory neurons within brain regions with neural pathways affecting limbic stress-integrative pathways.
authors: Department of Neurobiology, David Geffen School of Medicine at UCLA, 10833 Le Conte Avenue, Box 951763, Los Angeles, CA 90095-1763, USA. ataylor@mednet.ucla.edu
authors: Anna N
authors: AN
authors: Taylor
authors: Delia L
authors: DL
authors: Tio
authors: Richard L
authors: RL
authors: Sutton
mesh_terms: D000679:Amygdala / Q000187:drug effects / Q000473:pathology; D000704:Analysis of Variance; D000818:Animals; D001640:Bicuculline / Q000494:pharmacology; D001835:Body Weight / Q000187:drug effects; D001930:Brain Injuries / Q000188:drug therapy* / Q000503:physiopathology; D002452:Cell Count; D003345:Corticosterone / Q000097:blood; D007839:Functional Laterality / Q000502:physiology; D058787:GABA-A Receptor Antagonists / Q000494:pharmacology*; D005968:Glutamate Decarboxylase / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D008297:Male; D015735:Mifepristone / Q000494:pharmacology; D009490:Neurosecretory Systems / Q000503:physiopathology*; D010320:Parvalbumins / Q000378:metabolism; D017397:Prefrontal Cortex / Q000187:drug effects / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011965:Receptors, Glucocorticoid / Q000187:drug effects* / Q000378:metabolism; D013312:Stress, Physiological / Q000187:drug effects*
chemical_list: D058787:GABA-A Receptor Antagonists; D010320:Parvalbumins; D011965:Receptors, Glucocorticoid; D015735:Mifepristone; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1; D003345:Corticosterone; D001640:Bicuculline
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