Bryan L. Roth, M.D., Ph.D., NARSAD Scientific Council member, is a well known expert on psychopharmacology. In recent years, he has developed several experimental technologies that are now paying dividends in research that is explaining some of the mysteries of brain circuitry involved in addiction, schizophrenia and other neuro-behavioral disorders. The NARSAD investment of a 2008 Distinguished Investigator grant has made this work possible.

In the January issue of the journal Nature Neuroscience, Dr. Roth’s lab at the University of North Carolina Chapel Hill Medical School, in collaboration with scientists from the University of Washington, Seattle, reported success in what they called “deconstructing” the contributions of specific neural pathways to addiction-related behavior. Other members of the team include NARSAD Young Investigator Susan M. Ferguson, Ph.D., and NARSAD Independent Investigator John Neumaier, M.D., Ph.D., both from the University of Washington.

The experimental methods developed by Dr. Roth and initially funded solely by his NARSAD Distinguished Investigator award enable neuroscientists to follow the pathways taken by messages sent between neurons in complex networks in the brain. This has always been a very difficult feat to accomplish, in part because molecules used to stimulate or inhibit nerve cells have a tendency to be able to “dock” with a variety of receptors, found on the surfaces of various types of cells. Because of this, “off-target effects” are hard to tease out from intended ones when neuroscientists try to tweak a circuit experimentally to see how it functions.

In the study just published, Dr. Roth and colleagues focused on a part of the brain well known to be important in addiction, called the dorsal striatum. This part of the brain acts as a cohesive functional unit, and is involved, among other functions, in the control of movement. Parkinson’s disease, as well as the movement-related aspects of obsessive-compulsive disorder and Tourette’s syndrome are traced partly to problems in this part of the brain, in addition to some of the behavioral phenomena associated with drug addiction.

The team set out specifically to untangle the roles of two types of neurons in the dorsal striatum. One type, called striatopalladial neurons, form part of what neuroscientists call an “indirect” pathway in the striatum and adjacent brain areas. The other cell type, striatonigral neurons, is associated with a corresponding “direct” pathway. It has been theorized that these pathways have opposite effects in the regulation of movement.

In rats, Dr. Roth and colleagues looked at the activity of neurons in the direct and indirect pathways as the animals were becoming “sensitized” to amphetamines, an addictive drug. Sensitization is a progres- sive and persistent increase in an addicted person’s (or in this case, rat’s) behavioral response. Dr. Roth’s team was able to confirm experimentally what had only previously been theorized: direct and indirect pathway neurons do indeed have opposing roles. Striatonigral neurons promoted sensitization to amphetamines; striatopalladial neurons suppressed it.

This discovery will help inform ongoing attempts to develop therapeutic means to treat addiction. Additionally, Dr. Roth reports, the technologies used in this work will be used by other scientists, including John Allen, Ph.D. a NARSAD Young Investigator being mentored by Dr. Roth. He seeks to identify the neuronal circuits responsible for symptoms of schizophrenia.

Dr. Roth is a recipient of NARSAD Young, Independent and Distinguished Investigator grants in 1992, 1998 and 2008 respectively.