Chronic activation of corticotropin-releasing factor type 2 receptors reveals a key role for 5-HT1A receptor responsiveness in mediating behavioral and serotonergic responses to stressful challenge.
BACKGROUND
The corticotropin-releasing factor type 2 receptor (CRFR2) is suggested to play an important role in aiding recovery from acute stress, but any chronic effects of CRFR2 activation are unknown. CRFR2 in the midbrain raphé nuclei modulate serotonergic activity of this key source of serotonin (5-HT) forebrain innervation.


METHODS
Transgenic mice overexpressing the highly specific CRFR2 ligand urocortin 3 (UCN3OE) were analyzed for stress-related behaviors and hypothalamic-pituitary-adrenal axis responses. Responses to 5-HT receptor agonist challenge were assessed by local cerebral glucose utilization, while 5-HT and 5-hydroxyindoleacetic acid content were quantified in limbic brain regions.


RESULTS
Mice overexpressing urocortin 3 exhibited increased stress-related behaviors under basal conditions and impaired retention of spatial memory compared with control mice. Following acute stress, unlike control mice, they exhibited no further increase in these stress-related behaviors and showed an attenuated adrenocorticotropic hormone response. 5-HT and 5-hydroxyindoleacetic acid content of limbic nuclei were differentially regulated by stress in UCN3OE mice as compared with control mice. Responses to 5-HT type 1A receptor challenge were significantly and specifically reduced in UCN3OE mice. The distribution pattern of local cerebral glucose utilization and 5-HT type 1A receptor messenger RNA expression levels suggested this effect was mediated in the raphé nuclei.


CONCLUSIONS
Chronic activation of CRFR2 promotes an anxiety-like state, yet with attenuated behavioral and hypothalamic-pituitary-adrenal axis responses to stress. This is reminiscent of stress-related atypical psychiatric syndromes such as posttraumatic stress disorder, chronic fatigue, and chronic pain states. This new understanding indicates CRFR2 antagonism as a potential novel therapeutic target for such disorders.
Department of Neurobiology, Weizmann Institute of Science, Rehovot, Israel.
Adi
A
Neufeld-Cohen
Paul A T
PA
Kelly
Evan D
ED
Paul
Roderick N
RN
Carter
Elizabeth
E
Skinner
Henry J
HJ
Olverman
Joan M
JM
Vaughan
Orna
O
Issler
Yael
Y
Kuperman
Christopher A
CA
Lowry
Wylie W
WW
Vale
Jonathan R
JR
Seckl
Alon
A
Chen
Pauline M
PM
Jamieson
D000704:Analysis of Variance; D000818:Animals; D001007:Anxiety / Q000235:genetics / Q000378:metabolism*; D001921:Brain / Q000378:metabolism; D002853:Chromatography, Liquid; D003345:Corticosterone / Q000378:metabolism; D006897:Hydroxyindoleacetic Acid / Q000032:analysis; D007030:Hypothalamo-Hypophyseal System / Q000378:metabolism*; D017403:In Situ Hybridization; D051379:Mice; D008822:Mice, Transgenic; D010913:Pituitary-Adrenal System / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D044282:Receptor, Serotonin, 5-HT1A / Q000235:genetics / Q000378:metabolism*; D018019:Receptors, Corticotropin-Releasing Hormone / Q000235:genetics / Q000378:metabolism*; D012701:Serotonin / Q000032:analysis; D058825:Serotonin 5-HT1 Receptor Agonists / Q000378:metabolism*; D013312:Stress, Physiological; D013315:Stress, Psychological; D054832:Urocortins / Q000235:genetics* / Q000378:metabolism
D012333:RNA, Messenger; D018019:Receptors, Corticotropin-Releasing Hormone; D058825:Serotonin 5-HT1 Receptor Agonists; D054832:Urocortins; C549823:urocortin 3 protein, mouse; D044282:Receptor, Serotonin, 5-HT1A; D012701:Serotonin; D006897:Hydroxyindoleacetic Acid; D003345:Corticosterone