News and Publications

Neuropharmacology

Floyd E. Bloom, M.D., Chairman

lcohol, nicotine, drug addiction, depression, and viral infections are all noteworthy for the cost they inflict upon individuals and society. The direct and indirect public health costs of alcoholism are estimated to be in the hundreds of billions of dollars yearly. More than half a million Americans die each year from smoking-related illnesses. In any given year, one out of every ten people in the United States suffers through some form of major depression. And more than three quarters of a million people in this country have AIDS, which can have major deleterious effects on the brain.

The Department of Neuropharmacology addresses these disorders, exploring the function of the normal and diseased brain and establishing the fundamental mechanisms by which the environment and genes lead to various disorders of the brain. Some department scientists study the mechanisms of neuronal synaptic communication to determine the difference between normal signaling and signaling in AIDS patients or those who are dependent on alcohol, marijuana, cocaine, morphine, tobacco, or other drugs. Others focus on various aspects of the brain's chemicals, molecules, or cells to achieve a better understanding of how to devise effective treatments for these conditions.

The department has a large program to study the effect of HIV on the brain, a debilitating but often overlooked aspect of the disease. One quarter to one third of all AIDS patients suffer from some form of central nervous system disorder during the course of their infection, ranging from minor cognitive and motor disorders to severe dementia, symptoms collectively known as neuroAIDS. These problems are the direct result of the inflammation brought on by the immune cells coursing through the brain. This inflammation interferes with neuron signaling, slowing down the processes within the cerebral cortex, the part of the brain responsible for higher brain functions such as thought, sensation, voluntary muscle movement, reasoning, and memory.

In order to further research the cause, prevention, and treatment of HIV infection in the brain, Howard Fox, M.D., Ph.D., has organized the Scripps NeuroAIDS Preclinical Studies Center, funded last year through a $10 million grant from the National Institute of Mental Health. The center brings together researchers from throughout the institute to look at all neurological aspects of HIV infection and treatment. Fox himself has developed an experimental model of an HIV-like virus to establish the molecular and cellular basis of neuroAIDS pathogenesis.

VIRUSES AND THE BRAIN

Several other researchers in the department conduct programs that investigate how viruses get into the brain and how they cause disease. Michael B.A. Oldstone, M.D., studies the mechanisms of immune system interactions that mediate the pathologic effects of viral infection in the central nervous system. He also directs a multiple investigator initiative sponsored by the National Institute on Aging, investigating the role of viruses in brain pathology. Michael Buchmeier, Ph.D., studies the ability of hepatitis virus to remove myelin, the sheath surrounding nerve fibers, as an experimental model of human multiple sclerosis. Lindsay Whitton, M.D., Ph.D., studies the molecular and immune mechanisms involved in viral pathogenesis and antiviral immunity. He is also working on approaches to vaccinate against viral diseases using DNA.

The department also has a strong program in alcohol research. Many questions remain to be answered in this field. For instance, we know that the children of alcoholics are four to five times more likely to become alcoholics themselves, but we do not know the neurological basis for this trait.

THE LONG-TERM EFFECTS OF ALCOHOL ON THE BRAIN

For more than 20 years, TSRI's alcohol research center has been investigating the long-term effects of alcohol on the brain. Recently, the National Institute on Alcohol Abuse and Alcoholism (NIAAA) funded a multi-year consortium headed by researchers at TSRI to identify the molecular basis of alcoholism. The Integrative Neuroscience Initiative on Alcoholism, directed by George Koob, Ph.D., aims to address the basic science of alcoholism and to establish a platform upon which future treatments can be built. Identifying the nature of the neuron transmitters that addictive drugs act on makes it possible to design new therapies to interrupt those effects and blunt the influence of the drug.

Cindy Ehlers, Ph.D., studies the role of genetic factors and their interactions with brain motivational circuits in alcoholism. Understanding motivational circuits is critical to understanding drug abuse and the brain. Many drugs act as natural neural transmitters, turning on what is known as the reward system within the brain and making the drug user feel good. Drug dependence often develops because of these internal rewards.

Several researchers study the basis of this system of reward and motivation. Koob has conceptualized drug dependence as an allostatic break with homeostasis where the brain reward system becomes progressively dysregulated and where residual neuropharmacological changes persist post-dependence. Athina Markou, Ph.D., investigates the neurobiology of reward as it relates to drug abuse, depression, and schizophrenia. John Polich, Ph.D., uses electrophysiology to look at the role of drugs and the neurotransmitters they affect in altering human cognition. Friedbert Weiss, Ph.D., studies brain motivational circuits and their connections in animal models of drug craving and relapse. George Siggins, Ph.D., works on the interactions of drugs of abuse, such as amphetamines and alcohol, with the neuropeptide systems in the brain's reward pathways. Steve Henriksen, Ph.D., also studies the basis of reward, and directs a program looking at methamphetamines as a drug of abuse.

Many investigators in the department are interested in the effect of the body's own substances on the brain. Donna Gruol, Ph.D., studies the role of calcium signaling in regulating neuronal functioning and development. She also researches signaling related to the presence of cannanbinoid-containing drugs like marijuana. Merrill Mitler, Ph.D., examines the role of neurotransmitters and cytokines in disorders of sleep and waking. Iain Campbell, Ph.D., studies the role and mechanisms of action of cytokines and chemokines in the brain in inflammatory states.

Tamas Bartfai, Ph.D., studies molecular and cellular correlates of changes in cognition, long-term memory, and emotional states. Bartfai also directs the Harold L. Dorris Neurological Research Center, founded in 1999 with a remarkable $10 million endowment from Helen L. Dorris of San Diego. The center provides education and conducts research into neurological disorders, including schizophrenia and Alzheimer's disease, as well as advancing knowledge of the process of aging of the brain.

Understanding the link between the physiology of the brain and behavior is a key goal of all the investigators in the department, as is turning these basic observations into useful therapeutics for degenerative diseases, emotional disorders, and drug abuse.