Agonist and antagonist actions of yohimbine as compared to fluparoxan at α 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

Herein, we evaluate the interaction of the α 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)α 2A ‐, hα 2B ‐ and hα 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]GTPγS binding protocols, yohimbine exerts antagonist actions at hα 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 hα 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 α 2 ‐AR antagonist properties of yohimbine increase DA and NAD levels both alone and in association with fluoxetine. However, in contrast to the selective α 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.