Orexin B/hypocretin 2 increases glutamatergic transmission to ventral tegmental area neurons

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Appetite / physiology
  • Arousal / physiology
  • Glutamic Acid / metabolism*
  • Hypothalamic Area, Lateral / cytology
  • Hypothalamic Area, Lateral / metabolism*
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Intracellular Signaling Peptides and Proteins / pharmacology
  • Long-Term Potentiation / drug effects
  • Long-Term Potentiation / physiology
  • Male
  • Neural Pathways / cytology
  • Neural Pathways / metabolism
  • Neurons / metabolism*
  • Neuropeptides / metabolism*
  • Neuropeptides / pharmacology
  • Orexin Receptors
  • Orexins
  • Organ Culture Techniques
  • Patch-Clamp Techniques
  • Peptide Fragments / pharmacology
  • Presynaptic Terminals / drug effects
  • Presynaptic Terminals / metabolism
  • Protein Kinase C / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, G-Protein-Coupled / agonists
  • Receptors, G-Protein-Coupled / metabolism
  • Receptors, N-Methyl-D-Aspartate / drug effects
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Receptors, Neuropeptide / agonists
  • Receptors, Neuropeptide / metabolism
  • Synaptic Transmission / drug effects
  • Synaptic Transmission / physiology*
  • Ventral Tegmental Area / cytology
  • Ventral Tegmental Area / metabolism*


  • Intracellular Signaling Peptides and Proteins
  • Neuropeptides
  • Orexin Receptors
  • Orexins
  • Peptide Fragments
  • Receptors, G-Protein-Coupled
  • Receptors, N-Methyl-D-Aspartate
  • Receptors, Neuropeptide
  • Glutamic Acid
  • Protein Kinase C