Psychological stress reduces endocannabinoid tone: mechanisms and possible treatments

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One debilitating mental health problem among veterans is post-traumatic stress disorder (PTSD), which is an anxiety disorder (PTSD) and develops following the experience of life- threatening psychological trauma. Individuals with PTSD have reduced circulating levels of endocannabinoids (eCB) including 2-AG. Since disruption of 2-AG signaling leads to mood disorders, impaired memory extinction and enhanced pain, the ability to reverse the stress- induced change in 2-AG production/degradation holds great potential for the treatment of PTSD. Given the importance of 2-AG signaling in the stress response and associative fear learning, an understanding of how stress produces a lasting decrease in 2-AG levels is needed to bridge the knowledge gap that exists between traumatic stress and the associated reduction in 2-AG content. Exposure of rodents to natural predator odors causes psychological stress, leading to enhanced associative fear learning and thus has been used to model several aspects of PTSD. We have previously shown that fox urine exposure produced a lasting increase in excitatory synaptic transmission via the activation of adrenergic receptors in the mouse cerebellum. This brain region is required for the innate response to predator odor and for the consolidation of fear memory. Our pilot data show that predator odor exposure reduced 2-AG signaling in the cerebellum and this stressor abolished A-type K currents in inhibitory interneurons. Therefore our central hypothesis is that predator odor stress enhances excitability of GABAergic interneurons and thereby reduces 2-AG signaling, thus pharmacological interventions that inhibit 2-AG degradation and reduce neuronal excitability would reverse the stress-induced decrease in 2-AG levels. In Aim 1, we will determine whether a psychological stress reduces 2- AG tone by increasing 2-AG degradation or by reducing 2-AG production. Aim 2 will test the hypothesis that emotional stress reduces 2-AG signaling by increasing inhibitory interneuron activity. We will test whether several FDA approved drugs that reduce neuronal activity can reverse the stress-induced change. Because the proposed study investigates a new mechanism underlying the regulation of 2-AG metabolism by psychological stress, it could suggest novel treatment strategies for PTSD and new therapeutic targets.