Abuse Potential and Neurotoxic Effects of the Synthetic Cannabinoid 4F-ABUTINACA Self-Administration in Adult Male Rats.

4F-ABUTINACA, a fourth-generation synthetic cannabinoid, has been identified in branded herbal smoking mixtures and e-cigarettes seized in China. However, its potential for abuse and its corresponding neurotoxic effects remain poorly understood. In the present study, we evaluated the abuse potential of 4F-ABUTINACA using the intravenous self-administration (IVSA) model and assessed anxiety-like behaviour using the open-field test (OFT) and the elevated plus maze test (EPM). Additionally, neuronal injury, apoptosis, alterations in glia expression and the BDNF-TrkB-AKT signalling pathway in multiple brain regions were assessed simultaneously. Rats acquired stable nose-poke operant response for self-administering 4F-ABUTINACA (0.00625 mg·kg-1·infusion-1) and showed significant drug-seeking behaviour induced by conditioned cues. Persistent anxiety-like behaviours were observed both immediately after drug-taking (SA group) and cue-induced reinstatement testing after a 14-day extinction period (CIR group). Histochemical analysis revealed more pronounced neuronal injury and apoptosis in the hippocampus, prefrontal cortex (PFC) and nucleus accumbens (NAc) in the SA group than in the CIR group. Reactive astrogliosis and microgliosis were observed in the hippocampus and the PFC in the SA group, whereas the numbers of microglia and astrocytes decreased in the NAc of the CIR group. We also found the distinct region-specific alterations in the BDNF-TrkB-AKT signalling pathway expression profile between the SA and CIR groups. The present results demonstrate that 4F-ABUTINACA exhibits significant potential for abuse and produces anxiety-like behaviour during both the active drug-taking and cue-induced relapse stages, which are associated with the neuropathological alterations in specific brain regions.