Chronic stress is a major risk factor for many psychiatric disorders, which are also associated with prefrontal cortical dysfunction. We found that elevating norepinephrine (NE) in rat medial prefrontal cortex (mPFC) with atipamezole enhanced extra-dimensional (ED) cognitive set-shifting on the attentional set-shifting test (AST). By contrast, a 2-week exposure to chronic unpredictable stress (CUS) induced an antidepressant (DMI)-reversible defi cit on ED. To assess whether CUS-induced cognitive defi cits represent a loss of NE modulation in the mPFC, we tested if elevating NE activity in the mPFC is still capable of enhancing cognition after CUS. Again, CUS impaired ED cognitive set-shifting in saline treated rats, but this defi cit was attenuated in CUS rats given atipamezole prior to testing. Extracellular NE was not different between salinetreated CUS and control rats. However, atipamezole enhanced NE release in both control and CUS rats throughout the duration of the test. In the second experiment, CUS produced a cognitive defi cit, which was prevented by chronic DMI. Acute blockade of α1- adrenergic receptors in mPFC of CUS/DMI-treated rats prior to ED caused a cognitive defi cit similar to that of CUS/saline rats. These results suggest the benefi cial effects of chronic antidepressant treatment on cognitive performance are mediated through α1-adrenergic receptors in the mPFC. Furthermore, NE facilitation of cognitive fl exibility in the mPFC remains intact after CUS.
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