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Hcrtr1 and 2 signaling differentially regulates depression-like behaviors.

The orexin/hypocretin system has the potential to significantly modulate affect, based on both the neuroanatomical projection patterns of these neurons and on the sites of orexin receptor expression. However, there is little data supporting the role of specific orexin receptors in the modulation of depression-like behavior. Here we report behavioral profiling of mice after genetic or pharmacologic inhibition of hcrtr1 and 2 receptor signaling. Hcrtr1 null mice displayed a significant reduction in behavioral despair in the forced swim test and tail suspension test. Wild-type mice treated with the hcrtr1 antagonist SB-334867 also displayed a similar reduction in behavioral despair. No difference in anxiety-like behavior was noted following hcrtr1 deletion. In contrast, hcrtr2-null mice displayed an increase in behavioral despair with no effect on measures of anxiety. These studies suggest that the balance of orexin action at either the hcrtr1 or the hcrtr2 receptor produces an anti-depressant or pro-depressant like effect, depending on the receptor subtype activated.

Pubmed ID: 21377495


  • Scott MM
  • Marcus JN
  • Pettersen A
  • Birnbaum SG
  • Mochizuki T
  • Scammell TE
  • Nestler EJ
  • Elmquist JK
  • Lutter M


Behavioural brain research

Publication Data

September 23, 2011

Associated Grants

  • Agency: NIMH NIH HHS, Id: K08 MH084058
  • Agency: NIMH NIH HHS, Id: K08 MH084058-1A1
  • Agency: NIDA NIH HHS, Id: K99 DA024719-02
  • Agency: NIMH NIH HHS, Id: P50 MH066172
  • Agency: NIDDK NIH HHS, Id: RL1 DK081182
  • Agency: NIDDK NIH HHS, Id: RL1 DK081185
  • Agency: NCRR NIH HHS, Id: UL1RR024923

Mesh Terms

  • Animals
  • Anxiety
  • Benzoxazoles
  • Choice Behavior
  • Depression
  • Disease Models, Animal
  • Immobility Response, Tonic
  • Male
  • Maze Learning
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Motor Activity
  • Orexin Receptors
  • Receptors, G-Protein-Coupled
  • Receptors, Neuropeptide
  • Signal Transduction
  • Swimming
  • Urea