| Summary: | Background : Combat-related posttraumatic stress disorder (PTSD) is increasingly recognized as a primary challenge to the fitness of American military personnel and represents a significant military and national public health concern (Hoge et al. 2004; Thomas et al. 2010). A few available drugs (e.g., selective serotonin reuptake inhibitors and serotonin–norepinephrine reuptake inhibitors) provide some benefit in the management of PTSD symptoms and have been approved by the Food and Drug Administration for the treatment of PTSD, but most meta-analytic reviews (Stein et al., 2006) have concluded that the benefits are minimal and there may be relatively less benefit for combat veterans (Friedman et al., 2007). Popular augmentation strategies using second-generation antipsychotic medication were also recently shown to be ineffective in the treatment PTSD (Krystal et al., 2011). Deficits in CB1 receptor–mediated eCB signaling may play a key role in the etiology of PTSD and may mediate important components of the PTSD phenotype. Therefore, we propose to enhance eCB signaling as a novel, evidence-based treatment for PTSD with the potential to prevent both the behavioral (anxiety, impaired extinction) and molecular adaptations to trauma (increased CB1 receptor expression; Suarez et al., 2009) associated with PTSD. Methods : Using radioligands and positron emission tomography (PET) imaging on a high-resolution PET scanner, we tested novel models of the etiology of PTSD involving these systems and their associated receptors. Results : Four main lines of translational evidence implicate a defect in CB1 receptor–mediated eCB signaling in the pathogenesis of PTSD. In initial experiments, we found that (a) plasma AEA levels are decreased in PTSD patients (0.72±0.12 pmol/ml) relative to healthy control subjects without trauma history (HC 2.74±0.85 pmol/ml, t=2.47, df = 17, p=.024) or controls with trauma history (TC 2.67±0.36, t=2.81, df = 10, p=0.018); (b) there are statistically detectable correlations between earlier age at first trauma and lower AEA levels in PTSD (r=0.45, p = 0.073) and between magnitude of the decrease with a longer duration of PTSD (r= − 0.48, p=0.059); (c) there are elevated [11C]OMAR volume of distribution (V T) levels (corresponding to elevated CB1 receptor density) in the fear circuit in PTSD relative to healthy people. This upregulation develops to compensate for the existing eCB deficit in PTSD and causes impaired fear processing, increased stress sensitivity and anxiety in PTSD as supported by (d) a statistically detectable positive correlation between amygdala [11C]OMAR V T and anxiety symptoms (r=0.56, p=0.09), perceived stress (r=0.57, p=0.018), and abnormal fear processing measured during fear conditioning tests (r=0.69, p=0.003). Conclusions : These first data in PTSD provide evidence for abnormal CB1 receptor–mediated endocannabinoid signaling in PTSD and also provide a basis for evidence-based treatment development for this patient population. Inhibition of fatty acid amid hydrolase, the endocannabinoid degrading enzyme, appears to be an attractive candidate for such an undertaking.
|
|---|
