Synergistic Interactions between Cannabinoids and Environmental Stress in the Activation of the Central Amygdala

Abstract

Anxiety and panic are the most common adverse effects of cannabis intoxication; reactions potentiated by stress. Data suggest that cannabinoid (CB 1 ) receptor modulation of amygdalar activity contributes to these phenomena. Using Fos as a marker, we tested the hypothesis that environmental stress and CB 1 cannabinoid receptor activity interact in the regulation of amygdalar activation in male mice. Both 30 min of restraint and CB 1 receptor agonist treatment (D 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 CB 1 agonist administration produced robust Fos induction within the CeA, indicating a synergistic interaction between environmental stress and CB 1 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 À/À 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 1 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.

Cannabinoid Receptor Activation in the Basolateral Amygdala Blocks the Effects of Stress on the Conditioning and Extinction of Inhibitory Avoidance

“…Thus, cannabinoid activation in the BLA acts to modulate the effects of stress on conditioning and extinction. In support, Patel et al (2005) found a synergistic interaction between environmental stress and CB 1 receptor activation in the amygdala, because the combination of restraint stress and CB 1 agonist administration produces robust Fos induction within the BLA and the central amygdala.…”

Antidepressant-like activity and modulation of brain monoaminergic transmission by blockade of anandamide hydrolysis

“…First, stressful stimuli affect anandamide mobilization in brain regions that are involved in the control of emotions. In rats, for example, an electric shock to the paw elevates anandamide levels in the midbrain (33), whereas in mice, physical restraint decreases anandamide levels in the amygdala (34). Second, pharmacological blockade or genetic ablation of CB 1 receptors exacerbates normal reactions to acute stress, presumably by disabling an endocannabinoid modulation of these reactions (35)(36)(37)(38).…”

Dissociation of within- and between-Session Extinction of Conditioned Fear

“…Other markers of neuronal activity, such as phosphorylation of kinases, may better reflect differences in freezing behavior (in particular if analyzed in the absence of injection stress in CB1-KO and CB1-WT mice) (Cannich et al, 2004). Previous studies reported an increase in Fos-ir in the central amygdala of naive mice following pharmacological blockade of CB1 (Patel et al, 2005a). In addition, CB1 plays a complex role in the regulation of fear and anxiety within the medial prefrontal cortex (Lin et al, 2009), and neuronal activity within the prelimbic cortex seems to directly Figure 6.…”