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α 2 ‐Adrenergic Receptor Blockade Markedly Potentiates Duloxetine‐ and Fluoxetine‐Induced Increases in Noradrenaline, Dopamine, and Serotonin Levels in the Frontal Cortex of Freely Moving Rats
Author(s) -
Gobert A.,
Rivet J.M.,
Cistarelli L.,
Melon C.,
Millan M. J.
Publication year - 1997
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.1997.69062616.x
Subject(s) - chemistry , endocrinology , medicine , antidepressant , serotonin , pharmacology , dopamine , agonist , duloxetine , reuptake inhibitor , reuptake , 5 ht receptor , monoamine neurotransmitter , receptor , hippocampus , alternative medicine , pathology
Evidence exists that a reinforcement in monoaminergic transmission in the frontal cortex (FCX) is associated with antidepressant (AD) properties. Herein, we examined whether blockade of α 2 ‐adrenergic receptors modified the influence of monoamine reuptake inhibitors on FCX levels of serotonin (5‐HT), noradrenaline (NAD), and dopamine (DA). The selective α 2 ‐adrenergic receptor agonist S 18616 (0.16 mg/kg, s.c.) suppressed extracellular levels of NAD, DA, and 5‐HT (by 100, 51, and 63%, respectively) in single dialysates of FCX of freely moving rats. In contrast, the selective α 2 ‐adrenergic receptor antagonists atipamezole (0.16 mg/kg, s.c.) and 1‐(2‐pyrimidinyl)piperazine (1‐PP; 2.5 mg/kg, s.c.) increased levels of NAD (by 180 and 185%, respectively) and DA (by 130 and 90%, respectively), without affecting 5‐HT levels. Duloxetine (5.0 mg/kg, s.c.), a mixed inhibitor of 5‐HT and NAD reuptake, and fluoxetine (10.0 mg/kg, s.c.), a selective 5‐HT reuptake inhibitor, both increased levels of 5‐HT (by 150 and 120%, respectively), NAD (by 400 and 100%, respectively), and DA (by 115 and 55%, respectively). Atipamezole (0.16 mg/kg, s.c.) markedly potentiated the influence of duloxetine and fluoxetine on levels of 5‐HT (by 250 and 330%, respectively), NAD (by 1,030 and 215%, respectively), and DA (by 370 and 170%, respectively). 1‐PP similarly potentiated the influence of duloxetine on 5‐HT, NAD, and DA levels (by 290, 1,320, and 600%, respectively). These data demonstrate that α 2 ‐adrenergic receptors tonically inhibit NAD and DA and phasically inhibit 5‐HT release in the FCX and that blockade of α 2 ‐adrenergic receptors strikingly potentiates the increase in FCX levels of 5‐HT, NAD, and DA elicited by reuptake inhibitors. Concomitant α 2 ‐adrenergic receptor antagonism and inhibition of monoamine uptake may thus provide a mechanism allowing for a marked increase in the efficacy of AD agents.