Gobert A, Rivet J M, Cistarelli L, Melon C, Millan M J
Psychopharmacology Department, Institut de Recherches Servier, Centre de Recherches de Croissy, Croissy-sur-Seine, Paris, France.
J Neurochem. 1997 Dec;69(6):2616-9. doi: 10.1046/j.1471-4159.1997.69062616.x.
Evidence exists that a reinforcement in monoaminergic transmission in the frontal cortex (FCX) is associated with antidepressant (AD) properties. Herein, we examined whether blockade of alpha2-adrenergic receptors modified the influence of monoamine reuptake inhibitors on FCX levels of serotonin (5-HT), noradrenaline (NAD), and dopamine (DA). The selective alpha2-adrenergic receptor agonist S 18616 (0.16 mg/kg, s.c.) suppressed extracellular levels of NAD, DA, and 5-HT (by 100, 51, and 63%, respectively) in single dialysates of FCX of freely moving rats. In contrast, the selective alpha2-adrenergic receptor antagonists atipamezole (0.16 mg/kg, s.c.) and 1-(2-pyrimidinyl)piperazine (1-PP; 2.5 mg/kg, s.c.) increased levels of NAD (by 180 and 185%, respectively) and DA (by 130 and 90%, respectively), without affecting 5-HT levels. Duloxetine (5.0 mg/kg, s.c.), a mixed inhibitor of 5-HT and NAD reuptake, and fluoxetine (10.0 mg/kg, s.c.), a selective 5-HT reuptake inhibitor, both increased levels of 5-HT (by 150 and 120%, respectively), NAD (by 400 and 100%, respectively), and DA (by 115 and 55%, respectively). Atipamezole (0.16 mg/kg, s.c.) markedly potentiated the influence of duloxetine and fluoxetine on levels of 5-HT (by 250 and 330%, respectively), NAD (by 1,030 and 215%, respectively), and DA (by 370 and 170%, respectively). 1-PP similarly potentiated the influence of duloxetine on 5-HT, NAD, and DA levels (by 290, 1,320, and 600%, respectively). These data demonstrate that alpha2-adrenergic receptors tonically inhibit NAD and DA and phasically inhibit 5-HT release in the FCX and that blockade of alpha2-adrenergic receptors strikingly potentiates the increase in FCX levels of 5-HT, NAD, and DA elicited by reuptake inhibitors. Concomitant alpha2-adrenergic receptor antagonism and inhibition of monoamine uptake may thus provide a mechanism allowing for a marked increase in the efficacy of AD agents.
有证据表明，额叶皮质（FCX）中单胺能传递的增强与抗抑郁（AD）特性相关。在此，我们研究了α2-肾上腺素能受体的阻断是否会改变单胺再摄取抑制剂对FCX中血清素（5-HT）、去甲肾上腺素（NAD）和多巴胺（DA）水平的影响。选择性α2-肾上腺素能受体激动剂S 18616（0.16 mg/kg，皮下注射）可抑制自由活动大鼠FCX单次透析液中NAD、DA和5-HT的细胞外水平（分别降低100%、51%和63%）。相比之下，选择性α2-肾上腺素能受体拮抗剂阿替美唑（0.16 mg/kg，皮下注射）和1-(2-嘧啶基)哌嗪（1-PP；2.5 mg/kg，皮下注射）可提高NAD（分别提高180%和185%）和DA（分别提高130%和90%）的水平，而不影响5-HT水平。度洛西汀（5.0 mg/kg，皮下注射），一种5-HT和NAD再摄取的混合抑制剂，以及氟西汀（10.0 mg/kg，皮下注射），一种选择性5-HT再摄取抑制剂，均可提高5-HT（分别提高150%和120%）、NAD（分别提高400%和100%）和DA（分别提高115%和55%）的水平。阿替美唑（0.16 mg/kg，皮下注射）显著增强了度洛西汀和氟西汀对5-HT（分别提高250%和330%）、NAD（分别提高1030%和215%）和DA（分别提高370%和170%）水平的影响。1-PP同样增强了度洛西汀对5-HT、NAD和DA水平的影响（分别提高290%、1320%和600%）。这些数据表明，α2-肾上腺素能受体持续性抑制NAD和DA，并阶段性抑制FCX中5-HT的释放，且α2-肾上腺素能受体的阻断显著增强了再摄取抑制剂引起的FCX中5-HT、NAD和DA水平的升高。因此，同时进行α2-肾上腺素能受体拮抗和单胺摄取抑制可能提供一种机制，使AD药物的疗效显著提高。
