1. ¹Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI, USA
2. ²The Skaggs Institute for Chemical Biology and Department of Cell Biology, The Scripps Research Institute, San Diego, CA, USA

Correspondence: Dr CJ Hillard, Department of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA. Tel: +1 414 456 8493; Fax: +1 414 456 6545; E-mail: chillard@mcw.edu

Received 11 March 2004; Revised 14 June 2004; Accepted 17 June 2004; Published online 28 July 2004.

Abstract

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 (⁹-tetrahydrocannabinol (2.5 mg/kg) or CP55940 (0.3 mg/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 CB₁ 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.