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246 EFFECTS OF STRESSOne model that has been advanced is that stress may play a role in the transitionto psychosis (Corcoran et al., 2003; Grace, 2004; Thompson et al., 2004;Walker & Diforio, 1997). Of course, not all highly stressful environments willlead to the onset of schizophrenia. What is proposed here is that the genetic predispositionmay lead to deficits in the manner by which the prefrontal cortex (PFC)is capable of modulating responses to stressors, causing the individual to be particularlyvulnerable to the pathological changes that eventually culminate in psychosisin adulthood. Moreover, I present a potential means to circumvent thetransition to psychosis in predisposed individuals by pharmacotherapy of analready-present abnormal response to stress.Stress as a Factor in SchizophreniaStress is a factor that is ever-present in the life of an organism. The reaction to stresscan be adaptive, in enabling an organism to respond appropriately to a threateningenvironment. However, stress can also trigger pathological processes if it is extreme,maintained for extended periods of time, or if the individual is particularly vulnerable.Under such conditions, stress can lead to the onset or exacerbation of psychiatricdisorders, including posttraumatic stress syndrome, schizophrenia, or affectivedisorders. Schizophrenia patients who are in remission show a higher level of relapsewhen they are returned to a high-stress environment (Birley, 1970; Norman& Malla, 1993). Moreover, there is evidence to suggest that, of those individualswho are at genetic risk for developing schizophrenia, those who show significantlyhigher stress reactivity are the individuals most likely to convert to schizophrenialater in life (Johnstone et al., 2005).Stress CircuitryStressful stimuli elicit responses in a complex network of nuclei within the brain(e.g., see figure 11-2). There are several areas in particular that have been associatedwith stress responses. The locus coeruleus is a group of neurons in the brainstemthat contain and release the neurotransmitter norepinephrine. Norepinephrinehas been shown to increase when an animal is exposed to stress, and the primarymetabolite of norepinephrine, methyl-hydroxy-phenol glycol (MHPG), shows asubstantial increase in the CSF in an animal that has been exposed to stressors(Abercrombie & Jacobs, 1988; Abercrombie et al., 1988; Shanks et al., 1991;Thierry et al., 1968), The locus coeruleus will also show increased reaction tostressors in an animal that has been chronically stressed. Thus, chronically stressedanimals show an increase in stress-evoked norepinephrine release (Abercrombieet al., 1992), and the noradrenergic neurons of the locus coeruleus show a significantlygreater response to acute stressors following chronic stress (Jedema & Grace,2003a; Mana & Grace, 1997). The locus coeruleus neurons themselves are po-