Autoreceptor-mediated inhibition of norepinephrine release in rat medial prefrontal cortex is maintained after chronic desipramine treatment

April S. Garcia, Gabe Barrera, Teresa F. Burke, Shuaike Ma, Julie G. Hensler, David A. Morilak

Research output: Contribution to journalArticlepeer-review

30 Scopus citations

Abstract

Alterations in noradrenergic neurotransmission are important in the mechanism of action of many antidepressant drugs, including selective norepinephrine (NA) reuptake inhibitors such as desipramine (DMI). It has been suggested that chronic NA reuptake blockade induces a desensitization of inhibitory α2-adrenergic autoreceptors. This hypothesis was tested in experiment 1 using in vivo microdialysis to examine the degree of α2-autoreceptor-mediated inhibition of NA release in rat medial prefrontal cortex exerted by endogenous NA following chronic treatment with vehicle or DMI. This was accomplished by measuring the elevation of extracellular NA levels induced by acute administration of the α2-receptor antagonist yohimbine. An 8-fold increase in basal NA levels was observed after 21 days of DMI treatment. Further, acute yohimbine administration induced a robust elevation in NA levels which was not attenuated, and in fact at lower doses was greater in DMI-treated rats compared with vehicle-treated controls. In experiment 2, we addressed directly the functional status of terminal α2-autoreceptors in frontal cortex in vitro, in the absence of potentially confounding competition from elevated levels of endogenous NA, after chronic reuptake blockade. We observed no difference in the degree to which the α2-receptor agonist clonidine inhibited potassium-evoked [3H]-NA release from cortical slices taken from DMI- or vehicle-treated rats. Together, these data suggest that endogenous activation of α2-autoreceptors persists in restraining NA neurotransmission in the face of tonically elevated basal NA levels following chronic reuptake blockade.

Original languageEnglish (US)
Pages (from-to)683-693
Number of pages11
JournalJournal of neurochemistry
Volume91
Issue number3
DOIs
StatePublished - Nov 2004

Keywords

  • Antidepressants
  • Autoreceptors
  • Desipramine
  • Medial prefrontal cortex
  • Microdialysis
  • Norepinephrine
  • α-adrenergic

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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