Persistent brain alterations after adolescent exposure to the synthetic cannabinOid 5F-MDMB-PICA in male mice: a metabolomic fingerprint.

In the last decades, synthetic cannabinoid receptor agonists (SCRAs) have proliferated significantly outpacing toxicological characterization, global monitoring and regulatory plans. SCRAs widespread availability and misconceptions regarding their safety profile have driven an increase in consumption among adolescents posing a critical public health challenge. Here, we used a 1H Nuclear Magnetic Resonance (NMR)-based approach to investigate whether adolescent exposure to the SCRA 5F-MDMB-PICA induced metabolomic remodeling of selected brain regions detectable in adulthood. Thus, C57BL/6 male adolescent mice were exposed to 5F-MDMB-PICA (0.01mg/kg ip) for 14 consecutive days (from Post Natal Day 38 to 51). At 15 days after drug discontinuation, prefrontal cortex (mPFC), nucleus accumbens (NAc), caudate-putamen (CPu), and cerebellum (Cb) were analyzed. Results suggest that effects of 5F-MDMB-PICA adolescent exposure on the number of metabolites with significant treatment-associated changes are region-dependent (CPu > mPFC or Cb > NAc). In the CPu of adult mice exposed to 5F-MDMB-PICA during adolescence, we found increased GABA, O-phosphocholine, choline, and lysine, and decreased creatine, glutamate, glutamine, and lactate; in the mPFC, we found decreased glutamine and increased aspartate and in the Cb increased succinate and inosine. These data may be associated with alterations of mitochondrial respiration and neuron-astrocyte metabolic coupling with energetic deficits, neurotransmitter imbalances, and neuroinflammation. Of note, NAc exhibited a robust homeostatic buffering. Our results provide a basis for understanding detrimental effects from the use of SCRAs during adolescence and demonstrate a successful use of 1H NMR spectroscopy to capture metabolomic significant alterations of highly biological and toxicological interest.