Blockade of autoreceptor-mediated inhibition of norepinephrine release by atipamezole is maintained after chronic reuptake inhibition.
The role of alpha(2)-adrenergic autoreceptor desensitization in the delayed onset of antidepressant efficacy of selective norepinephrine (NE) reuptake inhibitors is unclear. Using the alpha(2)-antagonist yohimbine, we showed previously that chronic treatment with desipramine (DMI) did not alter autoreceptor-mediated inhibition of NE release in the cortex. However, yohimbine may have non-selective effects that could confound this interpretation. Thus, using microdialysis, we measured acute effects of the highly selective alpha(2)-antagonist atipamezole on NE release in the prefrontal cortex following chronic DMI treatment, after 0-8 d washout. Atipamezole induced a similar elevation of extracellular NE in all treatment groups, indicating no change in autoreceptor function. Further, the effect was most rapid in DMI-treated rats with 0- and 2-d washout, suggesting that autoreceptor-mediated inhibition was most prominent when NE levels were highest. This provides further evidence that autoreceptor-mediated inhibition of NE neurotransmission remains functional after chronic DMI treatment, arguing against the hypothesis that desensitization of alpha(2)-autoreceptors accounts for the delayed onset of action of selective NE reuptake inhibitors.
Lapiz
M Danet
MD
Department of Pharmacology and Center for Biomedical Neuroscience, University of Texas Health Science Center at San Antonio, San Antonio, TX 778229-3900, USA.
Zhao
Zaorui
Z
Bondi
Corina O
CO
O'Donnell
James M
JM
Morilak
David A
DA
D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology*; D058647:Adrenergic alpha-2 Receptor Agonists; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000818:Animals; D017660:Autoreceptors / Q000037:antagonists & inhibitors*; D003891:Desipramine / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology*; D008297:Male; D009638:Norepinephrine / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
D018759:Adrenergic Uptake Inhibitors; D058647:Adrenergic alpha-2 Receptor Agonists; D000317:Adrenergic alpha-Antagonists; D017660:Autoreceptors; D007093:Imidazoles; C050701:atipamezole; D003891:Desipramine; D004298:Dopamine; D009638:Norepinephrine