This is a proposal for continuation of a Program Project which has ben focused on several issues that are at the interface between the basic and clinical sciences. Over the course of this Program we have contributed to the understanding of the role of biogenic amines, particularly dopamine and norepinephrine, in the regulation of brain functions believed to be disturbed in some types of serious mental illness. Our synthesis of findings from the sequential development of our research, with findings of others in this field, has led us to propose that the dopaminergic system in the brain serves as a restitutive or buffer system whose function is to stabilize brain function in the face of severe persistent, biological or psychological insult. As a further test of this hypothesis we have studied the effect of inescapable stress on the conditioned avoidance response (CAR). This response is selectively inhibited by antipsychotic drugs. In our studies, rats trained to perform the CAR inhibited the response when they were subjected to mild, persistent, inescapable stress. We have proposed that this neuroleptic like response to stress may reflect the invocation of a dopamine dependent restitutive system, and that some types of psychosis may result from the dysfunction of such a system. We have also studied the interaction of D1 and D2 receptors and their adaptation to psychotropic drugs, and have proposed a role for D1 receptors in tardive dyskinesia. In other studies we have considered the influence of maternally transmitted chemicals on postnatal biogenic amine function, and have found evidence that prenatal programming could be a factor in postnatal adaptive dysfunction. As can be seen from the nature of our research, this is a Program Project in every sense, making possible the synthesis of findings from multiple approaches into new and challenging hypotheses.