A low dose of Δ9-THC improves cognitive functions and synaptogenesis in old mice through an epigenetic mechanism

THC, the active ingredient of cannabis has been reported to impair learning and memory in humans and in laboratory animals when administered acutely. Unfortunately, most studies have been performed with young individuals although the activity of the endocannabinoid system changes during the aging process. Here we report that low doses of Δ9-THC (Delta-9-Tetrahydrocannabinol) improves learning and memory in old mice, enhances synaptic density, increases the expression of anti-ageing genes and decreases expression of pro-ageing genes in old but not in young animals. Δ9-THC elicited its beneficial effect through the CB1 receptors and increased histone acetylation was crucial for the long lasting effect. Elevation of the cannabinoid signaling may thus represent an exciting new approach to improve brain functions in old individuals. Three-five male 2- and 12-month-old C57BL/6J mice were chronically treated with 3 mg/kg/day Δ9-tetrahydrocannabinol through subcutaneously implanted osmotic minipump (Alzet, Cupertino, CA, model 1004, delivery speed: 0.11 µl/h) for 28 days. Control animals received vehicle (ethanol: cremophor: saline 1:1:18). Five days after termination of drug treatment the animals were tested in water-mate test (between day 33 and 41). Animals were sacrificed 5 days after the behavioural tests (day 46) by CO2 inhalation, decapitated and their hippocampi were isolated. The hippocampi were snap frozen in dry ice cooled isopentane and stored at -80C until further processing.