Region-Specific Impact of Repeated Synthetic Cannabinoid Exposure and Withdrawal on Endocannabinoid Signaling, Gliosis, and Inflammatory Markers in the Prefrontal Cortex and Hippocampus

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.