Anxiety-like behaviors induced by chronic administration of the synthetic cannabinoid 4F-ABUTINACA in rats and the underlying mechanisms

OBJECTIVES: To elucidate the Δ⁹-tetrahydrocannabinol (THC)-like discriminative stimulus effects of 4F-ABUTINACA and to investigate the potential mechanisms underlying anxiety-like behaviors induced by chronic 4F-ABUTINACA administration. METHODS: A THC drug discrimination procedure was used in adult male rats to evaluate the THC-like discriminative stimulus effects of 4F-ABUTINACA and the effects of the cannabinoid receptor type 1 (CB1) antagonist rimonabant on these effects. In a separate cohort, rats received intraperitoneal injections of 4F-ABUTINACA at a high dose (2 mg/kg) or a low dose (0.3 mg/kg) for 15 consecutive days. Anxiety-like behaviors were assessed using the open field test and elevated plus maze at 1 day (short-term withdrawal) and 20 days (long-term withdrawal) after the final administration. Immunofluorescence staining was used to examine glial cell activation and changes in inhibitory synaptic markers in the hippocampus. Western blotting was performed to detect the expression of synaptic plasticity-related proteins in the rat hippocampus. CONCLUSIONS: 4F-ABUTINACA produces THC-like discriminative stimulus effects via CB1 receptor activation, suggesting that it has abuse liability. Chronic 4F-ABUTINACA administration induces anxiety-like behaviors in rats, and the underlying mechanism may involve sustained hippocampal glial activation and impaired synaptic plasticity.