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Basis for sex and stress hormone induced mood symptoms and diseases

Research project The projects aim is to discover the clinical and biological mechanisms behind sex- and stress-steroid induced symptoms and disorders and to develop treatments against the conditions.

Metabolites of stress and sex hormones (GABA-steroids) agonistically modulate the GABA-A receptor and cause mental symptoms and disorders but the mechanisms are poorly known. Only a few individuals react negatively on GABA-steroids but all individuals have variations in GABA-steroids especially women during the menstrual cycle. The reason for individual responses to GABA-steroids is unknown. Previous research indicates that tolerance development with decreased function in the GABA-A system may be one reason. Another is that GABA-steroids have a biphasic action with low levels provoking symptoms while absence or higher levels give less severe symptoms. Personality factors and chronic stress seem to be of importance. Aims are: In humans investigate if tolerance against GABA-steroids occurs in conditions with increased endogenous or exogenous GABA-steroid exposure by using sensitivity tests of the GABA-A system? With brain imaging studies, in humans, investigate if activity in neural structures responsible for emotions, change in response to stimuli under GABA-steroid influence? In animals studies investigate if psychological trait factors, or chronic social stress, are important for the sensitivity towards GABA-steroids? In HEK-cells, expressing single recombinant human GABA-A receptor, with patch-clamp methods, investigate if 3alpha-hydroxy metabolites of endogenous or therapeutic progestagens, androgens and glucocorticoids are active on the GABA-A receptor?

Head of project

Project overview

Project period:

2009-04-06 2009-12-31

Funding

Finansår , 2003, 2004, 2005, 2006, 2007, 2008, 2009

huvudman: T. Bäckström, finansiar: VR, y2003: 360, y2004: 460, y2005: 460, y2006: 460, y2007: 550, y2008: 550, y2009: 550,

huvudman: T. Bäckström, finansiar: EU, y2003: 3240, y2004: 3360, y2005: 3400, y2006: 1800, y2007: , y2008: , y2009: ,

huvudman: M. Wang, finansiar: VR, y2003: , y2004: , y2005: 186, y2006: 186, y2007: 186, y2008: , y2009: ,

huvudman: T. Bäckström, finansiar: Industri, y2003: , y2004: , y2005: , y2006: , y2007: 2095, y2008: 2095, y2009: 760,

Participating departments and units at Umeå University

Department of Clinical Sciences

Research area

Clinical medicine

Project description

The projects aim is to discover the clinical and biological mechanisms behind sex- and stress-steroid induced symptoms and disorders and to develop treatments against the conditions.

Background: Substances, with effects as benzodiazepines and alcohol are produced in the body. They are metabolites of sex and stress steroids, and enhance the GABA (gamma-amino butyrc acid) effect on the GABA-A receptor and are called GABA-steroids. GABA-steroids can induce symptoms and disorders e.g. cognitive disturbances, mood disorders, Alzheimer’s dementia, loss of impulse control, and relapse in substance abuse. We know that the subunit composition of the GABA-A receptor is related to function, disorders and different regions of CNS. We investigate if GABA-steroid antagonists can be used as treatment against the disorders induced by the GABA-steroids.

Content: To develop animal models for GABA-steroid induced conditions. Investigate changes in GABA-A receptor subunits at different conditions in specific regions of CNS and clarify GABA-steroid effects. To investigate all metabolites of stress and sex hormones of their effect on the human GABA-A receptor expressed in HEK-cells. Verify the animal results in humans with psycho physiological methods in different patient groups with cognitive, affective and other CNS disorders.

Importance: Stress and menstrual cycle related conditions are great problems in the society but the knowledge of the biological background is limited. That GABA-steroids are involved in the disorders is already known but not by which mechanisms. Women suffer more than men from these disorders and specific sex hormone related conditions exist. The GABA-steroid antagonists give an opportunity to treat and prevent the development of these CNS disorders