This project explores the proposal that abnormalities in prefrontal cortex (PFC) are central to the etiology of schizophrenia; that they lead to dysregulation of mesolimbic dopamine (DA), particularly during stress; and that defects in the temporal lobe and PFC that arise early in development may result in the emergence of schizophrenic symptoms as the CNS matures. The project may be divided into three components: First, we will further define the alterations produced by PFC lesions on DA activity in accumbens. We will examine the impact of lesions of either DA afferents to PFC or excitatory efferents from PFC on extracellular DA levels in accumbens in the basal state and during acute and chronic stress. The impact of lesions of PFC on amphetamine- and phencyclidine (PCP)-induced changes in extracellular DA in accumbens and locomotor activity will also be studied. Second, we will examine the basic mechanisms that may underlie the modulation of subcortical DA systems by glutamatergic corticofugal projections from PFC. This will involve the monitoring of extracellular glutamate, aspartate, and GABA in accumbens of intact and PFC-lesioned animals, using dialysates previously analyzed for DA. If lesion-induced changes in excitatory amino acid availability are observed, we will determine the mechanisms by which such changes might influence accumbens DA by exploring interactions among the area's principal transmitters, as well as measuring the effects of PFC lesions on the electrophysiological activity of mesoaccumbens DA neurons and the impact of PFC lesions and of stress on the depolarization block produced by DA receptor antagonists. Finally, we will examine the functional impact of changes in DA receptor stimulation on the physiology of dopaminoceptive cells in accumbens, and how it is affected by manipulation of PFC corticofugal projections. The project involves a combination of in vivo and in vitro approaches, and utilizes neurochemical, anatomical, and electrophysiological techniques.
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