Agonist and antagonist actions of yohimbine as compared to fluparoxan at alpha(2)-adrenergic receptors (AR)s, serotonin (5-HT)(1A), 5-HT1B, 5-HT1D and dopamine D-2 and D-3 receptors. Significance for the modulation of frontocortical monoaminergic transmission and depressive states

Herein, we evaluate the interaction of the alpha(2)-AR antagonist, yohimbin e, as compared to fluparoxan, at multiple monoaminergic receptors and exami ne their roles in the modulation of adrenergic, dopaminergic and serotonerg ic transmission in freely-moving rats. Yohimbine displays marked affinity a t human (h)alpha(2A)-, h alpha(2B)- and h alpha(2C)-ARs, significant affini ty for h5-HT1A, h5-HT1B, h5-HT1D, and hD(2) receptors and weak affinity for hD(3) receptors. In [S-35] GTP gamma S binding protocols, yohimbine exerts antagonist actions at h alpha(2A)-AR, h5-HT1B, h5-HT1D, and h(D2) sites, y et partial agonist actions at h5-HT1A sites. In vivo, agonist actions of yo himbine at 5-HT1A sites are revealed by WAY100,635-reversible induction of hypothermia in the rat. In guinea pigs, antagonist actions of yohimbine at 5-HT1B receptors are revealed by blockade of hypothermia evoked by the 5-HT 1B agonist, GR46,611. In distinction to yohimbine, fluparoxan shows only mo dest partial agonist actions at h5-HT1A sites versus marked antagonist acti ons at h alpha(2)-ARs. While fluparoxan selectively enhances hippocampal no radrenaline (NAD) turnover, yohimbine also enhances striatal dopamine (DA) turnover and suppresses striatal turnover of 5-HT. Further, yohimbine decre ases firing of serotonergic neurones in raphe nuclei, an action reversed by WAY100,635. Fluparoxan increases extracellular levels of DA and NAD, but n ot 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 influe nce of fluoxetine upon DA and NAD levels, but not those of 5-HT. In conclus ion, the alpha(2)-AR antagonist properties of yohimbine increase DA and NAD levels both alone and in association with fluoxetine. However, in contrast to the selective alpha(2)-AR antagonist, fluparoxan, the 5-HT1A agonist ac tions of yohimbine suppress 5-HT levels alone and underlie its inability to augment the influence of fluoxetine upon 5-HT levels. (C) 2000 Wiley-Liss, Inc.