Maria Morena1,2,3, Andrei S Nastase1,2,4, Alessia Santori5, Benjamin F Cravatt6, Rebecca M Shansky7, Matthew N Hill1,2,3. 1. Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada. 2. Mathison Centre for Mental Health Research, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada. 3. Department of Cell Biology and Anatomy & Psychiatry, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada. 4. Neuroscience Program, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada. 5. Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy. 6. The Skaggs Institute for Chemical Biology and Department of Chemistry, The Scripps Research Institute, La Jolla, California, USA. 7. Department of Psychology, Northeastern University, Boston, Massachusetts, USA.
Abstract
BACKGROUND AND PURPOSE: Women are twice as likely as men to develop post-traumatic stress disorder (PTSD) making the search for biological mechanisms underlying these gender disparities especially crucial. One of the hallmark symptoms of PTSD is an alteration in the ability to extinguish fear responses to trauma-associated cues. In male rodents, the endocannabinoid system can modulate fear extinction and has been suggested as a therapeutic target for PTSD. However, whether and how the endocannabinoid system may modulate fear expression and extinction in females remains unknown. EXPERIMENTAL APPROACH: To answer this question, we pharmacologically manipulated endocannabinoid signalling in male and female rats prior to extinction of auditory conditioned fear and measured both passive (freezing) and active (darting) conditioned responses. KEY RESULTS: Surprisingly, we found that acute systemic inhibition of the endocannabinoid anandamide (AEA) or 2-arachidonoyl glycerol (2-AG) hydrolysis did not significantly alter fear expression or extinction in males. However, the same manipulations in females produced diverging effects. Increased AEA signalling at vanilloid TRPV1 receptors impaired fear memory extinction. In contrast, inhibition of 2-AG hydrolysis promoted active over passive fear responses acutely via activation of cannabinoid1 (CB1 ) receptors. Measurement of AEA and 2-AG levels after extinction training revealed sex- and brain region-specific changes. CONCLUSION AND IMPLICATIONS: We provide the first evidence that AEA and 2-AG signalling affect fear expression and extinction in females in opposite directions. These findings are relevant to future research on sex differences in mechanisms of fear extinction and may help develop sex-specific therapeutics to treat trauma-related disorders.
BACKGROUND AND PURPOSE: Women are twice as likely as men to develop post-traumatic stress disorder (PTSD) making the search for biological mechanisms underlying these gender disparities especially crucial. One of the hallmark symptoms of PTSD is an alteration in the ability to extinguish fear responses to trauma-associated cues. In male rodents, the endocannabinoid system can modulate fear extinction and has been suggested as a therapeutic target for PTSD. However, whether and how the endocannabinoid system may modulate fear expression and extinction in females remains unknown. EXPERIMENTAL APPROACH: To answer this question, we pharmacologically manipulated endocannabinoid signalling in male and female rats prior to extinction of auditory conditioned fear and measured both passive (freezing) and active (darting) conditioned responses. KEY RESULTS: Surprisingly, we found that acute systemic inhibition of the endocannabinoid anandamide (AEA) or 2-arachidonoyl glycerol (2-AG) hydrolysis did not significantly alter fear expression or extinction in males. However, the same manipulations in females produced diverging effects. Increased AEA signalling at vanilloid TRPV1 receptors impaired fear memory extinction. In contrast, inhibition of 2-AG hydrolysis promoted active over passive fear responses acutely via activation of cannabinoid1 (CB1 ) receptors. Measurement of AEA and 2-AG levels after extinction training revealed sex- and brain region-specific changes. CONCLUSION AND IMPLICATIONS: We provide the first evidence that AEA and 2-AG signalling affect fear expression and extinction in females in opposite directions. These findings are relevant to future research on sex differences in mechanisms of fear extinction and may help develop sex-specific therapeutics to treat trauma-related disorders.
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