Jung M, Michaud J C, Steinberg R, Barnouin M C, Hayar A, Mons G, Souilhac J, Emonds-Alt X, Soubrié P, Le Fur G
Sanofi Recherche, Neuropsychiatry Department, Montpellier, France.
Neuroscience. 1996 Sep;74(2):403-14. doi: 10.1016/0306-4522(96)00150-9.
The objective of the present in vitro and in vivo experiments was to examine the involvement of neurokinin NK3 receptors in the regulation of the noradrenergic function in gerbils and guinea-pigs. Application of senktide, a peptide NK3 receptor agonist, on guinea-pig locus coeruleus slices increased the firing rate of presumed noradrenergic neurons (EC50 = 26 nM) in a concentration-dependent manner. Given i.c.v., senktide (0.5-2 micrograms) and (MePhe7)neurokinin B (1-10 micrograms), another NK3 receptor agonist, reduced exploratory behaviour in gerbils in a dose-dependent manner (2 micrograms of senktide producing a 50% reduction of locomotor activity and rearing). In vivo microdialysis experiments in urethane-anaesthetized guinea-pigs showed that senktide (2-8 micrograms i.c.v.) induced a dose-dependent increase in norepinephrine release in the medial prefrontal cortex. The electrophysiological, behavioural and biochemical changes elicited by senktide were concentration- or dose-dependently reduce by SR 142801, the selective non-peptide NK3 receptor antagonist. In the locus coeruleus slice preparation, complete antagonism of senktide (30 nM) was observed with 50 nM of SR 142801, while injected i.p. (0.1-1 mg/kg) it abolished the senktide-induced norepinephrine release in guinea-pigs. In gerbils, SR 142801 (1-10 mg/kg i.p.) reversed the reduction of exploratory behaviour induced by senktide (1 microgram). By contrast, the 100-fold less active enantiomer, SR 142806, did not exert any antagonism in these models. Finally, the reduction of exploratory behaviour in gerbils was found to be reversed by prazosin (0.25-2.56 micrograms/kg i.p.) and to some extent by clonidine, drugs known to depress noradrenergic function. All these experiments strongly support the hypothesis that brain noradrenergic neurons can be activated by stimulation of neurokinin NK3 receptors.
本体外和体内实验的目的是研究神经激肽NK3受体在沙鼠和豚鼠去甲肾上腺素能功能调节中的作用。将肽类NK3受体激动剂senktide应用于豚鼠蓝斑切片，以浓度依赖的方式增加了假定的去甲肾上腺素能神经元的放电频率（EC50 = 26 nM）。脑室内注射时，senktide（0.5 - 2微克）和另一种NK3受体激动剂（MePhe7）神经激肽B（1 - 10微克）以剂量依赖的方式降低了沙鼠的探究行为（2微克senktide使运动活性和竖毛行为减少50%）。在乌拉坦麻醉的豚鼠中进行的体内微透析实验表明，senktide（脑室内注射2 - 8微克）在内侧前额叶皮质中诱导去甲肾上腺素释放呈剂量依赖性增加。senktide引起的电生理、行为和生化变化被选择性非肽类NK3受体拮抗剂SR 142801浓度或剂量依赖性地减弱。在蓝斑切片制备中，50 nM的SR 142801可完全拮抗30 nM的senktide，而腹腔注射（0.1 - 1 mg/kg）时，它可消除senktide诱导的豚鼠去甲肾上腺素释放。在沙鼠中，SR 142801（腹腔注射1 - 10 mg/kg）可逆转senktide（1微克）诱导的探究行为减少。相比之下，活性低100倍的对映体SR 142806在这些模型中未表现出任何拮抗作用。最后，发现哌唑嗪（腹腔注射0.25 - 2.56微克/千克）可逆转沙鼠探究行为的减少，可乐定在一定程度上也有此作用，已知这两种药物可抑制去甲肾上腺素能功能。所有这些实验都有力地支持了以下假设：脑内去甲肾上腺素能神经元可通过刺激神经激肽NK3受体而被激活。
