Millan M J, Lejeune F, De Nanteuil G, Gobert A
Institut de Recherches Servier, Psychopharmacology Department, Croissy-sur-Seine, Paris, France.
J Neurochem. 2001 Mar;76(6):1949-54. doi: 10.1046/j.1471-4159.2001.00211.x.
The selective NK(1) receptor antagonist, GR205,171 (2.5-40.0 mg/kg, i.p.), dose-dependently elevated dialysate levels of noradrenaline (NA), but not serotonin (5-HT), in the frontal cortex of freely moving rats. This action was exerted stereospecifically inasmuch as its less active isomer, GR226,206, was ineffective. In the dorsal hippocampus, GR205,171 (but not GR226,206) also significantly increased dialysate levels of NA, whereas levels of 5-HT were unaffected. Further, in anaesthetized rats, GR205,171 dose-dependently (1.0-4.0 mg/kg, i.v.) increased the firing rate of adrenergic perikarya in the locus coeruleus. In contrast, their activity was not modified by GR226,206. These findings indicate that selective blockade of NK(1) receptors enhances the activity of ascending adrenergic pathways in rats. Adrenergic mechanisms may, thus, be involved in the potential antidepressant and other functional properties of NK(1) receptor antagonists.
选择性NK(1)受体拮抗剂GR205,171（2.5 - 40.0毫克/千克，腹腔注射）可使自由活动大鼠额叶皮质中去甲肾上腺素（NA）的透析液水平呈剂量依赖性升高，但对血清素（5 - HT）水平无影响。该作用具有立体特异性，因为其活性较低的异构体GR226,206无此效果。在背侧海马体中，GR205,171（而非GR226,206）也显著提高了NA的透析液水平，而5 - HT水平未受影响。此外，在麻醉大鼠中，GR205,171（1.0 - 4.0毫克/千克，静脉注射）可使蓝斑中肾上腺素能神经元胞体的放电频率呈剂量依赖性增加。相比之下，GR226,206对其活性无影响。这些发现表明，选择性阻断NK(1)受体可增强大鼠上行肾上腺素能通路的活性。因此，肾上腺素能机制可能参与了NK(1)受体拮抗剂的潜在抗抑郁及其他功能特性。
