Stress impairs 5-HT2A receptor-mediated serotonergic facilitation of GABA release in juvenile rat basolateral amygdala

Neuropsychopharmacology. 2009 Jan;34(2):410-23. doi: 10.1038/npp.2008.71. Epub 2008 Jun 4.


The occurrence of stress and anxiety disorders has been closely associated with alterations of the amygdala GABAergic system. In these disorders, dysregulation of the serotonergic system, a very important modulator of the amygdala GABAergic system, is also well recognized. The present study, utilizing a learned helplessness stress rat model, was designed to determine whether stress is capable of altering serotonergic modulation of the amygdala GABAergic system. In control rats, administration of 5-HT or alpha-methyl-5-HT, a 5-HT(2) receptor agonist, to basolateral amygdala (BLA) slices dramatically enhanced frequency and amplitude of spontaneous inhibitory postsynaptic currents (sIPSCs). This effect was blocked by selective 5-HT(2A) receptor antagonists while a selective 5-HT(2B) receptor agonist and a selective 5-HT(2C) receptor agonist were without effect on sIPSCs. Double immunofluorescence labeling demonstrated that the 5-HT(2A) receptor is primarily localized to parvalbumin-containing BLA interneurons. Thus, serotonin primarily acts via 5-HT(2A) receptors to facilitate BLA GABAergic inhibition. In stressed rats, the 5-HT(2A) receptor-mediated facilitative actions were severely impaired. Quantitative RT-PCR and western blot analysis showed that the impairment of 5-HT(2A) receptor signaling primarily resulted from receptor downregulation. The stress-induced effect appeared to be specific to 5-HT(2A) receptors because stress had no significant impact on other serotonin receptors, as well as histamine H(3) receptor and alpha(2) adrenoceptor signaling in the BLA. This severe impairment of 5-HT(2A) receptor-mediated facilitation of BLA GABAergic inhibition might result in an amygdala circuitry with hyperexcitability, and a lower threshold of activation, and thus be an important mechanism underlying the emergence of stress-associated psychiatric symptoms.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amygdala / metabolism*
  • Animals
  • Down-Regulation
  • Helplessness, Learned
  • In Vitro Techniques
  • Inhibitory Postsynaptic Potentials / drug effects
  • Interneurons / metabolism
  • Male
  • Neural Inhibition / physiology
  • Parvalbumins / metabolism
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Serotonin, 5-HT2A / metabolism*
  • Receptors, Adrenergic, alpha-2 / metabolism
  • Receptors, Histamine H3 / metabolism
  • Serotonin / analogs & derivatives
  • Serotonin / metabolism*
  • Serotonin / pharmacology
  • Serotonin 5-HT2 Receptor Agonists
  • Serotonin 5-HT2 Receptor Antagonists
  • Stress, Psychological / metabolism*
  • gamma-Aminobutyric Acid / metabolism*


  • Parvalbumins
  • RNA, Messenger
  • Receptor, Serotonin, 5-HT2A
  • Receptors, Adrenergic, alpha-2
  • Receptors, Histamine H3
  • Serotonin 5-HT2 Receptor Agonists
  • Serotonin 5-HT2 Receptor Antagonists
  • alpha-methylserotonin
  • Serotonin
  • gamma-Aminobutyric Acid