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

Year: 2025

Type: article

Abstract: 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.

Source: Biomolecules

DOI: 10.3390/biom15030417

Authors: Evelin Vadas, Antonio J. López-Gambero, Antonio Vargas, Miguel Rodríguez-Pozo, Patricia Rivera, Juan Decara, Antonia Serrano, Stella Martín-de-las-Heras, Fernando Rodríguez de Fonseca, Juan Suárez

Institutions: Hospital Regional Universitario de Málaga, Andalusian Centre for Nanomedicine and Biotechnology, Instituto de Investigación Biomédica de Málaga, Université de Bordeaux, Inserm, Neurocentre Magendie, Universidad de Málaga

Language: English

Topic: Cannabis and Cannabinoid Research

Subfield: Pharmacology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $3,258

Funders: Fondation pour la Recherche Médicale, Junta de Andalucía, Plan Nacional sobre Drogas, Instituto de Salud Carlos III

OpenAlex ID: W4408441623