ALPHA(2)-ADRENERGIC RECEPTOR BLOCKADE MARKEDLY POTENTIATES DULOXETINE-INDUCED AND FLUOXETINE-INDUCED INCREASES IN NORADRENALINE, DOPAMINE, AND SEROTONIN LEVELS IN THE FRONTAL-CORTEX OF FREELY MOVING RATS

Evidence exists that a reinforcement in monoaminergic transmission in the frontal cortex (FCX) is associated with antidepressant (AD) proper ties. Herein, we examined whether blockade of alpha(2)-adrenergic rece ptors modified the influence of monoamine reuptake inhibitors on FCX l evels of serotonin (5-HT), noradrenaline (NAD), and dopamine (DA). The selective alpha(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 r ats. In contrast, the selective alpha(2)-adrenergic receptor antagonis ts atipamezole (0.16 mg/kg, s.c.) and 1-(2-pyrimidinyl)piperazine (1-P P; 2.5 mg/kg, s.c) increased levels of NAD (by 180 and 185%, respectiv ely) and DA (by 130 and 90%, respectively), without affecting 5-HT lev els. Duloxetine (5.0 mg/kg, s.c.), a mixed inhibitor of 5-HT and NAD r euptake, and fluoxetine (10.0 mg/kg, s.c.), a selective 5-HT reuptake inhibitor, both increased levels of 5-HT (by 150 and 120%, respectivel y), NAD (by 400 and 100%, respectively), and DA (by 115 and 55%, respe ctively). Atipamezole (0.16 mg/kg, s.c.) markedly potentiated the infl uence 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). I-PP similarly potentiated the influence of d uloxetine on 5-HT, NAD, and DA levels (by 290, 1,320, and 600%, respec tively). These data demonstrate that alpha(2)-adrenergic receptors ton ically inhibit NAD and DA and phasically inhibit 5-HT release in the F CX and that blockade of alpha(2)-adrenergic receptors strikingly poten tiates the increase in FCX levels of 5-HT, NAD, and DA elicited by reu ptake inhibitors. Concomitant alpha(2)-adrenergic receptor antagonism and inhibition of monoamine uptake may thus provide a mechanism allowi ng for a marked increase in the efficacy of AD agents.