Inhibiting the enzyme fatty-acid amide hydrolase (FAAH) with URB597, which prevents the breakdown of the endocannabinoid anandamide, produces antidepressant-like effects in mice and rats. URB597 reduced immobility in the tail-suspension and forced-swim tests, and increased firing of serotonin and norepinephrine neurons in brain regions linked to mood. These effects required CB1 receptor activation and were accompanied by higher brain anandamide levels. Unlike direct THC-like drugs, URB597 showed no rewarding or abuse-related effects. The findings suggest FAAH inhibition as a potential target for antidepressant drugs without the psychotropic side effects of cannabis.
MDMA (ecstasy) neurotoxicity may involve nitrosative stress driven by the enzyme iNOS rather than by NOX enzymes that produce reactive oxygen species. In rats given MDMA, iNOS expression increased, and cells positive for 3-nitrotyrosine (a marker of nitrosative damage) rose in the frontal cortex. No changes occurred in NOX2, NOX1, or NOX4 immunoreactivity or in the oxidative stress marker 8OHdG. MDMA and nitrosative markers colocalized with dopamine-transporter-positive cells, which were neurons, not microglia or astrocytes. The findings indicate that iNOS-derived nitrosative stress, not NOX enzymes, likely contributes to MDMA-induced neurotoxicity.