Department of Pharmaceutical Chemistry, Drug Analysis and Drug Information, Center for Neuroscience, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium.
Neurosci Lett. 2012 Feb 29;510(2):143-7. doi: 10.1016/j.neulet.2012.01.023. Epub 2012 Jan 17.
Neuropeptide Y's (NPY) anticonvulsant effect is generally attributed to its inhibitory effect on glutamate release from presynaptic nerve terminals, which is nicely demonstrated in in vitro settings. To date no study has attempted to investigate the effect of NPY in vivo on extracellular (EC) glutamate levels thus, via intracerebral microdialysis, we determined NPY's effect on hippocampal glutamate concentrations in vivo, and consequently the involvement of Y(1) receptors to this effect. NPY or the Y(1) agonist D-His26-NPY was intrahippocampally administered in rats for 2h, during which the hippocampal glutamate dialysate levels were monitored. Pilocarpine was subsequently co-administered with NPY or D-His26-NPY to determine their effect on pilocarpine-induced limbic seizures. Unexpectedly we noted that intrahippocampal administration of NPY or D-His26-NPY increased glutamate dialysate levels in a reproducible manner. NPY attenuated pilocarpine induced seizures, whereas D-His26-NPY did not. To clarify the role of Y(1) receptors in NPY's glutamatergic effect, NPY was co-administered with the selective Y(1) antagonist BVD10. Hippocampal Y(1) receptor blockade prevented the NPY-induced increase in hippocampal glutamate, proving that this induced glutamate increase is clearly Y(1) receptor mediated. This is the first evidence that NPY enhances hippocampal EC glutamate overflow in vivo via hippocampal Y(1) receptors without interfering with or contributing to NPY's anticonvulsant effect. Whilst this finding contrasts with the supposed glutamatergic hypothesis for NPY in the hippocampus, it is of significance to further assist in deciphering NPY's mechanisms of action in in vivo settings.
神经肽 Y (NPY) 的抗惊厥作用通常归因于其对突触前神经末梢谷氨酸释放的抑制作用，这在体外环境中得到了很好的证明。迄今为止，尚无研究试图在体内研究 NPY 对细胞外 (EC) 谷氨酸水平的影响，因此，我们通过脑室内微透析法确定了 NPY 对体内海马谷氨酸浓度的影响，以及 Y(1)受体对这种影响的参与。在大鼠中，NPY 或 Y(1)激动剂 D-His26-NPY 被脑室内给药 2 小时，在此期间监测海马谷氨酸透析液水平。随后，将匹罗卡品与 NPY 或 D-His26-NPY 共同给药，以确定它们对匹罗卡品诱导的边缘性癫痫发作的影响。出乎意料的是，我们注意到 NPY 或 D-His26-NPY 的脑室内给药以可重复的方式增加了谷氨酸透析液水平。NPY 减弱了匹罗卡品诱导的癫痫发作，而 D-His26-NPY 则没有。为了阐明 Y(1)受体在 NPY 的谷氨酸能作用中的作用，将 NPY 与选择性 Y(1)拮抗剂 BVD10 共同给药。海马 Y(1)受体阻断阻止了 NPY 诱导的海马谷氨酸增加，证明这种诱导的谷氨酸增加显然是 Y(1)受体介导的。这是第一个证据表明，NPY 通过海马 Y(1)受体增强体内海马 EC 谷氨酸外溢，而不干扰或有助于 NPY 的抗惊厥作用。虽然这一发现与 NPY 在海马中的谷氨酸假说相矛盾，但它对进一步协助破译 NPY 在体内环境中的作用机制具有重要意义。
