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Background: 5F-CUMYL-PeGACLONE (5F-CP) is a novel synthetic cannabinoid containing a 5-fluoropentyl side chain and previous studies have suggested that its toxic effects are not restricted to the nervous system. Synthetic cannabinoids primarily act via the cannabinoid receptor type 1 (CB1) pathway; CB1 activation is generally associated with increased hepatic lipid production. However, emerging evidence suggest that its regulatory effects may vary under different physiological conditions.
Methods: Male C57BL/6J mice (8 weeks old) were administered 5F-CP (0.1 mg/kg, ip) once daily for five days. AM251 was administered 20 minutes before 5F-CP. Hypothermia, catalepsy, and hypolocomotion were assessed after the first and final administrations. 5 hours after the final administration, the mice were sacrificed, and their livers and serum were collected. The serum samples were used for biochemical analyses. The expression levels of target genes involved in hepatic lipid and energy metabolism were quantified using real-time RT-PCR.
Results: Repeated 5F-CP administration induced tolerance to typical cannabinoid effects (catalepsy, hypothermia, and hypolocomotion). Serum alanine aminotransferase and aspartate aminotransferase levels increased, accompanied by reduced serum triglyceride and high-density lipoprotein cholesterol levels. In the liver, the expression of genes involved in lipid uptake, transport, and de novo lipogenesis decreased, whereas phosphorylated AMP-activated protein kinase (AMPK) levels were elevated. Cholesterol synthesis was also downregulated in the liver.
Conclusions: Under normal physiological conditions, repeated low-dose exposure to 5F-CP induced behavioral tolerance and altered hepatic lipid and cholesterol metabolism. Moreover, AMPK, a key regulator of energy metabolism was activated suggesting potential systemic metabolic consequences beyond behavioral tolerance.
