Enhancing Endocannabinoid Signaling via ß-Catenin in the Nucleus Accumbens Attenuates PTSD- and Depression-like Behavior of Male Rats.

Inhibition of fatty acid amide hydrolase (FAAH), which increases anandamide levels, has been suggested as a potential treatment for stress-related conditions. We examined whether the stress-preventing effects of the FAAH inhibitor URB597 on behavior are mediated via ß-catenin in the nucleus accumbens (NAc). Male rats were exposed to the shock and reminders model of PTSD and then treated with URB597 (0.4 mg/kg; i.p.). They were tested for anxiety- (freezing, startle response), depression-like behaviors (despair, social preference, anhedonia), and memory function (T-maze, social recognition). We also tested the involvement of the CB1 receptor (CB1r), ß-catenin, and metabotropic glutamate receptor subtype 5 (mGluR5) proteins. URB597 prevented the shock- and reminders-induced increase in anxiety- and depressive-like behaviors, as well as the impaired memory via the CB1r-dependent mechanism. In the NAc, viral-mediated ß-catenin overexpression restored the behavior of rats exposed to stress and normalized the alterations in protein levels in the NAc and the prefrontal cortex. Importantly, when NAc ß-catenin levels were downregulated by viral-mediated gene transfer, the therapeutic-like effects of URB597 were blocked. We suggest a potentially novel mechanism for the therapeutic-like effects of FAAH inhibition that is dependent on ß-catenin activation in the NAc in a PTSD rat model.

Cannabinoids as therapeutics for PTSD.

Post-traumatic stress disorder (PTSD) is a complex disorder that involves dysregulation of multiple neurobiological systems. The traumatic stressor plays a causal role in producing psychological dysfunction and the pattern of findings suggests that the hypothalamic-pituitary-adrenal (HPA) axis, which is instrumental for stress adaptation, is critically dysfunctional in PTSD. Given the lack of understanding of the basic mechanisms and underlying pathways that cause the disorder and its heterogeneity, PTSD poses challenges for treatment. Targeting the endocannabinoid (ECB) system to treat mental disorders, and PTSD in particular, has been the focus of research and interest in recent years. The ECB system modulates multiple functions, and drugs enhancing ECB signaling have shown promise as potential therapeutic agents in stress effects and other psychiatric and medical conditions. In this review, we focus on the interaction between the ECB-HPA systems in animal models for PTSD and in patients with PTSD. We summarize evidence supporting the use of cannabinoids in preventing and treating PTSD in preclinical and clinical studies. As the HPA system plays a key role in the mediation of the stress response and the pathophysiology of PTSD, we describe preclinical studies suggesting that enhancing ECB signaling is consistent with decreasing PTSD symptoms and dysfunction of the HPA axis. Overall, we suggest that a pharmacological treatment targeted at one system (e.g., HPA) may not be very effective because of the heterogeneity of the disorder. There are abnormalities across different neurotransmitter systems in the pathophysiology of PTSD and none of these systems function uniformly among all patients with PTSD. Hence, conceptually, enhancing ECB signaling may be a more effective avenue for pharmacological treatment.

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.