At least 13 polymorphisms of NET have been identified,20 the functional significance of which is unknown. Alterations in the concentration of NE in the CNS have been hypothesized to cause, or contribute to, the development of psychiatric illnesses such as major depression and BPAD. Many studies have reported altered levels of NE and its metabolites NMN and dihydroxyphenylglycol (DHPG) in the CSF, plasma, and urine of depressed patients as compared with normal controls. These variances could reflect different underlying phenotypes of depressive disorders with varying effects on NE activity. The melancholic subtype of depression (with positive vegetative features, agitation, and increased hypothalamic-pituitary-adrenal (HPA) axis activity) is most often associated with increased NE. Alternatively, so-called atypical depression is associated with decreased NE and HPA axis hypoactivation. In one study, urinary NE and its metabolites were found to be significantly higher in unipolar and bipolar depressed patients than in healthy volunteers, suggesting that unmedicated unipolar and bipolar depressed patients have a hyperresponsive noradrenergic system. Increased NE activity has also been observed to be a contributor to the borderline personality disorder traits of impulsive aggression and affective instability, high levels of risk taking, irritability, and verbal aggression. Furthermore, abnormal regulation or expression of the human NET has been reported in major depression. In post-mortem human brain, [3H]-nisoxetine binding to NET was highest in dorsal raphe nuclei and locus coeruleus. Low levels of NET in the locus coeruleus in major depression may reflect a compensatory downregulation of this transporter protein in response to insufficient availability of its substrate (NE) at the synapse. These studies suggest that abnormalities that can cause impaired noradrenergic transmission could contribute to the pathophysiology of certain psychiatric disorders. However, results from other studies suggest that the investigated polymorphisms are not the main susceptibility factors in the etiology of major depression.19 This was also the case for the NET DNA sequence variants identified in patients suffering from schizophrenia or BPAD. Subsequent case-control studies did not reveal any significant association between the variances and those diseases.19
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