Stimulation of serotonin 2A receptors facilitates consolidation and extinction of fear memory in C57BL/6J mice

Neuropharmacology. 2013 Jan;64(1):403-13. doi: 10.1016/j.neuropharm.2012.06.007. Epub 2012 Jun 18.


Excessive fear is a hallmark of several emotional and mental disorders such as phobias and panic disorders. Considerable attention is focused on defining the neurobiological mechanisms of the extinction of conditioned fear memory in an effort to identify mechanisms that may hold clinical significance for remediating aberrant fear memory. Serotonin modulates the acquisition and retention of conditioned emotional memory, and the serotonin 2A receptor (5HT2AR) may be one of the postsynaptic targets mediating such effects. Here we tested the hypothesis that the 5HT2AR regulates the consolidation and extinction of fear memory in male C57BL/6J mice. The influence of 5HT2ARs on memory consolidation was further confirmed with a novel object recognition task. With a trace fear conditioning paradigm, administration of the 5HT2AR agonist TCB-2 (1.0 mg/kg, i.p.) before the extinction test facilitated the acquisition of extinction of fear memory as compared to vehicle treatment. In contrast, administration of the 5HT2AR antagonist MDL 11,939 (0.5 mg/kg, i.p.) delayed the acquisition of extinction of fear memory. Further, the post-conditioning administration of TCB-2 enhanced contextual and cued fear memory, possibly by facilitating the consolidation of fear memory. Administration of TCB-2 also facilitated the acquisition of extinction of fear memory in delay fear conditioned mice. Stimulation or blockade of 5HT2ARs did not affect the encoding or retrieval of conditioned fear memory. Finally, administration of TCB-2 right after training in an object recognition task enhanced the consolidation of object memory. These results suggest that stimulation of 5HT2ARs facilitates the consolidation and extinction of trace and delay cued fear memory and the consolidation of object memory. Blocking the 5HT2AR impairs the acquisition of fear memory extinction. The results support the view that serotonergic activation of the 5HT2AR provides an important modulatory influence on circuits engaged during extinction learning. Taken together these results suggest that the 5HT2AR may be a potential therapeutic target for enhancing hippocampal and amygdala-dependent memory. This article is part of a Special Issue entitled 'Cognitive Enhancers'.

Publication types

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

MeSH terms

  • Animals
  • Anti-Anxiety Agents / pharmacology
  • Anti-Anxiety Agents / therapeutic use*
  • Anxiety / prevention & control*
  • Anxiety Disorders / drug therapy*
  • Bridged Bicyclo Compounds / pharmacology
  • Bridged Bicyclo Compounds / therapeutic use
  • Cues
  • Extinction, Psychological / drug effects*
  • Fear / drug effects
  • Male
  • Memory / drug effects
  • Memory, Episodic
  • Methylamines / pharmacology
  • Methylamines / therapeutic use
  • Mice
  • Mice, Inbred C57BL
  • Molecular Targeted Therapy
  • Nerve Tissue Proteins / agonists
  • Nerve Tissue Proteins / antagonists & inhibitors
  • Nerve Tissue Proteins / metabolism
  • Nootropic Agents / pharmacology
  • Nootropic Agents / therapeutic use*
  • Piperidines / adverse effects
  • Piperidines / pharmacology
  • Receptor, Serotonin, 5-HT2A / chemistry
  • Receptor, Serotonin, 5-HT2A / metabolism*
  • Recognition, Psychology / drug effects
  • Reinforcement, Psychology
  • Serotonin 5-HT2 Receptor Agonists / pharmacology
  • Serotonin 5-HT2 Receptor Agonists / therapeutic use*
  • Serotonin 5-HT2 Receptor Antagonists / adverse effects
  • Serotonin 5-HT2 Receptor Antagonists / pharmacology


  • (4-bromo-3,6-dimethoxybenzocyclobuten-1-yl)methylamine
  • Anti-Anxiety Agents
  • Bridged Bicyclo Compounds
  • Methylamines
  • Nerve Tissue Proteins
  • Nootropic Agents
  • Piperidines
  • Receptor, Serotonin, 5-HT2A
  • Serotonin 5-HT2 Receptor Agonists
  • Serotonin 5-HT2 Receptor Antagonists
  • alpha-phenyl-1-(2-phenylethyl)-4-piperidinemethanol