Chronic exposure to a synthetic cannabinoid alters cerebral brain metabolism and causes long-lasting behavioral deficits in adult mice

In recent years, there has been growing evidence that cannabinoids have promising medicinal and pharmacological effects. However, the growing interest in medical cannabis highlights the need to better understand brain alterations linking phytocannabinoids or synthetic cannabinoids to clinical and behavioral phenotypes. Therefore, the aim of this study was to investigate the effects of long-term WIN 55,212-2 treatment-with and without prolonged abstinence-on cerebral metabolism and memory function in healthy wildtype mice. Adult C57BI/6J mice were divided into two treatment groups to study the acute effects of WIN 55,212-2 treatment as well the effects of WIN 55,212-2 treatment after an extended washout phase. We could demonstrate that 3 mg/kg WIN 55,212-2 treatment in early adulthood leads to a hypometabolism in several brain regions including the hippocampus, cerebellum, amygdala and midbrain, even after prolonged abstinence. Furthermore, prolonged acute WIN 55,212-2 treatment in 6-months-old mice reduced the glucose metabolism in the hippocampus and midbrain. In addition, Win 55,212-2 treatment during adulthood lead to spatial memory and recognition memory deficits without affecting anxiety behavior. Overall we could demonstrate that treatment with the synthetic CB1/CB2 receptor aganist Win 55,212-2 during adulthood causes persistent memory deficits, especially when mice were treated in early adulthood. Our findings highlight the risks of prolonged WIN 55,212-2 use and provide new insights into the mechanisms underlying the effects of chronic cannabinoid exposure on the brain and behavior.