NARSAD's Fourteenth Annual Symposium
October 11 - 12, 2002

Session 1: Basic Science Research

Michael Barrot, Ph.D.,of the University of Texas Southwestern Medical Center at Dallas , is studying the effects of emotional experiences on the regulation of a molecule called CREB. This molecule is known as a transcription factor, which programs the genes for messenger RNA, which then directs the way that proteins are built. Dr. Barrot created a mutated version of CREB and injected it into a brain region called the nucleus accumbens, which is involved in reward mechanisms. The animals with increased CREB had a markedly decreased intake of sugar, which was used as a reward in a behavioral test. Thus, CREB seems to be involved in sensitivity to reward. The animals with increased CREB also showed less anxiety and had decreased aversion to painful stimuli. Thus, Dr. Barrot theorizes that in a natural situation, CREB plays an important role in how an animal copes with a stressful situation--essentially by blunting the emotional impact of the stressor. This work has been published in the Proceedings of the National Academy of Sciences.

Comments by Dr. Francine Benes: "For a long time, neuroscience essentially ignored the neuropsychiatric conditions; not because neuroscientists didn't care about depression and anxiety, but because they simply did not have the means to study the psychiatric disorders. Over the last ten years, there has been a major thrust in the field to find ways that would give us a window of opportunity to learn about depression and anxiety.

Dr. Barrot has used two basic strategies. One was to find animal models that could be used as tools for studying reward mechanisms in depression and also the effects of stress on animals. Now, we all have stress in our everyday life. We know stress is associated with the onset of depression and anxiety. Dr. Barrot has used several different stress paradigms to apply to his rats. Why did he do that? Well, it took a long time for neuroscientists to understand that what was an appropriate behavioral model in rats could be used as a model for studying human stress and depression.

This is a very important piece of work...it is something we can consider to be at the cutting-edge of neuroscience research because it does not use an intact system within the brain; it brings together a precise understanding of neuroanatomy and a very detailed and intricate manipulation of gene expression. And, so with work of this type, I think we can start to look more specifically at the potential for developing novel treatment strategies that are based on transcription factors rather than the antidepressants that the field of psychiatry has been using over the last 50 years.

These drugs, as many in this room might be aware, are very effective. But the problem with them has been they have been largely atheoretical. We simply, and very honestly, stumbled onto these drugs over the years; never understood why they worked; found ways of defining the types of things these drugs could do in the central nervous system; and created whole hypothetical models around this to explain depression and anxiety. The work that Dr. Barrot is doing is a new beginning for us in neuroscienceÉ I think we can look forward to more rational treatments for depression and anxiety in the future."

Kevin Behar, Ph.D.,of Yale University , is studying the mechanisms that regulate the synthesis of gamma amino butyric acid (GABA) in the brain. Brain levels of GABA are diminished in patients with major depression. Using radioactive labeling of the chemicals involved in the metabolic pathways of GABA synthesis, magnetic resonance spectroscopy (MRS), and assessments of GABA-dependent gene expression, he is delving into relevant research questions, including the rate of flow of GABA transfer between neurons and astrocytes, brain cells that regulate metabolism in the neuron. This work is also facilitating the understanding of how these chemical pathways are related to brain energy metabolism.

Dr. Benes: "Once again we are seeing a presentation of work that represents the cutting-edge in imaging studies related to the psychiatric disorders. After an initial period of euphoria about magnetic resonance spectroscopy, it became clear to certain scientists, like Dr. Behar, that it was going to be necessary to bite the bullet and conduct very detailed experiments to identify precise metabolic pathways in the brain that are relevant to the psychiatric disorders. You heard Dr. Behar talk about the GABA system, as well as the glutamate system. These are the two most fundamental neurotransmitter systems in the brain. Glutamate is excitatory in nature while GABA is inhibitory in nature. The brain's ability to balance the activity of these neurotransmitter systems is critical to the normal functioning of the brain.

Dr. Behar is developing techniques for looking at these transmitters, but looking at them in ways in which he can actually manipulate their metabolic pathways. This is extraordinarily sophisticated work, and work that will eventually lead us to an understanding of how these neurotransmitter systems are being regulated at the cellular level. I think you can see from his presentation that it is far more complex than we had ever imagined. At one time, we only thought in terms of neurons being related to the activity of the brain. But as you heard there are also cells called astroglial cells. These are not neurons. They are non-neuronal cells. For many decades, it was a bit of a mystery as to what these cells did in the brain. We knew that in degenerating systems they would pick up the debris of dying neurons and leave scar tissue behind. But in recent years, it has become apparent that the astroglial cells work hand in hand with the neurons to maintain the normal metabolic function of the brain. It is essential that we learn about the dynamics of the interaction between these two cell types, and Dr. Behar's work is clearly going to tell us about that."

Joshua Berman, M.D., Ph.D., of Columbia University , is examining the interaction between systems that regulate the stress response and motivated behaviors. These pathways are complex and involve several brain regions, including the nucleus accumbens, amygdala, thalamus, and prefrontal cortex. Dr. Berman is using markers of activation of neurons to indicate the brain's response to stress. These markers include a transcription factor called c-fos, which is turned on when neuronal activity increases after stress, and corticotropin releasing factor (CRF), a hormone released from the brain in response to stress. Neurons that are active become labeled with a fluorescent dye, which indicates the brain regions that respond to stressful events. This model can also be used to identify those regions of the brain that are responsible for experiencing pleasure (hedonia) in response to drugs such as nicotine. If the neuronal pathways that influence hedonia can be identified, then it may be possible to identify targets for treatments that lessen the effects of stress on illnesses in which these pathways are involved.

