Agonist and Antagonist Actions of Yohimbine as Compared to Fluparoxan at  2 -Adrenergic Receptors (AR)s, Serotonin (5-HT) 1A , 5-HT 1B , 5-HT 1D and Dopamine D 2 and D 3 Receptors. Significance for the Modulation of Frontocortical Monoaminergic Transmission and Depressive States MARK J. MILLAN, 1, * ADRIAN NEWMAN-TANCREDI, 1 VALE ´ RIE AUDINOT, 1 DIDIER CUSSAC, 1 FRANC ¸ OISE LEJEUNE, 1 JEAN-PAUL NICOLAS, 2 FRANCIS COGE ´ , 2 JEAN-PIERRE GALIZZI, 2 JEAN A. BOUTIN, 2 JEAN-MICHEL RIVET, 1 ANNE DEKEYNE, 1 AND ALAIN GOBERT 1 1 Psychopharmacology Department, Institut de Recherches Servier, Centre de Recherches de Croissy, 125, Chemin de Ronde, 78290–Croissy-sur-Seine, Paris, France 2 Molecular and Cellular Pharmacology Department, Institut de Recherches Servier, Centre de Recherches de Croissy, 125, Chemin de Ronde, 78290–Croissy-sur-Seine, Paris, France KEY WORDS frontal cortex; antidepressant; depression; yohimbine; SSRI; fluox- etine; [ 35 S]GTPS binding. ABSTRACT Herein, we evaluate the interaction of the  2 -AR antagonist, yohimbine, as compared to fluparoxan, at multiple monoaminergic receptors and examine their roles in the modulation of adrenergic, dopaminergic and serotonergic transmission in freely- moving rats. Yohimbine displays marked affinity at human (h) 2A -, h 2B - and h 2C -ARs, significant affinity for h5-HT 1A , h5-HT 1B , h5-HT 1D , and hD 2 receptors and weak affinity for hD 3 receptors. In [ 35 S]GTPS binding protocols, yohimbine exerts antagonist actions at h 2A -AR, h5-HT 1B , h5-HT 1D , and hD 2 sites, yet partial agonist actions at h5-HT 1A sites. In vivo, agonist actions of yohimbine at 5-HT 1A sites are revealed by WAY100,635- reversible induction of hypothermia in the rat. In guinea pigs, antagonist actions of yohimbine at 5-HT 1B receptors are revealed by blockade of hypothermia evoked by the 5-HT 1B agonist, GR46,611. In distinction to yohimbine, fluparoxan shows only modest partial agonist actions at h5-HT 1A sites versus marked antagonist actions at h 2 -ARs. While fluparoxan selectively enhances hippocampal noradrenaline (NAD) turnover, yohimbine also enhances striatal dopamine (DA) turnover and suppresses striatal turnover of 5-HT. Further, yohimbine decreases firing of serotonergic neurones in raphe nuclei, an action reversed by WAY100,635. Fluparoxan increases extracellular levels of DA and NAD, but not 5-HT, in frontal cortex. In analogy, yohimbine enhances FCX levels of DA and NAD, yet suppresses those of 5-HT, the latter effect being antagonized by WAY100,635. The induction by fluoxetine of FCX levels of 5-HT, DA, and NAD is potentiated by fluparoxan. Yohimbine likewise facilitates the influence of fluoxetine upon DA and NAD levels, but not those of 5-HT. In conclusion, the  2 -AR antagonist properties of yohimbine increase DA and NAD levels both alone and in association with fluoxetine. However, in contrast to the selective  2 -AR antagonist, fluparoxan, the 5-HT 1A agonist actions of yohimbine suppress 5-HT levels alone and underlie its inability to augment the influence of fluoxetine upon 5-HT levels. Synapse 35:79–95, 2000.  2000 Wiley-Liss, Inc. *Correspondence to: Dr M.J. Millan, Psychopharmacology Department, Insti- tut de Recherches Servier, Centre de Recherches de Croissy, 125, Chemin de Ronde, 78290—Croissy-sur-Seine, France. Received 28 January 1999; Accepted 3 March 1999 SYNAPSE 35:79–95 (2000)  2000 WILEY-LISS, INC.