Norepinephrine transporter regulation mediates the long-term behavioral effects of the antidepressant desipramine.

The relationship between the ability of repeated desipramine treatment to cause downregulation of the norepinephrine transporter (NET) and produce antidepressant-like effects on behavior was determined. Treatment of rats with 15 mg/kg per day desipramine reduced NET expression, measured by (3)H-nisoxetine binding and SDS-PAGE/immunoblotting, in cerebral cortex and hippocampus and reduced the time of immobility in the forced-swim test. The antidepressant-like effect on forced-swim behavior was evident 2 days following discontinuation of desipramine treatment when plasma and brain levels of desipramine and its major metabolite desmethyldesipramine were not detectable. Reduced NET expression resulted in reduced norepinephrine uptake, measured in vitro, and increased noradrenergic neurotransmission, measured in vivo using microdialysis. Overall, the dose-response and time-of-recovery relationships for altered NET expression matched those for production of antidepressant-like effects on behavior. The importance of increased noradrenergic neurotransmission in the persistent antidepressant-like effect on behavior was confirmed by demonstrating that it was blocked by inhibition of catecholamine synthesis with alpha-methyl-p-tyrosine. The present results suggest an important role for NET regulation in the long-term behavioral effects of desipramine and are consistent with clinical data suggesting that enhanced noradrenergic neurotransmission is necessary, but not sufficient, for its antidepressant actions. Understanding the mechanisms underlying NET regulation in vivo may suggest novel targets for therapeutic intervention in the treatment of depression.

Chronic treatment with desipramine improves cognitive performance of rats in an attentional set-shifting test.

Alterations in central monoaminergic neurotransmission are important in the actions of many antidepressants. This study tested the hypothesis that tonic elevation of noradrenergic (NA) neurotransmission in medial prefrontal cortex (mPFC) by chronic treatment with the selective norepinephrine (NE) reuptake blocker desipramine (DMI) may contribute to the beneficial cognitive effects of this antidepressant drug (AD). Male Sprague-Dawley rats were treated with DMI acutely (15 mg/kg, i.p.) or chronically for 21 days (7.5 mg/kg/day via osmotic minipump) before assessing performance on an attentional set-shifting test. The extradimensional set-shifting component of this test reflects a process of cognitive flexibility that is dependent upon mPFC, and that we have shown previously to be facilitated by NA activity in mPFC. Microdialysis was performed to measure NE release in mPFC concurrently with behavioral testing. Acute DMI treatment produced an increase in extracellular NE levels in mPFC, and a modest improvement in overall performance across all task stages of the attentional set-shifting test, but failed to produce a significant improvement in any of the individual specific tasks comprising the test sequence. Chronic DMI treatment tonically elevated basal extracellular NE levels in mPFC, associated with a significant improvement in performance specifically on the extradimensional set-shifting component of the test. There was also a significant reduction in set loss errors in rats treated chronically with DMI. Hence, tonic elevation of NA transmission in mPFC by chronic DMI treatment was associated with a time-dependent facilitation of cognitive flexibility that may contribute to the mechanism whereby chronic treatment with ADs, specifically NE reuptake blockers, may exert a beneficial therapeutic effect on cognition in depressed patients.

Noradrenergic facilitation of shock-probe defensive burying in lateral septum of rats, and modulation by chronic treatment with desipramine.

We have previously shown that acute stress-induced release of norepinephrine (NE) facilitates anxiety-like behavioral responses to stress, such as reduction in open-arm exploration on the elevated-plus maze and in social behavior on the social interaction test. Since these responses represent inhibition of ongoing behavior, it is important to also address whether NE facilitates a response that represents an activation of behavior. Correspondingly, it is unknown how a chronic elevation in tonic steady-state noradrenergic (NA) neurotransmission induced by NE reuptake blockade might alter this acute modulatory function, a regulatory process that may be pertinent to the anxiolytic effects of NE reuptake blockers such as desipramine (DMI). Therefore, in this study, we investigated noradrenergic modulation of the shock-probe defensive burying response in the lateral septum (LS). In experiment 1, shock-probe exposure induced an acute 3-fold increase in NE levels measured in LS of male Sprague-Dawley rats by microdialysis. Shock-probe exposure also induced a modest rise in plasma ACTH, taken as an indicator of perceived stress, that returned to baseline more rapidly in rats that were allowed to bury the probe compared to rats prevented from burying by providing them with minimal bedding, indicating that the active defensive burying behavior is an effective coping strategy that reduces the impact of acute shock probe-induced stress. In experiment 2, blockade of either alpha(1)- or beta-adrenergic receptors in LS by local antagonist microinjection immediately before testing reduced defensive burying and increased immobility. In the next experiment, chronic DMI treatment increased basal extracellular NE levels in LS, and attenuated the acute shock probe-induced increase in NE release in LS relative to baseline. Chronic DMI treatment decreased shock-probe defensive burying behavior in a time-dependent manner, apparent only after 2 weeks or more of drug treatment. Moreover, rats treated chronically with DMI showed no significant rise of plasma ACTH in response to shock-probe exposure. Thus, acute stress-induced release of NE in LS facilitated defensive burying, an active, adaptive behavioral coping response. Chronic treatment with the NE reuptake blocker and antidepressant drug DMI attenuated acute noradrenergic facilitation of the active burying response, and also attenuated the level of perceived stress driving that response. These results suggest that long-term regulation of the acute modulatory function of NE by chronic treatment with reuptake blockers may contribute to the mechanisms by which such drugs exert their anxiolytic effects in the treatment of stress-related psychiatric conditions, including depression and anxiety.