Autoreceptor-mediated inhibition of norepinephrine release in rat medial prefrontal cortex is maintained after chronic desipramine treatment.
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 alpha(2)-adrenergic autoreceptors. This hypothesis was tested in experiment 1 using in vivo microdialysis to examine the degree of alpha(2)-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 alpha(2)-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 alpha(2)-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 alpha(2)-receptor agonist clonidine inhibited potassium-evoked [(3)H]-NA release from cortical slices taken from DMI- or vehicle-treated rats. Together, these data suggest that endogenous activation of alpha(2)-autoreceptors persists in restraining NA neurotransmission in the face of tonically elevated basal NA levels following chronic reuptake blockade.
Department of Pharmacology and Center for Biomedical Neuroscience, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229-3900, USA.
April S
AS
Garcia
Gabe
G
Barrera
Teresa F
TF
Burke
Shuaike
S
Ma
Julie G
JG
Hensler
David A
DA
Morilak
D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology*; D058647:Adrenergic alpha-2 Receptor Agonists; D058669:Adrenergic alpha-2 Receptor Antagonists; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D017660:Autoreceptors / Q000378:metabolism*; D003000:Clonidine / Q000494:pharmacology; D003891:Desipramine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D045604:Extracellular Fluid / Q000737:chemistry / Q000378:metabolism; D008297:Male; D017551:Microdialysis; D009638:Norepinephrine / Q000032:analysis / Q000378:metabolism*; D011188:Potassium / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013995:Time; D015016:Yohimbine / Q000494:pharmacology
D018759:Adrenergic Uptake Inhibitors; D058647:Adrenergic alpha-2 Receptor Agonists; D058669:Adrenergic alpha-2 Receptor Antagonists; D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D017660:Autoreceptors; D015016:Yohimbine; D003000:Clonidine; D011188:Potassium; D003891:Desipramine; D009638:Norepinephrine