Effects of Endocannabinoid System Modulation on Cholinergic-Induced Anxiety-like Behaviors in Mice.

Kruk-Slomka M.; Slomka T.; Dzik A.; Biala G. · Pharmaceuticals (Basel, Switzerland) · 2026

**Background & Methods** This review evaluated how endocannabinoid system (ECS) modulation affects anxiety-like behaviors induced by cholinergic dysfunction in mice. Anxiety responses were assessed using the elevated plus maze (EPM) test following pharmacological modification of cholinergic neurotransmission via nicotine or scopolamine administration, with ECS modulation achieved through both direct cannabinoid receptor agonists/antagonists and indirect enzyme inhibitors. **Key Findings** • CB1 receptor agonist oleamide, FAAH inhibitor URB 597, and MAGL inhibitor JZL 184 successfully attenuated anxiety-like behaviors induced by nicotine administration in mice. • Oleamide, the dual CB1/CB2 agonist WIN 55,212-2, CB2 receptor antagonist AM 630, and JZL 184 all reduced anxiety responses triggered by scopolamine-induced cholinergic blockade. • Both direct ECS modulation (via selective cannabinoid receptor ligands) and indirect modulation (via endocannabinoid-degrading enzyme inhibition) demonstrated anxiolytic effects in the context of cholinergic dysfunction. **Dosage & Administration** Oleamide: 5 mg/kg; URB 597 (FAAH inhibitor): 0.1 mg/kg; JZL 184 (MAGL inhibitor): 20 mg/kg; WIN 55,212-2 (CB1/CB2 agonist): 0.25 mg/kg; AM 630 (CB2 antagonist): 0.25 mg/kg; Nicotine: 0.1 mg/kg; Scopolamine: 1 mg/kg. Routes of administration not specified. **Safety & Adverse Effects** Not reported. **Evidence Quality** This is a review article rather than original research, limiting direct clinical applicability. The study was conducted exclusively in mice, requiring substantial validation before translation to human populations. The findings suggest a promising mechanistic relationship between ECS and cholinergic pathways in anxiety regulation, but the evidence remains preclinical. Key limitations include the use of animal models that may not fully recapitulate human anxiety disorders, and the lack of information regarding potential adverse effects or optimal dosing strategies for clinical translation. The review provides a foundation for further investigation into targeted anxiolytic mechanisms but does not establish clinical efficacy or safety profiles in humans.

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