Beneficial effects of desipramine on cognitive function of chronically stressed rats are mediated by α1-adrenergic receptors in medial prefrontal cortex

Corina O. Bondi, Julianne D. Jett, David A. Morilak

Research output: Contribution to journalArticlepeer-review

68 Scopus citations

Abstract

Chronic stress is a risk factor for many psychopathological conditions, including depression and anxiety disorders. Cognitive impairments associated with prefrontal cortical dysfunction are a major component of such illnesses. Using an attentional set-shifting test (AST), we have previously shown that elevating noradrenergic activity in rat medial prefrontal cortex (mPFC) can facilitate cognitive set-shifting, and that chronic unpredictable stress (CUS) caused set-shifting deficits. It is not known, however, if noradrenergic modulatory function is compromised by chronic stress, perhaps contributing to the stress-induced cognitive deficit. Thus, the first study investigated whether acutely elevating noradrenergic activity in mPFC still enhances cognitive function after chronic stress. As previously demonstrated, CUS impaired cognitive set-shifting on the AST. This deficit was abolished by acute systemic administration of the α2-adrenergic autoreceptor antagonist, atipamezole. Microdialysis revealed no differences in extracellular norepinephrine (NE) levels in mPFC of CUS-exposed and unstressed control rats at baseline or during behavioral testing, and comparable increases after atipamezole. In the second experiment, rats were treated chronically with the selective NE reuptake blocker, desipramine, during the CUS treatment through behavioral testing. Again, CUS impaired cognitive set-shifting in vehicle-treated rats, and chronic desipramine treatment prevented such deficits. Acute blockade of post-synaptic α1-adrenergic receptors in mPFC prior to testing blocked the beneficial effect of desipramine on cognitive set-shifting. These results suggest that desipramine restores cognitive set-shifting capability that has been compromised by chronic stress by activating α1-adrenergic receptors in the mPFC. Thus, noradrenergic modulatory capability in mPFC remains intact after CUS, and this represents one possible substrate by which antidepressants may exert their beneficial effects in the treatment of depression.

Original languageEnglish (US)
Pages (from-to)913-923
Number of pages11
JournalProgress in Neuro-Psychopharmacology and Biological Psychiatry
Volume34
Issue number6
DOIs
StatePublished - Aug 2010

Keywords

  • Antidepressant
  • Attentional set-shifting
  • Cognitive flexibility
  • Depression
  • Norepinephrine
  • Stress

ASJC Scopus subject areas

  • Pharmacology
  • Biological Psychiatry

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