Agonist and antagonist actions of yohimbine as compared to fluparoxan at α2-adrenergic receptors (AR)s, serotonin (5-HT)1A, 5-HT1B, 5-HT1D and dopamine D2 and D3 receptors. Significance for the modulation of frontocortical monoaminergic transmission and depressive states
✍ Scribed by Mark J. Millan; Adrian Newman-Tancredi; Valérie Audinot; Didier Cussac; Françoise Lejeune; Jean-Paul Nicolas; Francis Cogé; Jean-Pierre Galizzi; Jean A. Boutin; Jean-Michel Rivet; Anne Dekeyne; Alain Gobert
- Publisher
- John Wiley and Sons
- Year
- 2000
- Tongue
- English
- Weight
- 340 KB
- Volume
- 35
- Category
- Article
- ISSN
- 0887-4476
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✦ Synopsis
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 freelymoving 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 WAY100,635reversible 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.