What topics does this cannabis study cover?

This study covers research on: THC, Anxiety, Mental Health, Neuroprotection, Endocannabinoid.

THC Anxiety Mental Health Neuroprotection Endocannabinoid

Synthetic cannabinoid linked to anxiety-like behavior in rats

Q: What did this research study find?

In a rat *drug-discrimination* model, **2 mg/kg *4F-ABUTINACA* fully substituted for *THC***, and the effect was partly inhibited by a *CB1 receptor* antagonist.

Q: Where was this research published?

Published in Zhejiang da xue xue bao. Yi xue ban = Journal of Zhejiang University. Medical sciences on September 21, 2026.

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

Zhejiang da xue xue bao. Yi xue ban = Journal of Zhejiang University. Medical sciences • September 21, 2026 • Highly Relevant

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AI Summary

This animal study asked whether the synthetic cannabinoid 4F-ABUTINACA produces THC-like effects and whether repeated exposure is linked to anxiety-like behavior in rats. Adult male rats were trained to recognize THC (2 mg/kg), and 4F-ABUTINACA was then tested for similar discriminative stimulus effects. A separate group received intraperitoneal 4F-ABUTINACA at 0.3 or 2 mg/kg for 15 consecutive days, with behavior assessed 1 or 20 days after the final dose. The higher dose fully substituted for THC in the discrimination test, and this effect was partly reduced by the CB1 receptor antagonist rimonabant.

Following repeated exposure, rats showed anxiety-like behavior during withdrawal-related testing, with effects varying by dose and time point. The changes were accompanied by persistent activation of glial markers in the hippocampus and alterations in proteins involved in excitatory and inhibitory signaling and synaptic plasticity. The authors therefore propose that hippocampal glial activation and disrupted synaptic plasticity may contribute to the observed behavior, and interpret the THC-like, CB1-linked effects as evidence suggesting abuse liability. This abstract-based summary cannot establish that the same effects occur in humans, that the molecular changes caused the behavior, or that the findings apply to regulated cannabis products.

💡 Key Findings

In a rat drug-discrimination model, 2 mg/kg 4F-ABUTINACA fully substituted for THC, and the effect was partly inhibited by a CB1 receptor antagonist.

High

90%

Repeated 4F-ABUTINACA exposure was followed by anxiety-like behavior in rats during short- and/or long-term withdrawal testing, depending on dose and behavioral measure.

High

80%

The behavioral changes were accompanied by sustained hippocampal glial activation and changes in markers of excitatory, inhibitory, and synaptic plasticity signaling.

High

80%

The findings suggest—not prove—that hippocampal glial activation and impaired synaptic plasticity may underlie the anxiety-like behavior and indicate potential abuse liability.

Good

70%

📄 Original Abstract

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. RESULTS: After stable THC (2 mg/kg) discrimination was established, 4F-ABUTINACA (2 mg/kg) produced full substitution for THC, and this discriminative stimulus effect was partially inhibited by rimonabant. In the low-dose 4F-ABUTINACA group, rats exhibited anxiety-like behavior in the open field test at short-term withdrawal, accompanied by increased hippocampal glial marker expression (P<0.05), decreased expression of N-methyl-D-aspartate receptor subunits 2A (NR2A) and 2B (NR2B) and synaptosome-associated protein 25 kDa (SNAP25) (all P<0.05), and increased expression of glutamate receptor, ionotropic, AMPA 1 (GluA1) (P<0.05). Decreased gephyrin expression was observed at both short-term and long-term withdrawal (all P<0.05), whereas decreased vesicular GABA transporter (VGAT) expression and increased GluA2 expression were observed at long-term withdrawal (P<0.05). In the high-dose 4F-ABUTINACA group, rats exhibited anxiety-like behaviors and increased hippocampal glial marker expression at both short-term and long-term withdrawal (P<0.05), along with decreased NR2A, NR2B, and gephyrin expression (all P<0.05). Additionally, GluA1 expression increased at short-term withdrawal (P<0.05), while VGAT expression in the DG and CA3 subregions and SNAP25 expression were decreased at long-term withdrawal (all P<0.05). 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. 目的: 明确4F-ABUTINACA的四氢大麻酚（THC）样辨别刺激效应，并探讨4F-ABUTINACA慢性给药诱发类焦虑行为的潜在作用机制。方法: 通过成年雄性大鼠THC药物辨别实验测定4F-ABUTINACA的THC样辨别刺激效应，并观察大麻素受体1（CB1）拮抗剂利莫那班对其辨别刺激效应的影响。另一批大鼠连续腹腔注射4F-ABUTINACA（大剂量组2 mg/kg，小剂量组0.3 mg/kg）15 d，分别在给药结束1 d（短期停药）或20 d后（长期停药）通过开放旷场实验和高架十字迷宫实验评估大鼠类焦虑行为;通过免疫荧光染色观察海马区胶质细胞激活以及抑制性突触标志物的表达变化;采用蛋白质印迹法检测海马突触可塑性相关蛋白质表达。结果: 大鼠形成稳定的THC（2 mg/kg）辨别反应，4F-ABUTINACA（2 mg/kg）能完全替代THC，且该辨别刺激效应可被利莫那班部分抑制。4F-ABUTINACA小剂量组停药后短期在开放旷场实验中表现出类焦虑行为、海马胶质细胞表达增加（均P<0.05），N-甲基-D-天冬氨酸受体2A亚基（NR2A）、NR2B及突触小体相关蛋白 25 000（SNAP25）表达减少（均P<0.05），离子型谷氨酸受体AMPA亚型1（GluA1）表达增加（P<0.05）;停药后短期、长期抑制性突触标志物桥尾蛋白（gephyrin）表达均减少（均P<0.05）;停药后长期囊泡γ氨基丁酸转运体（VGAT）表达减少（P<0.05），GluA2表达增加（P<0.05）。44F-ABUTINACA大剂量组停药后短期、长期均表现出类焦虑行为、海马脑区胶质细胞表达增加（P<0.05），NR2A、NR2B、桥尾蛋白表达减少（均P<0.05）;停药后短期GluA1表达增加（P<0.05），停药后长期DG和CA3亚区VGAT表达减少、SNAP25表达减少（均P<0.05）。结论: 4F-ABUTINACA能通过激活CB1受体产生类似THC的辨别刺激效应，其慢性给药致大鼠产生类焦虑行为机制可能与海马脑区胶质细胞持续激活及突触可塑性损伤有关。.

Paper Type

📄 Research

Publication

Journal: Zhejiang da xue xue bao. Yi xue ban = Journal of Zhejiang University. Medical sciences
Published: September 21, 2026
PMID: 42767823
DOI: 10.3724/zdxbyxb-2025-0891

Authors (4)

Baobao Shi College of Psychology and Mental Health, North China University of Science and Technology, Tangshan 063210, Hebei Province, China. baobao5212021@163.com.
Haitao Wang College of Psychology and Mental Health, North China University of Science and Technology, Tangshan 063210, Hebei Province, China.
Wenhua Zhou Zhejiang Provincial Key Laboratory of Addiction Research, Affiliated Kangning Hospital of Ningbo University, Ningbo 315201, Zhejiang Province, China.
Miaojun Lai Zhejiang Provincial Key Laboratory of Addiction Research, Affiliated Kangning Hospital of Ningbo University, Ningbo 315201, Zhejiang Province, China. micklai80@163.com.