The Role of 5-HT1A and 5-HT7 Receptors in Anxiety-like Behavior in Mice Treated with Subchronic Atorvastatin

The polypharmacology of statins includes indirect interactions with the serotonergic system, particularly with the 5-HT1A and 5-HT7 receptors. Statins influence both the expression and function of these receptors, which may affect the regulation of anxiety. The main objective of this study was to examine the effects of subchronic treatment with atorvastatin (STA) and acute treatment with serotonergic drugs on anxiety-like behavior, as well as their possible relationship to changes in the expression of 5-HT1AR and 5-HT7R in different brain regions of mice. In the first phase, the effect of STA (10, 20, or 30 mg/kg daily for 21 days) on anxiety-related exploratory behavior was assessed in male CD1 mice using the avoidance exploratory behavior test. Concurrently, receptor expression levels were measured in the prefrontal cortex, hippocampus, and striatum following STA administration. In the second phase, the effect of serotonergic drugs (0.5 or 1 mg/kg of 8-OH-DPAT, a 5-HT1A/5-HT7 receptor agonist, or WAY100635, a 5-HT1A receptor antagonist) on anxiety-related behaviors was studied in separate groups of animals, stratified by dose, that had previously been treated with or without STA. The persistence of the anxiogenic effect following serotonergic drug administration in mice previously treated with STA may be related to the increased mRNA expression of 5-HT1AR and 5-HT7R observed in the hippocampus, striatum, and prefrontal cortex, although confirmation at the protein level is needed in future studies.