title: 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.
abstract: 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.
authors.affiliation: Psychopharmacology Department, Institut de Recherches Servier, Centre de Recherches de Croissy, 125, Chemin de Ronde, 78290-Croissy-sur-Seine, Paris, France.
authors.forename: M J
authors.initials: MJ
authors.lastname: Millan
authors.forename: A
authors.initials: A
authors.lastname: Newman-Tancredi
authors.forename: V
authors.initials: V
authors.lastname: Audinot
authors.forename: D
authors.initials: D
authors.lastname: Cussac
authors.forename: F
authors.initials: F
authors.lastname: Lejeune
authors.forename: J P
authors.initials: JP
authors.lastname: Nicolas
authors.forename: F
authors.initials: F
authors.lastname: Cogé
authors.forename: J P
authors.initials: JP
authors.lastname: Galizzi
authors.forename: J A
authors.initials: JA
authors.lastname: Boutin
authors.forename: J M
authors.initials: JM
authors.lastname: Rivet
authors.forename: A
authors.initials: A
authors.lastname: Dekeyne
authors.forename: A
authors.initials: A
authors.lastname: Gobert
mesh_terms: D058647:Adrenergic alpha-2 Receptor Agonists; D058669:Adrenergic alpha-2 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology; D001831:Body Temperature / Q000187:drug effects; D005625:Frontal Lobe / Q000187:drug effects / Q000502:physiology*; D006168:Guinea Pigs; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D006801:Humans; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D010883:Piperoxan / Q000031:analogs & derivatives* / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology*; D051381:Rats; D044302:Receptor, Serotonin, 5-HT1B; D044346:Receptor, Serotonin, 5-HT1D; D017448:Receptors, Dopamine D2 / Q000187:drug effects / Q000502:physiology*; D050637:Receptors, Dopamine D3; D011985:Receptors, Serotonin / Q000187:drug effects / Q000502:physiology*; D044263:Receptors, Serotonin, 5-HT1; D013552:Swine; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*; D015016:Yohimbine / Q000494:pharmacology*
chemical_list: D058647:Adrenergic alpha-2 Receptor Agonists; D058669:Adrenergic alpha-2 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists; D000928:Antidepressive Agents; C493593:DRD3 protein, human; C493594:Drd3 protein, mouse; C493595:Drd3 protein, rat; C470302:HTR1B protein, human; D011758:Pyrroles; D044302:Receptor, Serotonin, 5-HT1B; D044346:Receptor, Serotonin, 5-HT1D; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D015016:Yohimbine; D010883:Piperoxan; C065161:fluparoxan