The dopaminergic system in the prefrontal cortex appears to be involved in the phenomenology, and perhaps the etiology, of schizophrenia. Despite the delayed onset of this disorder in early adulthood, evidence suggests that brain pathology is present earlier, perhaps from birth. An improved understanding of the development of the dopamine system in the prefrontal cortex is thus critical to the evolution of theoretical models of this illness and improved treatments. Another, probably related, aspect of schizophrenia is the ability of stress to precipitate exacerbations. Animal work has already shown that the dopamine system of the prefrontal cortex is selectively activated by conditioned stress, suggesting that an impaired system might account for the low stress tolerance of schizophrenic patients. FG 7142, a beta carboline which acts as an inverse agonists at the benzodiazepine receptor, appears to be anxiogenic in humans and animals and, interestingly, selectively activates dopamine in the prefrontal cortex of the rat. We have designed a series of studies to increase the understanding of how the dopaminergic stress response changes as an animal matures, using mild food shock and an anxiogenic drug as stressors. When normal functioning of this system is understood, we can then work to create models of the dysfunction which schizophrenic patients exhibit (e.g. through lesioning experiments) and look at how pharmacologic and other treatments might effect this model.
