Chronic Stress Increases the Plasmalemmal Distribution of the Norepinephrine Transporter and the Coexpression of Tyrosine Hydroxylase in Norepinephrine Axons in the Prefrontal Cortex

Abstract

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.

Enhanced noradrenergic activity in the amygdala contributes to hyperarousal in an animal model of PTSD

“…Alternatively, the lower basal release of noradrenaline could be the result of an increased expression of the noradrenaline transporter in noradrenaline terminals (Miner et al, 2006). In turn, the basal low levels of noradrenaline could potentiate the stress induced release due to a lower inhibitory tone through autoreceptors.…”

Inhibition of protein kinase C signaling protects prefrontal cortex dendritic spines and cognition from the effects of chronic stress

“…High levels of PKC activity during chronic stress may arise from increased ␣1-AR stimulation (Fig. 1), as chronic stress sensitizes noradrenergic axons in prefrontal cortex (50)(51)(52). PKC activity could also be increased by stress-induced release of serotonin acting via 5HT2 receptors, and/or glucocorticoids acting via nongenomic mechanisms (53), although these mechanisms have not been demonstrated in prefrontal cortex.…”

Methylphenidate Administration to Juvenile Rats Alters Brain Areas Involved in Cognition, Motivated Behaviors, Appetite, and Stress

“…The present immunolabeling conditions favored detection of cytosolic NET, because the use of detergents can dissolve membranes containing plasmalemmal NET; NET is primarily cytosolic under resting conditions but redistributes to the plasmalemma with certain stimuli (Miner et al, 2003(Miner et al, , 2006. Because dopamine is the preferred substrate for NET and can be taken up by noradrenergic PFC axons (Sesack et al, 1998), NET may have moved to the plasmalemma in response to MPHinduced dopamine increases.…”