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The Journal of Neuroscience, March 19, 2008, 28(12):3202-3208; doi:10.1523/JNEUROSCI.4426-07.2008

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Brief Communications
Hypocretin-1 Potentiates NMDA Receptor-Mediated Somatodendritic Secretion from Locus Ceruleus Neurons

Xiao-Wei Chen,1,2,3 * Yu Mu,3,5 * Hong-Ping Huang,3 Ning Guo,3 Bo Zhang,3 Shuang-Yi Fan,1 Jia-Xiang Xiong,1 Shi-Rong Wang,3 Wei Xiong,3 Wei Huang,1,3 Tao Liu,3 Liang-Hong Zheng,3 Claire Xi Zhang,3 Li-Huan Li,5 Zheng-Ping Yu,2 Zhi-An Hu,1 and Zhuan Zhou3,4

Departments of 1Physiology and 2Occupational Health, Third Military Medical University, Chongqing 400038, China, 3Institute of Molecular Medicine and 4State Key Laboratory of Biomembrane Engineering, Peking University, Beijing 100871, China, and 5Fuwai Hospital, Peking Union Medical College, Beijing 100005, China

Correspondence should be addressed to Zhi-An Hu or Zhuan Zhou at the above addresses. Email: zhianhu{at}yahoo.com.cn or Email: zzhou{at}pku.edu.cn

Our previous observations showed that several stimuli, including high-K+ solution, glutamate, and voltage pulses, induce somatic noradrenaline (NA) secretion from locus ceruleus (LC) neurons. Hypocretin (orexin), a hypothalamic peptide critical for normal wakefulness, has been shown to evoke NA release from the axon terminals of LC neurons. Here, we used amperometry to test the effect of hypocretin-1 (HCRT) on NMDA receptor-mediated somatodendritic release in LC neurons. Either HCRT or NMDA applied alone dose-dependently induced somatodendritic secretion. Bath application of HCRT notably potentiated NMDA receptor-mediated somatodendritic NA release. This potentiation was blocked by SB 334867, a selective HCRT receptor (Hcrtr 1) antagonist, or bisindolylmaleimide, a specific protein kinase C (PKC) inhibitor, indicating the involvement of Hcrtr 1 and PKC. Consistent with this, phorbol 12-myristate 13-acetate, a PKC activator, mimicked the HCRT-induced potentiation. Furthermore, HCRT enhanced NMDA-induced intracellular Ca2+ elevation via activation of Hcrtr 1 and PKC, which may contribute to HCRT-potentiated somatodendritic secretion. These results suggest that HCRT modulates LC activity not only by regulating noradrenergic input to its targets, but also by affecting noradrenergic communication in the soma and dendrites.

Key words: hypocretin; locus ceruleus; noradrenaline; NMDA; somatic secretion; amperometry

Received July 26, 2007; revised Jan. 29, 2008; accepted Feb. 7, 2008.

Correspondence should be addressed to Zhi-An Hu or Zhuan Zhou at the above addresses. Email: zhianhu{at}yahoo.com.cn or Email: zzhou{at}pku.edu.cn






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