Serotonin 1B autoreceptors originating in the caudal dorsal raphe nucleus reduce expression of fear and depression-like behavior

Biol Psychiatry. 2011 Apr 15;69(8):780-7. doi: 10.1016/j.biopsych.2010.12.029. Epub 2011 Feb 26.


Background: Serotonin 1B (5-HT(1B)) autoreceptors regulate release of serotonin from terminals of dorsal raphe nucleus (DRN) projections. Expression of 5-HT(1B) in the DRN inversely correlates with behavioral measures of emotion, and viral-mediated overexpression of 5-HT(1B) receptors in the middle DRN inversely reduces measures of fear and anxiety in unstressed rats. Because the caudal subregion of the DRN is important in translating stress into emotional dysregulation, we explored behavioral functions of 5-HT(1B) autoreceptors in the caudal DRN.

Methods: We manipulated 5-HT(1B) autoreceptor function in rats using either viral-mediated gene transfer into the caudal DRN or systemic injections of the 5-HT(1B) agonist 3-(1,2,5,6-tetrahydro-4-pyridyl)-5-propoxypyrrolo[3,2-b]pyridine (CP-94253). Rats were tested in forced swim test, open field test, and contextual fear conditioning.

Results: Overexpression of 5-HT(1B) in the caudal DRN increased swimming in the forced swim test. It did not alter locomotion or thigmotaxis in the open field test but did reduce conditioned freezing. Freezing was reduced when 5-HT(1B) overexpression was present only during testing but not training. The CP-94253 exerted an inverted U-shaped dose response curve on conditioned freezing, with most pronounced effects seen at 1 mg/kg. At this dose, CP-94253 administered before a fear retention test reduced freezing both during that session and in subsequent drug-free testing, but only when drug was paired with re-exposure to the fear context.

Conclusions: The 5-HT(1B) autoreceptors originating in the caudal DRN regulate behavioral expression of helplessness and fear. Because systemic pharmacologic treatment with a 5-HT(1B) agonist facilitates reductions in fear, 5-HT(1B) receptors may be a target for the treatment of certain anxiety disorders.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Analysis of Variance
  • Animals
  • Association Learning / drug effects
  • Association Learning / physiology
  • Behavior, Animal / drug effects
  • Behavior, Animal / physiology*
  • Conditioning, Psychological / drug effects
  • Conditioning, Psychological / physiology
  • Depression / physiopathology*
  • Depression / psychology
  • Electroshock
  • Fear / drug effects
  • Fear / physiology*
  • Fear / psychology
  • Gene Transfer Techniques
  • Male
  • Pyridines / pharmacology
  • Raphe Nuclei / drug effects
  • Raphe Nuclei / metabolism*
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Serotonin, 5-HT1B / metabolism*
  • Serotonin Receptor Agonists / pharmacology
  • Swimming


  • CP 94253
  • Pyridines
  • Receptor, Serotonin, 5-HT1B
  • Serotonin Receptor Agonists