News Release

Mice Free Of Anxiety By A Deficient Stress Hormone Receptor--A Hint For A NewTherapeutic Regimen In The Treatment Of Depression And Anxiety

Peer-Reviewed Publication

Max-Planck-Gesellschaft

Depressed patients show an altered stress hormone regulation and psychopathological symptoms. Researchers at the Max Planck Institute of Psychiatry in Munich, Germany, and the GSF Research Centre, Institute for Mammalian Genetics in Neuherberg generated a stress hormone receptor-deficient mouse exhibiting a blunted stress response and reduced anxiety. This finding, published in Nature Genetics, vol. 19, June 1998, may provide new possibilities of treating depression and anxiety.

The hypothalamus, located at the ventral diencephalon, is a relay station to integrate the central and the autonomic nervous system by regulating the secretion of various hormones into the blood stream. One of the hormones, which is secreted under acute stress conditions in the hypothalamus, is the neuropeptide corticotropin-releasing hormone (CRH). CRH triggers the release of the adrenocorticotropic hormone (ACTH) in the anterior pituitary. Subsequently, ACTH stimulates the release of cortisol from the zona fasciculata of the adrenal cortex.

In patients with severe depression, the stress hormone cortisol is highly elevated in the cerebrospinal fluid and blood plasma causing alterations of various tissues such as the brain and immune system. Under normal stress condition, there is an immediate down-regulation of cortisol via the hypothalamic-pituitary-adrenal (HPA) axis--negative feedback loop--which results in a normal plasma concentration of the stress hormone cortisol. For patients with a depression, and healthy individuals with a genetic pre-disposition for depression, it has been shown that the down-regulation of the stress hormone cortisol is altered. In pharmacological studies, it has been shown that antidepressants are able to down-regulate elevated cortisol levels.

These results indicate that the clinical relevance of antidepressants is the down-regulation of the stress hormone cortisol. Moreover, it has been shown in animal models, in patients with depression, and by molecular biological examinations that the negative feed back loop of the HPA axis is altered and that cortisol is unable to suppress CRH secretion. The elevated CRH level is probably responsible for the symptoms of depression.

As now published in Nature Genetics, the researcher at the Max Planck Institute of Psychiatry, Munich, in collaboration with the GSF Research Center, have been able to show by generating a mouse mutant with CRHR1-deficiency that the anxiogenic effect of CRH is mediated by the CRHR1 receptor. Indeed, these CRHR1-deficient mice show reduced stress hormone response (cortisol response) under acute stress conditions, and were less anxious in behavioral tests. In general, when wild-type mice are subjected to forced alcohol consumption and, subsequently, alcohol withdrawal conditions, they exhibit enhanced anxiogenic reactions. In contrast, CRHR1-deficient mice showed less anxiogenic behavior under alcohol withdrawal then wild-type mice. Thus by eliminating CRHR1 functions, anxiogenic behavior can be manipulated and probably other symptoms correlated with depression.

These findings have now led to the assumption that new drugs which suppress CRHR1 function might be able to reduce symptoms of depression and anxiety in patients. The clinical use of CRH-antagonists could therefore lead to a faster and more effective therapeutic response than classical antidepressants, and represents a completely new mode of action.

###



Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.