Buspirone modulates basal and fluoxetine-stimulated dialysate levels of dopamine, noradrenaline and serotonin in the frontal cortex of freely moving rats: Activation of serotonin(1A) receptors and blockade of alpha(2)-adrenergic receptors underlie its actions

The serotonin(1A) receptor partial agonist, buspirone, also displays antago nist properties at D-2 receptors and is metabolized to the alpha(2)-adrener gic receptor antagonist, 1-(2-pyrimidinyl-piperazine). Herein, we examined mechanisms underlying the influence of buspirone alone, and in association with the serotonin reuptake inhibitor, fluoxetine, upon extracellular level s of serotonin, dopamine and noradrenaline simultaneously quantified in the frontal cortex of freely moving rats. Buspirone (0.01-2.5 mg/kg, s.c.) dos e-dependently decreased dialysate levels of serotonin (- 50%), and increase d those of dopamine (+ 100%) and noradrenaline (+ 140%). The reduction by b uspirone of serotonin levels was abolished by the serotonin(1A) receptor an tagonist, WAY 100,635 (0.16), which did not, however, modify its influence upon dopamine and noradrenaline. In contrast to buspirone, the serotonin re uptake inhibitor, fluoxetine (10.0), increased frontocortical levels of ser otonin (+ 120%), dopamine (+ 55%) and noradrenaline (+ 90%). Buspirone dose -dependently (0.01-2.5) decreased the induction by fluoxetine of serotonin levels yet potentiated (three-fold) its elevation of dopamine and noradrena line levels. The serotonin(1A) agonist, 8-hydroxy-2-(di-n-propylamino)-tetr alin (0.16), mimicked the action of buspirone in reducing resting levels of serotonin (- 60%) and in enhancing those of dopamine (+ 135%) and noradren aline (+ 165%). Like buspirone, it attenuated the influence of fluoxetine u pon serotonin levels, yet facilitated its influence upon dopamine and norad renaline levels. In contrast, WAY 100,635 selectively potentiated the incre ase in levels of serotonin (two-fold) versus dopamine and noradrenaline eli cited by fluoxetine. Further, WAY 100,635 abolished the inhibitory influenc e of buspirone upon fluoxetine-induced serotonin release, but only partly i nterfered with its potentiation of fluoxetine-induced increases in dopamine and noradrenaline levels. The D-2/D-3 receptor antagonist, raclopride (0.1 6), increased basal dopamine (+ 60%) levels but little influenced those of serotonin and noradrenaline, and failed to modify the action of fluoxetine. The alpha(2)-adrenergic receptor antagonist, 1-(2-pyrimidinyl-piperazine) (2.5), which did not modify resting levels of serotonin, markedly increased those of dopamine (+ 90%) and noradrenaline (+ 190%) and potentiated (two- fold) the increases in dialysate levels of dopamine, noradrenaline and sero tonin provoked by fluoxetine. Further, the alpha(2)-adrenergic receptor ago nist, S18616, attenuated the enhancement by buspirone of the fluoxetine-ind uced increase in levels of dopamine and noradrenaline. In conclusion, the inhibitory influence of buspirone upon resting and fluox etine-stimulated serotonin levels reflects its agonist properties at seroto nin(1A) autoreceptors. The facilitatory influence of buspirone upon resting and fluoxetine-stimulated dopamine and noradrenaline levels may also invol ve its serotonin(1A) properties. However, its principal mechanism of action in this respect is probably the alpha(2)-adrenergic antagonist properties of its metabolite, 1 -(2-pyrimidinyl-piperazine). The present observations are of significance to experimental and clinical studies of the influence o f buspirone upon depressive states, alone and in association with antidepre ssant agents. (C) 1999 IBRO. Published by Elsevier Science Ltd.