Sidney B. Auerbach - US grants

The research by Dr. Sidney Auerbach examines the role of serotonin in mammalian physiology. There are two conflicting views of the functional organization of serotonin-containing nerve cells in the brain. Some evidence indicates that separate groups of these cells are involved in specific processes such as control of pain. In opposition is recent evidence that the discharge rate of all serotonin cells is very regular and is not increased by physiological or behavioral challenges. To reexamine the controversy raised by the electrophysiology data, Dr. Auerbach will use intracerebral dialysis to measure release in four anatomically and functionally distinct brain areas of freely behaving rats. If release is not affected by challenges such as environmental cooling or physical restraint, it will corroborate the electrophysiology and suggest that serotonin is not actively involved in responses to stress. If serotonin release is increased, it will suggest that release is regulated at nerve endings independently of cell body discharge. Dr. Auerbach will locally administer antagonists to vasopressin and opioids to test the possibility that brain substances released during stress act at serotonin nerve terminals to regulate serotonin release. The research is expected to yield new insights into contradictory evidence concerning how serotonin cells function within the brain to regulate physiology.

Clinical depression is a devastating disorder. Treatments are available but recovery is usually slow. The effectiveness of drugs that block serotonin (5-HT) uptake suggests that an increase in 5-HT transmission is an important factor in recovery. It is puzzling however, that recovery takes weeks although uptake is rapidly blocked. This delay has been ascribed to a negative feedback mechanism whereby activation of autoreceptors suppresses 5-HT release. The proposed research will examine the factors controlling 5-HT release after administering uptake blockers. In vivo microdialysis will be used to test the hypothesis that the increase in extracellular 5-HT after acute administration of uptake blockers in restrained by autoreceptor-mediated inhibition of release. Selective and non-selective uptake blockers, will be administered to rats, and changes in extracellular 5-HT will be measured in three different brain sites. Autoreceptor antagonist drugs will be used to test the influences of negative feedback modulation of 5-HT release after uptake inhibition. Additional experiments will address the possibility that the delayed therapeutic effect of antidepressant drugs is correlated with gradual desensitization of autoreceptors and increased 5-HT release. Specifically, changes in extracellular 5-HT will be measured after chronic drug treatment, and the influence of autoreceptors and excitatory inputs evaluated using receptor antagonists. Related experiments will test the hypothesis that increased excitation of 5-HT neurons during behavioral arousal can offset the inhibitory influence of autoreceptors stimulation. This result would provide an experimental basis for the clinical observation that physical activity can speed recovery from depression. Understanding the factors influencing 5-HT release could aid in development of improved clinical treatment of depression.