Oral administration of a corticotropin-releasing hormone receptor antagonist significantly attenuates behavioral, neuroendocrine, and autonomic responses to stress in primates.
We evaluated the effects of the lipophilic nonpeptide corticotropin-releasing hormone (CRH) type 1 receptor antagonist antalarmin on the behavioral, neuroendocrine, and autonomic components of the stress response in adult male rhesus macaques. After oral administration, significant antalarmin concentrations were detected in the systemic circulation and the cerebrospinal fluid by a mass spectrometry-gas chromatography assay developed specifically for this purpose. Pharmacokinetic and dose-response studies suggested that an oral dose of 20 mg/kg was optimal for behavioral and endocrine effects. We then administered this dose in a double-blind, placebo-controlled fashion to monkeys exposed to an intense social stressor: namely, placement of two unfamiliar males in adjacent cages separated only by a transparent Plexiglas screen. Antalarmin significantly inhibited a repertoire of behaviors associated with anxiety and fear such as body tremors, grimacing, teeth gnashing, urination, and defecation. In contrast, antalarmin increased exploratory and sexual behaviors that are normally suppressed during stress. Moreover, antalarmin significantly diminished the increases in cerebrospinal fluid CRH as well as the pituitary-adrenal, sympathetic, and adrenal medullary responses to stress. We conclude that CRH plays a broad role in the physiological responses to psychological stress in primates and that a CRH type 1 receptor antagonist may be of therapeutic value in human psychiatric, reproductive, and cardiovascular disorders associated with CRH system hyperactivity.
Habib
K E
KE
Clinical Neuroendocrinology Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892-1284, USA. habib@codon.nih.gov
Weld
K P
KP
Rice
K C
KC
Pushkas
J
J
Champoux
M
M
Listwak
S
S
Webster
E L
EL
Atkinson
A J
AJ
Schulkin
J
J
Contoreggi
C
C
Chrousos
G P
GP
McCann
S M
SM
Suomi
S J
SJ
Higley
J D
JD
Gold
P W
PW
D000284:Administration, Oral; D000324:Adrenocorticotropic Hormone / Q000097:blood; D000818:Animals; D014151:Anti-Anxiety Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D001007:Anxiety / Q000188:drug therapy* / Q000209:etiology; D001127:Arginine Vasopressin / Q000134:cerebrospinal fluid; D003346:Corticotropin-Releasing Hormone / Q000134:cerebrospinal fluid / Q000502:physiology*; D004311:Double-Blind Method; D004353:Drug Evaluation, Preclinical; D004837:Epinephrine / Q000097:blood; D005106:Exploratory Behavior / Q000187:drug effects; D005239:Fear / Q000187:drug effects; D006854:Hydrocortisone / Q000097:blood; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects / Q000503:physiopathology; D008253:Macaca mulatta; D008297:Male; D009638:Norepinephrine / Q000097:blood; D010913:Pituitary-Adrenal System / Q000187:drug effects / Q000503:physiopathology; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D011758:Pyrroles / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors* / Q000502:physiology; D012726:Sexual Behavior, Animal / Q000187:drug effects; D012930:Social Dominance; D013315:Stress, Psychological / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology / Q000523:psychology; D000099052:CRF Receptor, Type 1
D014151:Anti-Anxiety Agents; D011743:Pyrimidines; D011758:Pyrroles; D018019:Receptors, Corticotropin-Releasing Hormone; C103016:antalarmin; D001127:Arginine Vasopressin; D000099052:CRF Receptor, Type 1; D000324:Adrenocorticotropic Hormone; D003346:Corticotropin-Releasing Hormone; D006854:Hydrocortisone; D009638:Norepinephrine; D004837:Epinephrine