A UCC researcher is working on new drug development to treat stress, a potential cause of mental disorders, writes Dick Ahlstrom
Many people talk about being stressed out when work gets a bit busy, but genuine stress has a more sinister side. It is closely associated with serious disorders such as depression and anxiety, and stress can cause physical changes in the structures of the brain.
The physiological and psychological impact of stress is the focus of research being undertaken by University College Cork neuropharmacologist Dr John F Cryan. The senior lecturer in the department of pharmacology and therapeutics is principal investigator in the Alimentary Pharmabiotic Centre and wants to map out exactly what is going on inside the brain in its response to stress.
It goes beyond scientific curiosity. There is a strong correlation between chronic exposure to stress and the development of depression and other mental disorders.
"One of the most well-known aspects of depression and anxiety is that stress is a major factor in the development of the disease in certain people," he explains.
"We are trying to understand the impact of stress on the brain, and how drugs modify this. A lot of my work to date has been based on antidepressant drugs and how they work."
Surprisingly, we don't know how most of the commonly used antidepressant drugs actually work, what they are doing in the brain. Dr Cryan's goal is to explain the biochemistry behind these drugs in an effort to develop better treatments.
"The ultimate goal is to try and make these disorders as treatable as possible and bridge the gap between pre-clinical and clinical therapies," he says.
One of the challenges is agreeing what stress actually is. What produces stress in one person may have no effect on another, he points out.
"If someone perceives something to be a stress then it is a stress," he says.
But there are clear physiological changes that show when someone is genuinely stressed.
Stress is an "acute activation" of our "fight or flight" response, the ancient physiological system that prepares our bodies to fight or flee an enemy. This system is based on the "hypothalmic pituitary adrenal axis", he says.
The hypothalamic pituitary adrenal axis (HPA axis) refers to a complex set of direct influences and feedback interactions between these three structures. Together they control reactions to stress and regulate essential functions such as digestion, the immune system, mood, sexuality and energy use.
"The HPA axis is under a lot of different regulatory controls and following chronic repeated activation of this you get rewiring in the brain," says Dr Cryan. "There are certain regions of the brain - for example, the hippocampus - that gets smaller. Cells die off and it shrinks." Other areas affected by stress include the hypothalamus, amygdala and frontal cortex.
"The goal is to try to get drugs to work directly on these circuits," he adds.
Dr Cryan is applying a wide variety of techniques in pursuit of this goal. He and colleagues are looking at the functioning of normal circuitry in the brain and how this changes under stress.
He is using a multidisciplinary approach combining behavioural, molecular, cellular and physiological techniques. His group is looking at genes and the proteins they produce, trying to see how each contributes to behaviour. The team is also studying the signalling pathways activated by stress.
He will then link this back to our understanding of depression and anxiety states to measure the contribution of stress to these pathologies. By extension, he is also looking at functional bowel disorders and addiction, whether to drugs or tobacco. All of these can arise as a direct result of chronic stress.
He has spent 11 years studying this subject in Australia, the US and Switzerland and more recently at UCC. He was recently awarded the inaugural Wyeth Psychopharmacology Award from the British Association of Psychopharmacology.