It does not seem that long ago that most ADHD research was looking primarily at the roles of the neurotransmitters dopamine and norepinephrine in focus, concentration, self-control, and ADHD. But since one-third of the neurotransmitters in the brain are glutamate, and brain research is now looking at the intricate relationships between glutamate, dopamine, and norepinephrine in the functioning of the pre-frontal cortex.
Research is revealing that the glutamate network neurotransmissions from the pre-frontal cortex to other areas of the brain are more important than previously thought, and that they are enhanced by dopamine and norepinephrine. Too little dopamine or norepinephrine is a problem, and too much is a problem. The importance of glutamate in PFC functioning is beginning to come to the forefront in research.
Neuro-science is beginning to move away from seeing ADHD as just a problem with dopamine and/or norepinephrine, and is moving toward a better understanding of the brain as a network with networks of relationships such as the relationship between dopamine, norepinephrine, the glutamate excitatory neurotransmitters which are about 30-35% of all neurotransmitters in the brain, and their relationship to ADHD.
In this newer framework of understanding the PFC and ADHD, the new medication Intuniv from Shire has caused a bit of a buzz. It seems that Intuniv enhances the glutamate in the PFC. This is a new approach to ADHD treatment.
Amy Arnsten, Ph.D., is the Director of the Arnsten Lab, Dept or Neurobiology at Yale University. According to its website, the Arnsten Lab “studies molecular influences on the higher cognitive functions of the prefrontal cortex (PFC), with the overarching goal of developing rational treatments for cognitive disorders and mental illness… Research has focused on how the catecholamines norepinephrine (NE) and dopamine (DA), powerfully and dynamically modulate PFC cognitive function and physiology through intracellular signaling mechanisms.” The lab helped Shire Pharmaceuticals in the development of Intuniv for ADHD treatment.
The Arnsten Lab has been able show how the relationship between dopamine and norepinephrine and the ratios of dopamine to norepinephrine, can impact and improve cognitive functions such as focus, memory, and attention. Too much or too little of either neurotransmitter decrease cognitive functions, both in terms of the performance of brain cells, and in real world behaviors and performance. But when the ratios and relationships are just right, performance is improved.
Their work, along with the work of many others, is often focused on the a2-receptor sites in the pre-frontal cortex. These researchers have reported on the benefits of norepinephrine at these PFC receptor sites, and have also shown the benefits of stimulating these receptor sites with the medication guanfacine (intuniv). It appears that guanfacine improved cognitive functioning in the pre-frontal cortex.
In addition, the research of Craig Berridge and his team at the University of Wisconsin-Madison has focused on the effects of stimulants on the brain. He has shown that the main effects of stimulants are on the frontal lobes of the brain, and that small doses of methylphenidate actually impact the effects of norepinephrine in the pre-frontal cortex more than they impact the effects of dopamine in the PFC, though both are enhanced. This research has also shown that when the a2 receptors in the pre-fronatal cortex are blocked that the symptoms of ADHD can be created in a subject, including lack of self-control, impulsivity, and hyperactivity (Berridg et al, 2006).
All of this new understanding of the effects of neurotransmitters in the pre-frontal cortex, and the impact of medications on the PFC, will help future research on new medication treatments to help children and adults who suffer from ADHD.