Hypocretin /orexin preferentially activates caudomedial ventral tegmental area dopamine neurons

Eur J Neurosci. 2008 Oct;28(8):1629-40. doi: 10.1111/j.1460-9568.2008.06453.x.


The hypocretin/orexin (HCRT) neuropeptide system modulates behavioral state and state-dependent processes via actions on multiple neuromodulatory transmitter systems. Recent studies indicate that HCRT selectively increases dopamine (DA) neurotransmission within the prefrontal cortex (PFC) and the shell subregion of the nucleus accumbens (NAs), but not the core subregion of the nucleus accumbens (NAc). The circuitry underlying the differential actions of HCRT across distinct DA systems is unclear. The current study examined whether HCRT preferentially activates PFC- and NAs-projecting relative to NAc-projecting DA neurons within the VTA. One week after infusion of the retrograde tracer fluorogold (FG) into the medial PFC, NAc or NAs, animals received a ventricular infusion of HCRT-1. Subsequent analyses conducted across the rostral-caudal extent of the VTA determined the degree to which: (i) Fos-immunoreactivity (ir) was observed within tyrosine hydroxylase (TH)-ir neurons; (ii) TH-ir was observed within FG-ir neurons; and (iii) Fos-ir was observed within FG-ir neurons. HCRT significantly increased Fos-ir in VTA DA (TH-ir) neurons, primarily in a restricted population of small-to-medium-sized DA neurons located within the caudomedial VTA. Furthermore, within this region of the VTA, PFC- and NAs-projecting TH-ir neurons were more likely to contain Fos-ir than were NAc-projecting TH-ir neurons. These results provide novel evidence that HCRT selectively activates PFC- and NAs-projecting DA neurons within the VTA, and suggest a potential role for HCRT in PFC- and NAs-dependent cognitive and/or affective processes. Moreover, these and other observations suggest that the dysregulation of HCRT-DA interactions could contribute to cognitive/affective dysfunction associated with a variety of behavioral disorders.

Publication types

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

MeSH terms

  • Animals
  • Cognition Disorders / metabolism
  • Cognition Disorders / physiopathology
  • Dopamine / metabolism*
  • Immunohistochemistry
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Intracellular Signaling Peptides and Proteins / pharmacology
  • Male
  • Mood Disorders / metabolism
  • Mood Disorders / physiopathology
  • Neural Pathways / cytology
  • Neural Pathways / drug effects
  • Neural Pathways / metabolism
  • Neurons / drug effects
  • Neurons / metabolism*
  • Neuropeptides / metabolism*
  • Neuropeptides / pharmacology
  • Nucleus Accumbens / cytology
  • Nucleus Accumbens / drug effects
  • Nucleus Accumbens / metabolism*
  • Orexins
  • Proto-Oncogene Proteins c-fos / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Staining and Labeling
  • Stilbamidines
  • Synaptic Transmission / drug effects
  • Synaptic Transmission / physiology
  • Tyrosine 3-Monooxygenase / metabolism
  • Up-Regulation / drug effects
  • Up-Regulation / physiology
  • Ventral Tegmental Area / cytology
  • Ventral Tegmental Area / drug effects
  • Ventral Tegmental Area / metabolism*


  • 2-hydroxy-4,4'-diamidinostilbene, methanesulfonate salt
  • Intracellular Signaling Peptides and Proteins
  • Neuropeptides
  • Orexins
  • Proto-Oncogene Proteins c-fos
  • Stilbamidines
  • Tyrosine 3-Monooxygenase
  • Dopamine