| Autor: |
Ivy D; Department of Anatomy and Neurobiology, University of California, Irvine, 3103 Gillespie Neuroscience Research Facility, Irvine, CA, 92697-4625, USA., Palese F; Department of Anatomy and Neurobiology, University of California, Irvine, 3103 Gillespie Neuroscience Research Facility, Irvine, CA, 92697-4625, USA., Vozella V; Department of Anatomy and Neurobiology, University of California, Irvine, 3103 Gillespie Neuroscience Research Facility, Irvine, CA, 92697-4625, USA., Fotio Y; Department of Anatomy and Neurobiology, University of California, Irvine, 3103 Gillespie Neuroscience Research Facility, Irvine, CA, 92697-4625, USA., Yalcin A; Department of Anatomy and Neurobiology, University of California, Irvine, 3103 Gillespie Neuroscience Research Facility, Irvine, CA, 92697-4625, USA., Ramirez G; Department of Anatomy and Neurobiology, University of California, Irvine, 3103 Gillespie Neuroscience Research Facility, Irvine, CA, 92697-4625, USA., Mears D; Department of Anatomy, Physiology, and Genetics, Uniformed Service University of the Health Sciences, Bethesda, MD, USA.; Center for the Study of Traumatic Stress, Department of Psychiatry, Uniformed Service University of the Health Sciences, Bethesda, MD, USA., Wynn G; Center for the Study of Traumatic Stress, Department of Psychiatry, Uniformed Service University of the Health Sciences, Bethesda, MD, USA., Piomelli D; Department of Anatomy and Neurobiology, University of California, Irvine, 3103 Gillespie Neuroscience Research Facility, Irvine, CA, 92697-4625, USA. piomelli@uci.edu.; Department of Pharmaceutical Sciences, University of California, Irvine, Irvine, 92697, CA, USA. piomelli@uci.edu.; Department of Biological Chemistry, University of California, Irvine, Irvine, 92697, CA, USA. piomelli@uci.edu. |
| Abstrakt: |
The endocannabinoid system is a key regulator of the response to psychological stress. Inhibitors of monoacylglycerol lipase (MGL), the enzyme that deactivates the endocannabinoid 2-arachidonoyl-sn-glycerol (2-AG), exert anxiolytic-like effects in rodent models via 2-AG-dependent activation of CB 1 cannabinoid receptors. In the present study, we examined whether the MGL inhibitor JZL184 might modulate persistent predator-induced fear in rats, a model that captures features of human post-traumatic stress disorder. Exposure to 2,5-dihydro-2,4,5-trimethylthiazoline (TMT), a volatile chemical that is innately aversive to some rodent species, produced in male rats a long-lasting anxiety-like state that was measured 7 days later in the elevated plus maze test. Systemic administration of JZL184 [4, 8 and 16 mg/kg, intraperitoneal (IP)] 4 h before testing caused dose-dependent inhibition of MGL activity and elevation of 2-AG content in brain tissue. Concomitantly, the inhibitor suppressed TMT-induced fear behaviors with a median effective dose (ED 50 ) of 4 mg/kg. A similar behavioral response was observed with another MGL inhibitor, KML29 (4 and 16 mg/kg, IP). Surprisingly, the effect of JZL184 was prevented by co-administration of the CB 2 inverse agonist AM630 (5 mg/kg, IP), but not the CB 1 inverse agonist rimonabant (1 mg/kg, IP). Supporting mediation of the response by CB 2 receptors, the CB 2 agonist JWH133 (0.3, 1 and 3 mg/kg, IP) also produced anxiolytic-like effects in TMT-stressed rats, which were suppressed by AM630. Notably, (i) JWH133 was behaviorally ineffective in animals that had no prior experience with TMT; and (ii) CB 2 mRNA levels in rat prefrontal cortex were elevated 7 days after exposure to the aversive odorant. The results suggest that JZL184 attenuates the behavioral consequences of predator stress through a mechanism that requires 2-AG-mediated activation of CB 2 receptors, whose transcription may be induced by the stress itself. |
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