Activating the endocannabinoid system has become a major focus in the search for novel therapeutics for anxiety and deficits in fear extinction, two defining features of PTSD. We examined whether chronic treatment with the fatty acid amide hydrolase (FAAH) inhibitor URB597 (0.2, 0.3, 0.4 mg/kg, i.p.) or the CB1/2 receptor agonist WIN55,212-2 (0.25, 0.5 mg/kg, i.p.) injected for 3 weeks to rats exposed to the shock and reminders model of PTSD would attenuate post-stress symptoms and affect basolateral amygdala (BLA) and CA1 CB1 receptors. Exposure to shock and reminders enhanced acoustic startle response and impaired extinction. Rats exposed to shock and reminders and chronically treated with URB597 demonstrated normalized startle response and intact extinction kinetics. WIN55,212-2 only affected the startle response. The therapeutic effects of URB597 and WIN55,212-2 were found to be CB1 receptor dependent, as these effects were blocked when a low dose of the CB1 receptor antagonist AM251 (0.3 mg/kg, i.p. for 3 weeks) was co-administered. Moreover, URB597, but not WIN55,212-2, normalized the shock/reminders-induced upregulation in CB1 receptor levels in the BLA and CA1. One hour after the shock, N-arachidonoylethanolamine (AEA) was increased in the BLA and decreased in the CA1. Circulating 2-arachidonoylglycerol (2-AG) concentrations were decreased in shocked rats, with no significant effect in the BLA or CA1. FAAH activity was increased in the CA1 of shocked rats. Chronic cannabinoid treatment with URB597 can ameliorate PTSD-like symptoms suggesting FAAH inhibitors as a potentially effective therapeutic strategy for the treatment of disorders associated with inefficient fear coping.
Bibliographical noteFunding Information:
This research was supported by The Binational Science Foundation (BSF) grant No. 2015/084 to I.A. and C.J.H. (URL: www.bsf.org.il/ ) and by the Advancing a Healthier Wisconsin Endowment at the Medical College of Wisconsin.
This research was supported by The Binational Science Foundation (BSF) grant No. 2015/084 to I.A. and C.J.H. (URL: www.bsf.org.il/) and by the Advancing a Healthier Wisconsin Endowment at the Medical College of Wisconsin.
© 2018 Elsevier B.V. and ECNP
- N-arachidonylethanolamine (AEA)
- Post traumatic stress disorder (PTSD)
- fatty acid hydrolase (FAAH) inhibitor URB597
ASJC Scopus subject areas
- Clinical Neurology
- Psychiatry and Mental health
- Biological Psychiatry
- Pharmacology (medical)