Hcrtr1 and 2 signaling differentially regulates depression-like behaviors

Michael M. Scott, Jacob N. Marcus, Ami Pettersen, Shari G. Birnbaum, Takatoshi Mochizuki, Thomas E. Scammell, Eric J. Nestler, Joel K. Elmquist, Michael Lutter

Research output: Contribution to journalArticlepeer-review

98 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)289-294
Number of pages6
JournalBehavioural Brain Research
Issue number2
StatePublished - Sep 23 2011


  • Anxiety
  • Depression
  • Orexin

ASJC Scopus subject areas

  • Behavioral Neuroscience


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