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

Background: Anxiety disorders are clinically significant non-cognitive symptoms of many neuropsychiatric disorders, often accompanying progressive memory deficits and reflecting neurochemical dysregulation, particularly cholinergic dysfunction. Current therapy for these disorders is focused on the memory deficits but does not improve emotional symptoms and may even worsen anxiety. Therefore, novel therapeutic strategies are needed that address both cognitive and non-cognitive symptoms. Aim: Recent studies suggest that the endocannabinoid system (ECS) may play a key role in regulating cognitive and emotional processes, including anxiety. The aim of the study was to evaluate how direct (via selective ligands of cannabinoid CB1 and CB2 receptors) and indirect (via inhibitors of endocannabinoid-degrading enzymes-fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL)) modulation of ECS activity affects anxiety-like behaviors induced by pharmacological modification of cholinergic neurotransmission (by using nicotine or scopolamine). Methods: Anxiety-related behaviors were assessed in mice using the elevated plus maze (EPM) test. Results: CB1 receptor agonist oleamide (5 mg/kg), FAAH inhibitor URB 597 (0.1 mg/kg), and MAGL inhibitor JZL 184 (20 mg/kg) attenuated the anxiogenic effects of nicotine (0.1 mg/kg). Additionally, oleamide (5 mg/kg), CB1/CB2 receptor agonist WIN 55,212-2 (0.25 mg/kg), CB2 receptor antagonist AM 630 (0.25 mg/kg), and JZL 184 (20 mg/kg) attenuated the anxiogenic effects induced by scopolamine (1 mg/kg). Conclusions: Both direct and indirect ECS modulation demonstrated an impact on anxiety-like responses induced by cholinergic ligands. This potential relationship between ECS and cholinergic pathways provides additional insights into anxiety regulation and may represent a promising starting point for further research into targeted anxiolytic mechanisms in the central nervous system (CNS).