David Grandy

Millions of people suffer from some form of mental illness. Of these many will become poor, homeless, and even imprisoned. Although the financial impact that the mentally ill have on society is significant, the pain and suffering endured by these individuals, their families, and their friends is immeasurable. Unfortunately, in the past society’s responses to the needs of the mentally ill have largely been guided without the benefit of knowing much about the brain and how it works. It is our hope that by learning more about the basics of brain function, the treatment mentally ill receive, both as patients and members of society will improve.

One area of research that is contributing much to our understanding of basic mental processes focuses on how nerve cells communicate , or talk to one another. We now appreciate that nerve cells communicate by chemical messengers. This form of signaling is characterized by the release of a chemical messenger, the neurotransmitter, (of which there are hundreds known and more yet to be discovered!) from one neuron and its detection by a second neuron. For a neuron to be receptive to chemical neurotransmitters it must express on its surface receptor proteins that can recognize a particular neurotransmitter.

Historically the Grandy laboratory has concentrated its efforts on G protein-coupled neurotransmitter-receptor systems that are activated by dopamine, opiate, and related ligands. We originally chose to study the dopamine and opioid systems because years of research and clinical experience demonstrating that they can contribute to the etiologies of schizophrenia and drug addiction, two major manifestations of mental illness. As molecular neuroscientists we have been able to isolate and clone (copy) DNAs that code for the dopamine and opioid receptors. In the course of our cloning efforts we discovered several novel receptors and have identified their chemical messengers. One is now referred to as the nociceptin/ orphaninFQ (N/OFQ) system, a close relative of the opioid system. To date one of the exciting properties of the N/OFQ system is its ability to significantly inhibit the activity of both dopamine and opioid neurons in the brain. By potently influencing these two systems N/

Arttamangkul, S., V. Alvarez-Maubecin, G. Thomas, J.T. Williams, and D.K. Grandy (2000) Binding and internalization of fluorescent opioid peptide conjugates in living cells. Molecular Pharmacology 58:1570-1580.

Cunningham C.L., M.A. Howard, S. Gill, M. Rubinstein, M.J. Low, and D.K. Grandy (2000) Ethanol conditioned place preference is reduced in dopamine D2 receptor deficient mice. Pharmacology, Biochemistry and Behavior 67:693-699.

Rubinstein, M., C. Cepeda, R.S. Hurst, J. Flores-Hernandez, M.A. Ariano, T.L. Falzone, L.B. Kozell, C.K. Meshul, J.R. Bunzow, M.J. Low, M.S. Levine, and D.K. Grandy (2001) Dopamine D4 receptor-deficient mice display cortical hyperexcitability. Journal of Neuroscience, 21:3756-3763.

Khan, Z.U., P. Koulen, M. Rubinstein, D.K. Grandy, and P.S. Goldman-Rakic (2001) An astroglia linked dopamine D2-receptor action in prefrontal cortex. Proceedings of the National Academy of Sciences, U.S.A. 98:1964-1969.

To contact Dr. Grandy directly: grandyd@ohsu.edu