Synergistic interactions between cannabinoids and environmental stress in the activation of the central amygdala

Sachin Patel, Benjamin F. Cravatt, Cecilia J. Hillard*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

131 Scopus citations


Anxiety and panic are the most common adverse effects of cannabis intoxication; reactions potentiated by stress. Data suggest that cannabinoid (CB1) receptor modulation of amygdalar activity contributes to these phenomena. Using Fos as a marker, we tested the hypothesis that environmental stress and CB1 cannabinoid receptor activity interact in the regulation of amygdalar activation in male mice. Both 30 min of restraint and CB1 receptor agonist treatment (Δ9- tetrahydrocannabinol (2.5 mg/kg) or CP55940 (0.3mg/kg); by i.p. injection) produced barely detectable increases in Fos expression within the central amygdala (CeA). However, the combination of restraint and CB1 agonist administration produced robust Fos induction within the CeA, indicating a synergistic interaction between environmental stress and CB1 receptor activation. An inhibitor of endocannabinoid transport, AM404 (10 mg/kg), produced an additive interaction with restraint within the CeA. In contrast, fatty acid amide hydrolase (FAAH) inhibitor-treated mice (URB597, 1 mg/kg) and FAAH-/- mice did not exhibit any differences in amygdalar activation in response to restraint compared to control mice. In the basolateral (BLA) and medial amygdala, restraint stress produced a low level of Fos induction, which was unaffected by cannabinoid treatment. Interestingly, the CB receptor antagonist SR141716 dose-dependently increased Fos expression in the BLA and CeA. These data suggest the CeA is an important neural substrate subserving the interactions between cannabinoids and environmental stress, and could be relevant to understanding the context-dependent emotional and affective changes induced by marijuana intoxication and the role of endocannabinoid signaling in the modulation of amygdalar activity.

Original languageEnglish (US)
Pages (from-to)497-507
Number of pages11
Issue number3
StatePublished - Mar 2005
Externally publishedYes


  • 2-AG
  • Anandamide
  • Anxiety
  • CB receptor
  • Endocannabinoid
  • FAAH
  • Fos
  • Marijuana
  • Restraint

ASJC Scopus subject areas

  • Pharmacology
  • Psychiatry and Mental health


Dive into the research topics of 'Synergistic interactions between cannabinoids and environmental stress in the activation of the central amygdala'. Together they form a unique fingerprint.

Cite this