When hunches pay off
Dr Ian Musgrave freely admits his involvement in a world-leading research project into depression came almost completely by accident.
The Senior Lecturer at the University of Adelaide's Department of Clinical & Experimental Pharmacology was originally researching the role of an enigmatic brain receptor, known as imidazoline receptors, in regulating blood pressure.
By accident, he found that the imidazoline receptor cloned by US researcher Dr John Piletz, and known as IRAS, acts as a nerve growth factor. This has profound implications and suggests imidazoline receptors play a key role in mood and memory.
"It was one of those situations where you think 'I wonder what happens if we do that'," Dr Musgrave says.
"We had stained tumour cells with IRAS cloned into them, to see if the network of protein filaments that help cells maintain their shape was affected by IRAS.
"When we first looked down the microscope, we could see that the cells were turning into nerve cells. I just about fell off my chair and what I said was unprintable."
Dr. Musgrave's group had found that the imidazoline receptor, long thought to be a simple regulator of blood pressure, was a nerve growth factor.
Suddenly, imidazoline receptors entered the world of depression.
"Depression has previously been understood to have been a disorder of nerve communication in the brain: how nerves in the mood control centres talk to each other," Dr Musgrave says.
"In response to that thinking, drugs like Prozac have been developed which improve nerve communication by increasing neurotransmitter concentrations.
"We now know it is far more complex than that. Drugs like Prozac take several weeks to take effect, when by the neurotransmitter hypothesis they should act rapidly.
"It turns out that these drugs also have the effect of causing cells in the brain to make more cell connections. It is this increase in nerve cell connections, which takes place over weeks, that may be causing the antidepressive effect.
"John Piletz and I found that imidazoline receptors are most concentrated in the areas
of the brain responsible for mood and learning.
"John also found that imidazoline receptor number is altered in depressed people, and thought that imidazoline receptors might play a role in depression.
"Our discovery that imidazoline receptors increase the formation of nerve connections provides a mechanism for this action."
On the basis of this unexpected finding, Dr Piletz, from Jackson State University in Mississippi, spent a month in Dr. Musgrave's lab, investigating the interaction of IRAS with other nerve growth factors.
Dr Musgrave is now part of a three-country research project further examining imidazoline and its benefits. He is collaborating with Dr Piletz, and the Anding Psychiatric Hospital in Beijing, China.
Dr Musgrave's role is researching the effects that IRAS has on the memory and learning of mice, Dr Piletz will be examining the basic neurochemistry of its effects while Anding Hospital will examine how IRAS works on human patients by looking at natural IRAS mutations in human populations.
Part of Dr Musgrave's research will involve knocking out the IRAS gene in mice, and replacing it with mutant human versions identified by Anding Hospital.
"Eventually we hope to use IRAS to come up with a much clearer picture of depression and how it works, and because of that it will be easier to develop better treatments for it," he said.
The developments surrounding IRAS's impact on depression could lead to a better understanding of other conditions, including high blood pressure--the focus of Dr Musgrave's original research--and neuro-degenerative diseases such as Alzheimer's.
"It's still early days for a lot of our research concerning IRAS and the role it can play in the brain," Dr Musgrave says.
"At the same time it's very exciting, because the more we learn about it and what it can do, the more we are realising how important it could be." ■
Story Ben Osborne