Consequences of chronic social stress on behaviour and vasopressin gene expression in the PVN of DBA/2OlaHsd mice--influence of treatment with the CRHR1-antagonist R121919/NBI 30775.
Accumulating evidence suggests that corticotropin-releasing hormone (CRH) neurocircuitry modulate the neuroendocrine and behavioural phenotypes in depression and anxiety. Thus, the administration of the selective CRH-receptor 1 (CRHR1)-antagonist R121919/NBI 30775 has proven its ability to act as an anxiolytic in rats. It is still unclear whether vasopressinergic neuronal circuits, which are known to be involved in the regulation of emotionality, are affected by R121919/NBI 30775. Using DBA/2OlaHsd mice, we investigated the effects of chronic social defeat and concomitant treatment with R121919/NBI 30775 on 1) the behavioural profile in the modified hole board test and 2) in-situ hybridization analysis-based expression of arginine vasopressin (AVP) and CRH mRNA in both the hypothalamic paraventricular nucleus and supraoptic nucleus. The results suggest that chronic social defeat leads to increased avoidance behaviour and reduction in directed exploration, general exploration, and locomotion. Chronic treatment with the CRHR1-antagonist was effective in reversing the directed exploration to control level. The dissection of the antagonist-treated group into responders and non-responders using the parameter time spent on board revealed further positive effects of R121919/NBI 30775 on avoidance behaviour and locomotion. Behavioural changes were accompanied by alterations in AVP gene expression in the paraventricular nucleus. Taken together, the anxiolytic action of the CRHR1 antagonist was found in a subgroup of animals only, and further studies have to be done to clarify the inter-individual biological differences in response patterns to this compound to optimise its application under clinical conditions.
Erhardt
A
A
MD Max Planck Institute of Psychiatry, Munich, Germany. erhardt@mpipsykl.mpg.de
Müller
M B
MB
Rödel
A
A
Welt
T
T
Ohl
F
F
Holsboer
F
F
Keck
M E
ME
D000284:Administration, Oral; D000374:Aggression / Q000523:psychology; D000818:Animals; D001127:Arginine Vasopressin / Q000235:genetics*; D001522:Behavior, Animal / Q000187:drug effects*; D003346:Corticotropin-Releasing Hormone / Q000235:genetics; D015870:Gene Expression / Q000235:genetics*; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D009415:Nerve Net / Q000187:drug effects / Q000502:physiology; D010286:Paraventricular Hypothalamic Nucleus / Q000187:drug effects / Q000502:physiology*; D011743:Pyrimidines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors*; D013315:Stress, Psychological / Q000503:physiopathology*; D013495:Supraoptic Nucleus / Q000187:drug effects / Q000502:physiology
D011743:Pyrimidines; C412383:R 121919; D012333:RNA, Messenger; D018019:Receptors, Corticotropin-Releasing Hormone; D001127:Arginine Vasopressin; D003346:Corticotropin-Releasing Hormone