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Synthetic cannabinoid use raises concerns about its neuroinflammatory effects, including molecular adaptations of the endocannabinoid system (ECS) in the brain. This study investigates the pharmacological effects of 14-day repeated intraperitoneal administration, as well as 14-day administration followed by a 7-day withdrawal period of two synthetic cannabinoids: WIN55,212-2 and HU-210. The study assessed gene expression and protein markers related to the ECS, gliosis, and inflammation in two brain regions critical for cognitive processes and memory-key components of addiction pathways-the prefrontal cortex (PFC) and the hippocampus of rats. Our findings showed that repeated WIN55,212-2 administration induced adaptations in the ECS and reduced IBA1, a glial protein marker, along with inflammatory responses likely mediated through CB2 activity. Notably, regional differences emerged in the hippocampus, where repeated administration of WIN55,212-2 and HU-210 increased IBA1 and inflammatory markers, effects unrelated to CB2 activity. Withdrawal from WIN55,212-2 in the PFC, as well as from both compounds in the hippocampus, decreased IBA1 levels. This was associated with altered protein expression of cannabinoid-synthesizing and degrading enzymes, favoring acylethanolamide synthesis. These findings highlight region-specific effects of synthetic cannabinoids on cannabinoid signaling, gliosis, and inflammation. Further research is needed to elucidate the long-term neurobiological consequences of synthetic cannabinoid use and withdrawal.
Vadas et al. (Fri,) studied this question.