Norepinephrine (NE) potently modulates the cognitive and affective functions of the prefrontal cortex (PFC). Deficits in NE transmissionare implicated in psychiatric disorders, and antidepressant drugs that block the NE transporter (NET) effectively treat these conditions. Our initial ultrastructural studies of the rat PFC revealed that most NE axons (85-90%) express NET primarily within the cytoplasm and lack detectable levels of the synthetic enzyme tyrosine hydroxylase (TH). In contrast, the remaining 10 -15% of PFC NE axons exhibit predominantly plasmalemmal NET and evident TH immunoreactivity. These unusual characteristics suggest that most PFC NE axons have an unrecognized, latent capacity to enhance the synthesis and recovery of transmitter. In the present study, we used dual-labeling immunocytochemistry and electron microscopy to examine whether chronic cold stress, a paradigm that persistently increases NE activity, would trigger cellular changes consistent with this hypothesis. After chronic stress, neither the number of profiles exhibiting NET labeling nor their size was changed. However, the proportion of plasmalemmal NET nearly doubled from 29% in control animals to 51% in stressed rats. Moreover, the expression of detectable TH in NET-labeled axons increased from only 13% of profiles in control rats to 32% of profiles in stressed animals. Despite the consistency of these findings, the magnitude of the changes varied across individual rats. These data represent the first demonstration of activity-dependent trafficking of NET and expression of TH under physiological conditions and have important implications for understanding the pathophysiology and treatment of stress-related affective disorders.

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