4F-ABUTINACA self-administration in rats induces abuse potential, anxiety, and neurotoxic brain damage

Synthetic cannabinoids (SCs) are a diverse class of psychoactive substances often found in illicit herbal mixtures and e-cigarettes, posing significant public health risks. While their effects are primarily mediated by cannabinoid receptor type 1 (CB1) and cannabinoid receptor type 2 (CB2), the specific abuse potential and neurotoxic profiles of newer SCs like 4F-ABUTINACA remain largely uncharacterized. Understanding these effects is crucial, especially given the widespread availability and potential for severe neurological consequences, which current standard-of-care for SC intoxication often struggles to mitigate effectively without specific mechanistic insights.

Researchers evaluated the abuse potential of 4F-ABUTINACA in adult male rats using an intravenous self-administration (IVSA) model. Rats were trained to nose-poke for 4F-ABUTINACA (0.00625 mg·kg-1·infusion-1). Anxiety-like behaviors were assessed using the open-field test (OFT) and elevated plus maze (EPM) immediately after drug-taking (SA group) and after a 14-day extinction period followed by cue-induced reinstatement (CIR group). Neuronal injury, apoptosis, glial expression, and BDNF-TrkB-AKT signaling pathway alterations were analyzed via histochemical methods across multiple brain regions.

Rats successfully acquired stable operant responses for self-administering 4F-ABUTINACA, demonstrating significant drug-seeking behavior when exposed to conditioned cues. Persistent anxiety-like behaviors were observed in both the SA group (immediately after drug-taking) and the CIR group (after a 14-day extinction period and cue-induced reinstatement). Histochemical analysis revealed more pronounced neuronal injury and apoptosis in the hippocampus, prefrontal cortex (PFC), and nucleus accumbens (NAc) in the SA group compared to the CIR group. Reactive astrogliosis and microgliosis were evident in the hippocampus and PFC of the SA group, while microglia and astrocytes decreased in the NAc of the CIR group. > Distinct, region-specific alterations in the BDNF-TrkB-AKT signaling pathway expression profile were also identified between the SA and CIR groups, indicating complex neurobiological changes.