Agonist and antagonist actions of yohimbine as compared to fluparoxan at alpha(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 alpha(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)alpha(2A)-, halpha(2B)- and halpha(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]GTPgammaS binding protocols, yohimbine exerts antagonist actions at halpha(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 halpha(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 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-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.
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Fluparoxan DA NAD 5-HT yohimbine DA NAD 5-HT WAY100,635 5-HT fluparoxan DA NAD fluparoxan Yohimbine fluoxetine DA NAD 5-HT yohimbine DA noradrenaline NAD fluparoxan 5-HT yohimbine 5-HT fluoxetine 5-HT Yohimbine (35)S yohimbine NAD yohimbine yohimbine 5-HT WAY100,635 yohimbine 5-HT 5-HT GR46,611 fluparoxan yohimbine yohimbine fluparoxan serotonin 5-HT 5-HT 5-HT dopamine yohimbine fluparoxan h5-HT(1A) halpha(2)-ARs dopamine monoaminergic receptors alpha(2)-AR alpha(2)-AR 5-HT(1A) human (h)alpha(2A)-, halpha(2B)- and halpha(2C)-ARs h5-HT(1A) h5-HT(1B) h5-HT(1D) hD(2) receptors alpha(2)-AR antagonist DA hD(3) receptors halpha(2A)-AR h5-HT(1B) h5-HT(1D) hD(2) h5-HT(1A) 5-HT(1A) 5-HT(1B) 5-HT(1B) (AR)s 5-HT (5-HT)(1A) 5-HT(1B) 5-HT(1D) dopamine D(2) and D(3) receptors alpha(2)-adrenergic receptors yohimbine WAY100,635