Neonatal treatment of rats with the neuroactive steroid tetrahydrodeoxycorticosterone (THDOC) abolishes the behavioral and neuroendocrine consequences of adverse early life events.
Stressful experience during early brain development has been shown to produce profound alterations in several mechanisms of adaptation, while several signs of behavioral and neuroendocrine impairment resulting from neonatal exposure to stress resemble symptoms of dysregulation associated with major depression. This study demonstrates that when applied concomitantly with the stressful challenge, the steroid GABA(A) receptor agonist 3,21-dihydropregnan-20-one (tetrahydrodeoxycorticosterone, THDOC) can attenuate the behavioral and neuroendocrine consequences of repeated maternal separation during early life, e.g., increased anxiety, an exaggerated adrenocortical secretory response to stress, impaired responsiveness to glucocorticoid feedback, and altered transcription of the genes encoding corticotropin-releasing hormone (CRH) in the hypothalamus and glucocorticoid receptors in the hippocampus. These data indicate that neuroactive steroid derivatives with GABA-agonistic properties may exert persisting stress-protective effects in the developing brain, and may form the basis for therapeutic agents which have the potential to prevent mental disorders resulting from adverse experience during neonatal life.
Patchev
V K
VK
Department of Neuroendocrinology, Max Planck Institute of Psychiatry, Munich, Germany.
Montkowski
A
A
Rouskova
D
D
Koranyi
L
L
Holsboer
F
F
Almeida
O F
OF
D000302:Adrenal Cortex / Q000378:metabolism; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D001007:Anxiety; D001522:Behavior, Animal / Q000187:drug effects*; D003346:Corticotropin-Releasing Hormone / Q000235:genetics / Q000378:metabolism; D003900:Desoxycorticosterone / Q000031:analogs & derivatives* / Q000494:pharmacology; D005260:Female; D018756:GABA Antagonists / Q000378:metabolism / Q000494:pharmacology; D005938:Glucocorticoids / Q000502:physiology; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D007031:Hypothalamus / Q000378:metabolism; D017403:In Situ Hybridization; D007231:Infant, Newborn; D008297:Male; D009490:Neurosecretory Systems / Q000187:drug effects* / Q000254:growth & development*; D011247:Pregnancy; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018079:Receptors, GABA / Q000502:physiology; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism; D013312:Stress, Physiological / Q000503:physiopathology*; D014158:Transcription, Genetic
D014151:Anti-Anxiety Agents; D018756:GABA Antagonists; D005938:Glucocorticoids; D012333:RNA, Messenger; D018079:Receptors, GABA; D011965:Receptors, Glucocorticoid; D003900:Desoxycorticosterone; C009413:tetrahydrodeoxycorticosterone; D003346:Corticotropin-Releasing Hormone