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256 EFFECTS OF STRESSPFCmodulation ofamygdalaLocus coereleusresponsivenessMesocorticalDASTRESSHypothalamic andglucocorticoidresponse to stressDAmodulationof PFCTonic DA inaccumbensPhasic DA inaccumbensHippocampalsuppression ofstress responseHippocampaldamageFigure 11-2 In the schizophrenia patient, a preexisting deficit in prefrontal cortical functionis proposed to initiate a cascade of events that may lead to schizophrenia in late adolescence/earlyadulthood. The pathology within the prefrontal cortex may relate to thereported decrease in dopamine modulation of this region, given that: (1) dopamine is knownto increase output neuron excitability in the prefrontal cortex, (2) stress is known to increasedopamine levels in the prefrontal cortex, and (3) schizophrenia patients are reportedto have deficits in dopamine innervation of the prefrontal cortex. Such prefrontal corticaldysfunction would lead to abnormal regulation of the dopamine system, as well as a decreasein control of the amygdala response to stress; each of which would be expected toincrease the response of the organism to acute stressors. This would be further exacerbatedby an increased amygdala drive of the locus coeruleus, a region that has been associatedwith stress responses. The net effect of this would be activation of hypothalamicglucocorticoid response and a resultant glucocorticoid-mediated degeneration of the hippocampus.Such interlocking positive feedback loops have the characteristic that the loopmay be engaged by pathological changes within any of the interconnected structures, withthe common result being abnormal augmentation of the stress response and hippocampaldamage.would be augmentation of the autonomic outflow, and in particular increasedglucocorticoid release (Sapolsky, 1996, 1999).The increase in stress-induced glucocorticoid release may be of particular significancefor the pathophysiology of schizophrenia. Thus, studies by Sapolskyet al. (Sapolsky, 1996; Sapolsky et al., 1985; Sapolsky et al., 1990) show that increasedglucocorticoid levels, particularly when combined with other stress factors,can lead to damage to the hippocampus. The hippocampus has been repeatedlyassociated with schizophrenia pathology. Thus, Lipska et al. (1993) have shownthat a ventral hippocampal lesion in neonatal rats is an effective animal model ofthe schizophrenia pathology in animals. Moreover, studies have shown that ofmonozygotic schizophrenia twins discordant for schizophrenia, the afflicted twinalways had a smaller hippocampal volume (Baare et al., 2001; Weinberger et al.,