期刊
EUROPEAN JOURNAL OF NEUROSCIENCE
卷 28, 期 8, 页码 1545-1556出版社
WILEY
DOI: 10.1111/j.1460-9568.2008.06397.x
关键词
AMPA; dopamine; motivation; NMDA; orexin B; VTA
资金
- State of California for medical research on alcohol and substance misuse
- University of California, San Francisco
- National Institutes of Health [1RO1DA15096-01]
- NARSAD young investigators grant
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.
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