Borgland S L, Storm E, Bonci A
Ernest Gallo Clinic and Research Center, Department of Neurology, University of California, San Francisco, CA, USA.
Eur J Neurosci. 2008 Oct;28(8):1545-56. doi: 10.1111/j.1460-9568.2008.06397.x. Epub 2008 Sep 10.
The orexins (hypocretins) play a crucial role in arousal, feeding and reward. Highly relevant to these functions, orexin-containing neurons from the lateral hypothalamus project densely to the ventral tegmental area (VTA), which is the origin of dopamine projections implicated in motivation and reward. Orexin A/hypocretin 1 (oxA/hcrt-1) can enable long-term changes associated with drugs of abuse; however, the effects of orexin B/hypocretin 2 (oxB/hcrt-2) on excitatory synaptic transmission in the VTA are unknown. We used whole-cell patch-clamp electrophysiology in rat horizontal midbrain slices to examine the effects of oxB/hcrt-2 on excitatory synaptic transmission. We observed that oxB/hcrt-2 has distinct effects from oxA/hcrt-1 in the VTA. oxB/Hcrt-2 (100 nM) increased presynaptic glutamate release in addition to a postsynaptic potentiation of NMDA receptors (NMDARs). The oxB/hcrt-2-mediated postsynaptic potentiation of NMDARs was mediated via activation of orexin/hypocretin 2 (OX2/Hcrt-2) receptors and protein kinase C (PKC). Furthermore, the increase in transmitter release probability was also PKC-dependent, but not through activation of orexin/hypocretin 1 (OX1/Hcrt-1) or OX2/Hcrt-2 receptors. Finally, oxB/hcrt-2 or the selective OX2/Hcrt-2 receptor agonist ala(11)-D-leu(15)-orexin B, significantly reduced spike-timing-induced long-term potentiation. Taken together, these results support a dual role for oxB/hcrt-2 in mediating enhanced glutamatergic transmission in the VTA, and suggest that oxA/hcrt-1 and oxB/hcrt-2 exert different functional roles in modulating the enhancement of the motivational components of arousal and feeding.
食欲素（下丘脑泌素）在觉醒、进食和奖赏过程中发挥着关键作用。与这些功能高度相关的是，来自下丘脑外侧的含食欲素神经元密集投射至腹侧被盖区（VTA），而VTA正是与动机和奖赏相关的多巴胺投射的起源部位。食欲素A/下丘脑泌素1（oxA/hcrt-1）能够引发与滥用药物相关的长期变化；然而，食欲素B/下丘脑泌素2（oxB/hcrt-2）对VTA中兴奋性突触传递的影响尚不清楚。我们运用全细胞膜片钳电生理学技术，在大鼠水平中脑切片上研究了oxB/hcrt-2对兴奋性突触传递的影响。我们观察到，oxB/hcrt-2在VTA中的作用与oxA/hcrt-1不同。oxB/Hcrt-2（100 nM）除了能使NMDA受体（NMDARs）发生突触后增强外，还能增加突触前谷氨酸的释放。oxB/hcrt-2介导的NMDARs突触后增强是通过激活食欲素/下丘脑泌素2（OX2/Hcrt-2）受体和蛋白激酶C（PKC）实现的。此外，递质释放概率的增加也是PKC依赖性的，但并非通过激活食欲素/下丘脑泌素1（OX1/Hcrt-1）或OX2/Hcrt-2受体。最后，oxB/hcrt-2或选择性OX2/Hcrt-2受体激动剂ala(11)-D-leu(15)-食欲素B能显著降低峰时诱导的长时程增强。综上所述，这些结果支持了oxB/hcrt-2在介导VTA中谷氨酸能传递增强方面具有双重作用，并表明oxA/hcrt-1和oxB/hcrt-2在调节觉醒和进食动机成分增强方面发挥着不同的功能作用。
