OHSU

Grandy Lab

TAAR1HEK_1

Walk around any major American city and you are likely to see, if not have an encounter with, a person suffering with a disabling mental condition.  They are easy to spot because of their odd behavior and unkempt appearance. But mental illness isn't always so easy to recognize. In fact most mentally ill people don't look it.  Mental illness affects people of all ages, races, and walks of life. 

It is estimated that everyone at some time in their life will suffer with a diagnosable mental condition or debilitating mental illness.  It is also estimated that 22% of American adults, roughly 44 million people, will suffer from a diagnosable mental disorder in the coming year. World-wide, the number exceeds hundreds of millions!  The sum total of deaths by suicide among American teenagers and young adults surpasses that of cancer, heart disorders, AIDs, birth defects, stroke, pneumonia, and influenza – combined!

The current cost of mental illness, notwithstanding its emotional impact on affected individuals and their families, is estimated to exceed $450 billion annually when costs associated with the abuse of alcohol and other drugs (heroin, cocaine, amphetamine, methamphetamine, marijuana) are taken into account.  

In spite of the magnitude and pervasiveness of mental illness in all its guises from florid psychosis, to substance abuse, to depression there remains widespread negative stigma associated with anyone seeking help for or diagnosed with a mental condition.

It is Grandy's assertion that at the core of this stigmatism is ignorance about the true causes of mental illness. Therefore, the overarching goal of Grandy's research efforts is to lay bare the molecular roots of debilitating mental conditions with particular emphasis on those that involve motivation and reward. In other words, describe in molecular detail the brain circuits influenced by opiates (heroin and morphine), and the psychostimulants cocaine and methamphetamine. 

One, if not the most important, motivation and reward circuit is made up of neurons that synthesize dopamine. Dopamine is one of the major neurotransmitters in the brain. Dopamine's release is dramatically influenced by opiates and psychostimulants.  Grandy's research efforts over the last 20 years have focused on identifying and characterizing the molecular components of dopamine-sensitive neurons known as receptor proteins. 

In the course of their efforts Grandy's group has not only expanded our understanding of the complexity of dopamine signaling in the brain but they also discovered three previously unknown signaling systems.  Chronologically, the first of these new signaling circuits consists of an opiate-like receptor and its endorphin-like peptide ligand orphanin FQ /nociceptin.  The second is a family of "trace amine" receptors that respond to the endogenous biogenic amines phenylethylamine, p-tyramine, and octopamine, and the synthetic amines meth/amphetamine.  The third signaling system involves molecules known as iodo-thyronamines. Discovered by Grandy and his colleague Thomas Scanlan, these endogenously synthesized molecules are structurally related to thyroid hormone, T3, but rapidly act in completely opposite ways through completely different mechanisms. 

The promise of Grandy's research is manifold. One aspect is the potential development of novel drugs that target the receptors and their ligands that his laboratory has identified. Ultimately these drugs could help ameliorate mental conditions including schizophrenia, attention deficit hyperactivity disorder, depression, suicidal ideation, compulsive behavior, and drug abuse to name just a few. 

However, another and equally important dimension to his effort is raising the level of mental health awareness locally, nationally, and internationally by educating individuals from all socioeconomic levels because helping those with mental illness achieve parity (equality) under the law is everyone's responsibility.