Dr. Benes: "In Dr. Berman's presentation, he spoke of the complexity of the circuitry that is involved in the stress response...there are many different portions of the brain, and they contribute different aspects of the stress response. For humans, as all of us know, some things that are stressful for one person are not stressful for another. That's because of the associations we makeÉour memories about certain events and the kinds of people that we are

In Dr. Berman's presentation, he is really saying that there is one part of this complex circuitry that plays a very central role--the dopamine system. The dopa-mine projections are sent to several areas of the brain integrally involved in stress. His work is aimed at identifying the specific neurons that are activated when stress is being experienced. This is extremely important, because the work in neuroscience over the last 20 years showed us that in any region of the brain there are many different types of neurons within that region that can be identified by the transmitters they use. But there also are specific patterns of connectivity. The first step in this process of understanding what role stress is playing is to identify which neurons are responding early to stress, and in what way they are responding. This is very important work. It's work that requires a great deal of patience, and we look forward to hearing further about his progress."

Joshua Gordon, M.D., Ph.D., of Columbia University , is using an animal model to study the role of the serotonin system in anxiety disorders. His laboratory has engineered a "knockout" mouse, in which the gene for a specific subtype of a serotonin receptor (5HT-1a) has been removed. These mice demonstrate behaviors that are interpreted as anxiety, such as spending less time in an open arm of a radial maze. Dr. Gordon is putting electrodes into the brains of these mice, including a structure called the hippocampus, in order to examine the brain waves that are emitted. These brain waves have characteristic rhythms--the theta rhythm is increased in the mice that lack the 5HT-1a receptor. It is theorized that one way in which serotonin reuptake inhibitors, such as fluoxetine (Prozac), work is by increasing serotonin activity, which in turn dampens activity of the hippocampus. The model system in this research study may therefore have implications for understanding the mechanism of action of antidepressant medications that target the serotonin system.

Dr. Benes: "Dr. Gordon's discussion is related to anxiety disorders, a very important part of what we deal with in the field of psychiatry. The area of the brain that was examined, the hippocampus, is now considered the key area of the brain in several different psychiatric disorders and part of a larger network of connections that we call the corticolimbic system. This system is probably involved in schiz-ophrenia and bipolar disorder. It may be involved in depression and anxiety disorders. The question is, how can one system be involved in all these disorders when at the clinical level they look completely different from one another? The answer is that there are probably differences in wiring patterns within these areas. And there are probably differences in the types of genetic expression, in the types of molecules that are being expressed in one disorder versus another. The hippocampus was a logical place for Dr. Gordon to be conducting this type of work. He was using electrophysiology. None of the speakers so far have used this particular approach, one that is very basic in the field of neuroscience. It is also one that is extremely important in neuroscience because when push comes to shove all the neuronal systems work by virtue of the electrical activity that is generated by the neurons. Neurons talk to one another, generating electrical activity. This is what we call state-of-the-art genetic work. It is very important because it brings together genetics and electrophysiology."

Patricia Szot, Ph.D., of the University of Washington , is examining the role of the neurotransmitter norepinephrine (NE) in brain systems that may be involved in depression. She is using a genetically engineered mouse which lacks the en-zyme dopamine beta hydroxylase, which produces NE from dopamine (DA). These mice lack NE but have normal levels of DA. Another genetically engineered mouse was created which lacks the enzyme tyrosine hydroxylase, which is the precursor to both DA and NE; these mice lack both of these neurotransmitters. She demonstrated that mice that lack only NE have normal numbers of NE transporters (receptors that NE attaches to), whereas mice that lack both NE and DA have decreased NE transporters. This suggests that the lack of both neurotransmitters are required for a decrease in the number of NE transporters. She also showed that chronic administration of the antidepressant desipramine resulted in a decrease in the NE transporter irrespective of whether NE was present or not. This suggests that desipramine, which is believed to act mainly by increasing NE, has effects that are independent of NE.

Dr. Benes: "I'd like to give historical context to the presentation that you just heard from Dr. Szot regarding the role of the neuroadrenergic transporter in relation to antidepressant effects. I think a historical perspective is useful. The antidepressant medications were developed decades ago. The first antidepressant was actually a drug used to treat tuberculosis. It was completely accidental when it was discovered and it was a monoamine oxidase inhibitor (MAOI). It was noted that when people who had tuberculosis were given the drug Isoniazid, not only did the TB seem to get better, but they seemed to be less depressed. That triggered a whole generation of MAOI drugs--notably they were very effective antidepressants. More recently, the tricyclic antidepressants were brought into the picture. They were an improvement in many respects. They were also very effective in treating depression and very non-selective in working on the noradrenergic, serotonin, and dopamine systems. They caused a lot of side effects. So the pharmaceutical companies developed a third generation of antidepressants and tried to focus on which of the monoamines they thought was most important to the antidepressive effective drugs of the past. Serotonin seemed to be supported by a key element in the therapeutic efficacy. So the so-called selective serotonin reuptake inhibitors (SSRI's) were born and Prozac was a prototype of this drug. It worked very well in general, however some people with severe depression, and some people for reasons we don't understand, simply don't respond to the SSRI's. This has raised a question as to whether there are some forms of depression or indeed some components of depression that may involve the other monoaminergic systems like the norepinephrine and dopamine systems.

There are new studies looking into how antidepressants work, looking as Dr. Szot is, at important changes in the noradrinergic system. Her work is timely and offers potential advantages of our having a fourth generation of drugs that help certain people with depression to get a better therapeutic effect.

• Session 2: Affective Disorders Research

• Session 3: Schizophrenia Research

• Return to the symposia index