The response of the central nervous system to stress is often critical to an organism's adaptation to a stressful environment. In humans, however, an over-response to stress can be maladaptive, resulting in the expression or exacerbation of many neuropsychiatric disorders. Such disorders often exhibit a number of features that indicate abnormal functioning of the PFC (Mattes, 1980; Weinberger et al., 1986; Deutch, 1993; Fibiger, 1995). The influence of dopaminergic and serotonergic systems on PFC function in neuropsychiatric disorders remains unclear, but some observations support the idea that these systems play a role in the pathogenesis of several. For example, Dolan et al. (1994) have provided evidence that neuropsychological symptoms in depression, including cognitive deficits, are associated with profound hypometabolism, involving the medial PFC in particular. Similarly, it has been reported that both bipolar and unipolar depressives are characterized by decreases in cerebral blood flow and the rate of glucose metabolism in the PFC (Drevets et al., 1997). Furthermore, agents such as bupropion that enhance DA transmission have been successfully used as antidepressants (Calabrese and Markovitz, 1991). Various other serotonergic antidepressants, such as fluoxetine, clomipramine, and imipramine, also increase the release of DA as well as 5-HT in the rat PFC (Tanda et al., 1994), indicating that the PFC is a target site of antidepressants. These findings implicate a reduction in dopaminergic and serotonergic transmission in the PFC in the pathogenesis of depression. A similar association has been suggested in patients with Parkinson's disease who suffer from depression (Cummings, 1992; Deutch, 1993). Depression occurs in large populations of patients with Parkinson's disease, and such patients have greater frontal lobe dysfunction and a more frequent occurrence of reduced dopaminergic function than non-depressed patients with the same disease. In addition, negative or defect symptoms of schizophrenia, which include not only impaired working memory but also low volition, social withdrawal, and impaired insight and judgment, are suspected to be attributed to reduced dopaminergic transmission in the PFC (Knable and Weinberger, 1997). Thus, dopaminergic and serotonergic systems in the PFC are thought to play an important role in many neuropsychic activities, including working memory impairment and depressive states. Although other neuropsychic activities of chronically stressed rats have not been examined here, it is likely that the significance of dopaminergic and serotonergic dysfunction induced by chronic stress is not restricted to working memory impairment and the depressive state, but involves the disruption of other neuropsychic activities in stress-related neuropsychiatric disorders.
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