Abstract
Impairments in fear extinction are thought to be central to the psychopathology of posttraumatic stress disorder, and endocannabinoid (eCB) signaling has been strongly implicated in extinction learning. Here we utilized the monoacylglycerol lipase inhibitor JZL184 to selectively augment brain 2-AG levels combined with an auditory cue fear-conditioning paradigm to test the hypothesis that 2-AG-mediated eCB signaling modulates short-term fear extinction learning in mice. We show that systemic JZL184 impairs short-term extinction learning in a CB1 receptor-dependent manner without affecting non-specific freezing behavior or the acquisition of conditioned fear. This effect was also observed in over-conditioned mice environmentally manipulated to re-acquire fear extinction. Cumulatively, the effects of JZL184 appear to be partly due to augmentation of 2-AG signaling in the basolateral nucleus of the amygdala (BLA), as direct microinfusion of JZL184 into the BLA produced similar results. Moreover, we elucidate a short ~3-day temporal window during which 2-AG augmentation impairs extinction behavior, suggesting a preferential role for 2-AG-mediated eCB signaling in the modulation of short-term behavioral sequelae to acute traumatic stress exposure.
Highlights
Emerging conceptualizations of several psychiatric disorders including addiction, schizophrenia and anxiety disorders highlight dysregulation of learning and memory processes as key contributors to disease pathogenesis
JZL184 on freezing of non-conditioned mice placed in a novel context during the presentation of auditory tones. (c) Effects of JZL184 on freezing of contextual-conditioned mice placed in a novel context. (d) Effects of JZL184 on freezing of contextual-conditioned mice placed in a novel context with the presentation of auditory tones. †Po 0.05 significant effect of drug treatment by two-way analysis of variance (ANOVA). *Po 0.05 significantly different from vehicle treatment by unpaired two-tailed t-test
We found that global 2-AG augmentation using systemic administration of JZL184 prior to extinction training sessions was capable of impairing short-term extinction learning as measured by within-session freezing behavior
Summary
Emerging conceptualizations of several psychiatric disorders including addiction, schizophrenia and anxiety disorders highlight dysregulation of learning and memory processes as key contributors to disease pathogenesis This is especially true for anxiety disorders including posttraumatic stress disorder (PTSD), where substantial preclinical and clinical data have identified specific abnormalities in fear-learning processes central to the pathophysiology of this illness.[1,2,3,4,5,6,7,8,9]. Exposure to traumatic stress initiates multiple neural processes, some of which are adaptive responses aimed at preventing harm These include, for example, conditioned fear behavior triggered by cues or context associated with stress exposure. Key pathophysiological substrates of PTSD include impairments in extinction learning and fear habituation, and exaggerated fear generalization and sensitization after traumatic stress exposure.[10]
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