[Anxiety-like behaviors induced by chronic administration of the synthetic cannabinoid 4F-ABUTINACA in rats and the underlying mechanisms].
Baobao Shi, Haitao Wang, Wenhua Zhou, Miaojun Lai
Zhejiang da xue xue bao. Yi xue ban = Journal of Zhejiang University. Medical sciences September 25, 2026 DOI: 10.3724/zdxbyxb-2025-0891 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental animal study Peer reviewed |
|---|---|
| Sample size | 54 |
| Population | Adult male Sprague-Dawley rats |
| Interventions | 4F-ABUTINACA THC rimonabant |
| Dose | 4F-ABUTINACA 0.3 mg/kg and 2.0 mg/kg; THC 2.0 mg/kg |
| Duration | 15 consecutive days of injection; behavioral testing on day 21 (short-term withdrawal) and day 40 (long-term withdrawal) |
| Measures | Drug discrimination procedure, open field test (OFT), elevated plus maze (EPM) test, immunofluorescence staining, Western blotting |
| Topics | Neuroplasticity Anxiety |
| Keywords | 4f-abutinaca Anxiety-like behavior Glial cells Sprague-dawley rats Synthetic cannabinoid |
| Key findings | 4F-ABUTINACA produced full substitution for THC's discriminative stimulus effects, partially inhibited by rimonabant, suggesting THC-like effects via CB1 receptor activation and possible abuse liability. Chronic administration induced anxiety-like behaviors and hippocampal neuroinflammation and synaptic changes; at long-term withdrawal, neuroinflammation and synaptic damage persisted in the high-dose (2.0 mg/kg) group but largely recovered in the low-dose (0.3 mg/kg) group. |
Abstract
To elucidate the Δ9-tetrahydrocannabinol (THC)-like discrimina-tive stimulus effects of 4F-ABUTINACA and to investigate the potential mechanisms underlying anxiety-like behaviors induced by chronic 4F-ABUTINACA administration. A THC drug discrimination procedure was employed in six adult male Sprague-Dawley rats to assess the THC-like discriminative stimulus effects of 4F-ABUTINACA and to observe the effects of the cannabinoid receptor type 1 (CB1 receptor) antagonist rimonabant on these effects. A separate cohort of 48 rats underwent 5 days of adaptive feeding and was randomly divided into three groups (n=16 per group): vehicle control group, 4F-ABUTINACA low-dose group (0.3 mg/kg), and 4F-ABUTINACA high-dose group (2.0 mg/kg). All rats received intraperitoneal injections of vehicle or 4F-ABUTINACA for 15 consecutive days. Anxiety-like behaviors were assessed using the open field test (OFT) and elevated plus maze (EPM) test on day 21 (short-term withdrawal) and day 40 (long-term withdrawal). 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. After stable THC (2.0 mg/kg) discrimination was established, 4F-ABUTINACA (2.0 mg/kg) produced full substitution for THC, and this discriminative stimulus effect was partially inhibited by rimonabant. At short-term withdrawal, the low-dose 4F-ABUTINACA group exhibited anxiety-like behaviors in the OFT, whereas the high-dose group showed such behaviors in both the OFT and the EPM test; at long-term withdrawal, only the high-dose 4F-ABUTINACA group exhibited anxiety-like behaviors in the EPM test. At short-term withdrawal, both low-dose and high-dose 4F-ABUTINACA exposure induced hippocampal neuroinflammation [increased ionized calcium-binding adaptor molecule 1 (IBA-1)-positive cell counts and glial fibrillary acidic protein (GFAP) expression], altered synaptic receptors expression [decreased N-methyl-D-aspartate receptor (NMDAR) 2A and NMDAR2B levels, increased glutamate receptor ionotropic AMPA type subunit 1 (GluA1) levels in both groups, as well as decreased synaptosome-associated protein 25 (SNAP25) levels in the low-dose group], and inhibitory synaptic damage [decreased gephyrin levels, with decreased vesicular GABA transporter (VGAT) levels also observed in the high-dose group], with some changes being more pronounced in the high-dose group. At long-term withdrawal, the neuroinflammatory indicators in the low-dose 4F-ABUTINACA group had largely recovered, whereas neuroinflammation persisted in the high-dose group (IBA-1-positive cell counts and GFAP expression remained elevated), accompanied by more extensive synaptic damage (decreased NMDAR2A, NMDAR2B, and SNAP25 levels) and inhibitory synaptic damage. 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 upregulation of microglial and astrocytic markers and impaired synaptic plasticity in the hippocampus.
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