|Psychopharmacology (Berl). 2018 Sep 24. doi: 10.1007/s00213-018-5020-7. [Epub ahead of print]|
Effects of fatty acid amide hydrolase inhibitor URB597 in a rat model of trauma-induced long-term anxiety.
Danandeh A1, Vozella V1, Lim J1,2, Oveisi F1, Ramirez GL1, Mears D3,4, Wynn G4, Piomelli D5,6,7.
Department of Anatomy and Neurobiology, University of California, 3101 Gillespie NRF, Irvine, CA, 92697-4625, USA.
Department of Molecular & Cellular Biology, The University of Arizona, Tucson, AZ, USA.
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.
Department of Anatomy and Neurobiology, University of California, 3101 Gillespie NRF, Irvine, CA, 92697-4625, USA. firstname.lastname@example.org.
Department of Pharmacology, University of California, Irvine, CA, 92697, USA. email@example.com.
Department of Biological Chemistry, University of California, Irvine, CA, 92697, USA. firstname.lastname@example.org.
The endocannabinoid neurotransmitter, anandamide, has been implicated in the central modulation of stress responses. Previous animal experiments have shown that inhibitors of the anandamide-degrading enzyme, fatty acid amide hydrolase (FAAH), enhance the ability to cope with acute and chronic stress.
Here, we investigated the effects of the globally active FAAH inhibitor URB597 in a rat model of predator stress-induced long-term anxiety.
Rats exposed to 2,5-dihydro-2,4,5-trimethylthiazoline (TMT), a chemical constituent of fox feces, developed a persistent anxiety-like state, which was assessed 7 days after exposure using the elevated plus maze (EPM) test. Systemic administration of URB597 [0.03-0.1-0.3 mg/kg, intraperitoneal (ip)] 2 h before testing suppressed TMT-induced behaviors with a median effective dose (IC50) of 0.075 mg/kg. This effect was strongly correlated with inhibition of brain FAAH activity (r2?=?1.0) and was accompanied by increased brain levels of three FAAH substrates: the endocannabinoid anandamide and the endogenous peroxisome proliferator-activated receptor-a (PPAR-a) agonists, oleoylethanolamide (OEA), and palmitoylethanolamide (PEA). The anxiolytic-like effects of URB597 were blocked by co-administration of the CB1 receptor antagonist rimonabant (1 mg/kg, ip), but not of the PPAR-a antagonist GW6471 (1 mg/kg, ip). Finally, when administered 18 h after TMT exposure (i.e., 6 days before the EPM test), URB597 (0.3 mg/kg, ip) prevented the consolidation of anxiety-like behavior in a CB1-dependent manner.
The results support the hypothesis that anandamide-mediated signaling at CB1 receptors serves an important regulatory function in the stress response, and confirm that FAAH inhibition may offer a potential therapeutic strategy for post-traumatic stress disorder.
Neurotox Res. 2018 Aug 24. doi: 10.1007/s12640-018-9944-9. [Epub ahead of print]
Neuroprotective Action of the CB1/2 Receptor Agonist, WIN 55,212-2, against DMSO but Not Phenobarbital-Induced Neurotoxicity in Immature Rats.
Huizenga MN1, Forcelli PA2,3,4.
Department of Pharmacology and Physiology, Georgetown University, Washington, DC, 20007, USA.
Department of Pharmacology and Physiology, Georgetown University, Washington, DC, 20007, USA. email@example.com.
Department of Neuroscience, Georgetown University, Washington, DC, USA. firstname.lastname@example.org.
Interdisciplinary Program in Neuroscience, Georgetown University, Washington, DC, USA. email@example.com.
The developing brain is uniquely susceptible to drug-induced increases in programmed cell death or apoptosis. Many compounds, including anticonvulsant drugs, anesthetic agents, and ethanol, when administered in a narrow postnatal window in rodents, result in increased pruning of neurons. Here, we report that dimethyl sulfoxide (DMSO) triggers widespread neurodegeneration in the immature (postnatal day, P7) rat brain, an effect consistent with a prior report in neonatal mice. We found that the synthetic cannabinoid receptor agonist WIN 55,212-2 (WIN) exerts a neuroprotective effect against DMSO-induced cell death. We extended these findings to determine if WIN is neuroprotective against another drug class known to increase developmental cell death, namely antiseizure drugs. The antiseizure drug phenobarbital (PB) remains the primary treatment for neonatal seizures, despite significantly increasing cell death in the developing rodent brain. WIN exerts antiseizure effects in immature rodent seizure models, but increases the toxicity associated with neonatal ethanol exposure. We thus sought to determine if WIN would protect against or exacerbate PB-induced cell death. Unlike either the prior report with ethanol or our present findings with DMSO, WIN was largely without effect on PB-induced cell death. WIN alone did not increase cell death over levels observed in vehicle-treated rats. These data suggest that WIN has a favorable safety profile in the developing brain and could potentially serve as an adjunct therapy with phenobarbital (albeit one that does not attenuate PB-induced toxicity).