Post-traumatic stress disorder (PTSD) is triggered by a traumatic life event and is characterized by the recurrent retrieval of the traumatic memory in the form of context-induced flashbacks and recurrent nightmares. The amygdala is a critical brain structure involved in both the formation and the extinction of emotional memories. Glucocorticoids, steroid hormones secreted as part of the general stress response, and endocannabinoids, lipid molecules that bind to CB1 receptors in the brain, have been shown to be important for the consolidation and extinction of fear conditioning. Both glucocorticoids and endocannabinoids enhance fear memory formation and extinction via actions within the basolateral amygdaloid complex (BLA). Patients suffering from PTSD typically show low circulating levels of corticosteroids, particularly at the nadir of the diurnal cortisol secretory rhythm, and corticosteroid treatment leads to improvement in subjective measures of PTSD symptoms. The current study will test the hypothesis that glucocorticoids trigger endocannabinoid synthesis and retrograde release at GABA synapses in the BLA, leading to the suppression of synaptic inhibitory input to BLA neurons. Pharmacological and genetic manipulations of corticosteroid and cannabinoid receptors and intracellular signaling pathways will be employed to characterize the novel molecular interactions between glucocorticoids and endocannabinoids in the BLA. The outcome of this study will provide important insight into, and possible future targets for, pharmacological treatment of stress-related disorders such as PTSD.
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