Chronic Treatment with Desipramine Improves Cognitive Performance of Rats in an Attentional Set-Shifting Test

Abstract

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.

Norepinephrine Transporter Regulation Mediates the Long-Term Behavioral Effects of the Antidepressant Desipramine

“…It has been suggested that the functional consequence of downregulation of monoamine transporters is greater than pharmacological inhibition (Klimek et al, 1997) due to its noncompetitive nature vs the competitive nature of pharmacological inhibition. The results of the microdialysis experiment indicate that reduced NET expression does result in increased extracellular concentrations of NE, indicative of enhanced noradrenergic neurotransmission, similar to what is observed when the NET is inhibited acutely by desipramine (Lapiz et al, 2007a). Clinical actions of antidepressants develop gradually over weeks of treatment Katz et al, 1996Katz et al, , 2004, leading to the suggestion that neuroadaptive processes underlie the long-term behavioral effects.…”

Similar Effects of the Selective Noradrenaline Reuptake Inhibitor Atomoxetine on Three Distinct Forms of Impulsivity in the Rat

“…Atomoxetine is more selective than the TCA and the lack of cholinergic and histaminergic effects seen with this drug may underlie the differences observed. Moreover, a larger impact on prefrontal NA is observed when DMI is administered chronically (Lapiz et al, 2006) and it is possible that the doses administered of acute DMI produced insufficiently effective increases in NA levels.…”

Pupil Diameter Predicts Changes in the Exploration–Exploitation Trade-off: Evidence for the Adaptive Gain Theory

“…Furthermore, several pharmacological studies have shown that drug-induced activation of the LC-NE system increases cognitive flexibility and behavioral disengagement. For example, drugs that increase tonic NE levels (i.e., mimic the effects of elevated NE release that characterize the tonic LC mode) have been found to improve attentional-set shifting and reversal learning in rats and monkeys (Seu, Lang, Rivera, & Jentsch, 2008;Lapiz, Bondi, & Morilak, 2007;Lapiz & Morilak, 2006;Steere & Arnsten, 1997;Devauges & Sara, 1990; but see Chamberlain et al, 2006). In humans, increased NE levels induced by the selective NE reuptake inhibitor atomoxetine have been found to improve the ability to stop an ongoing motor response when cued to do so (Chamberlain et al, 2006).…”