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.
THC, the intoxicating component of cannabis, activates CB1 and CB2 cannabinoid receptors in the brain and body, affecting numerous physiological processes. The endocannabinoid system's functions change across the lifespan, with adolescence being a period of particular sensitivity. This article describes a protocol for preparing and administering THC to adolescent and young adult mice of both sexes via intraperitoneal injection at doses of 1, 5, and 10 mg/kg. The protocol illustrates THC's well-known effects: catalepsy, reduced locomotor activity, and suppressed nociception. Procedures for legally obtaining and storing THC in compliance with U.S. regulations are also outlined.
Adolescent female mice given Δ9-THC had eight times higher peak plasma concentrations than adult females, but adult females had 25-50% higher brain concentrations and brain-to-plasma ratios. Metabolite levels were higher in plasma but lower in brain of adolescents compared to adults. These age-dependent differences in how the drug is distributed and metabolized may affect its pharmacological effects.
The psychoactive component of cannabis, Δ9-tetrahydrocannabinol (THC), alters protein signaling in extracellular vesicles (EVs) in the brain. In cell cultures, THC activated choroid plexus epithelial cells, increasing cannabinoid 1 receptor and c-fos gene expression and releasing RNA-containing EVs. In male and female rats, acute or chronic exposure to aerosolized THC changed the protein composition of brain EVs in cerebrospinal fluid, with effects differing by sex and exposure duration. These results suggest that THC modulates intercellular communication in the brain through EV signaling, offering new insight into how external substances can influence brain signaling.