Chronic exposure to cannabinoids before an emotional trauma may have negative effects on emotional function

Chronic direct activation of cannabinoid CB1 receptors (CB1r) may lead to downregulation of CB1r which may in turn result in a depression-like phenotype in certain individuals. We examined the effects of chronic cannabinoid receptor activation before exposure to an emotional traumatic event on CB1r expression in the basolateral amygdala (BLA) and CA1 and on protracted anxiety- and depression-like behaviors. We used exposure to severe shock and situational reminders (SRs) in an inhibitory apparatus as a model for emotional trauma. Chronic treatment with the CB1/2 receptor agonist WIN55,212-2 (1.2 mg/kg, i.p.) before shock exposure had differential effects on depression- and anxiety-like behavioral measures depending on withdrawal periods. In the 24 hrs withdrawal condition, WIN55,212-2 enhanced fear retrieval and impaired extinction, increased anhedonia and despair, but had a therapeutic effect in the startle test. In the 10 days withdrawal condition, WIN55,212-2 enhanced fear retrieval and impaired extinction without preventing the shock/SR-induced negative effects on anhedonia or startle response, but had a therapeutic effect in the despair test. Chronic treatment with WIN55,212-2 was found to down regulate CB1r protein levels in the BLA in the 10 days withdrawal condition, and to upregulate CB1r protein levels in the 24 hrs condition. In the CA1, rats chronically injected with vehicle or WIN55,212-2 demonstrated downregulation of CB1r protein levels. Chronic exposure to cannabinoids prior to an emotional trauma may have deleterious effects on emotional function suggesting that direct CB1/2 receptor activation may not be an optimal way to manipulate the endocannabinoid system in stressful individuals.