The effect of prolonged simvastatin application on serotonin uptake, membrane microviscosity and behavioral changes in the animal model

• Prolonged simvastatin treatment causes decrease of membrane microviscosity.
• Prolonged simvastatin treatment causes decrease of serotonin transporter activity.
• Behavioral changes after simvastatin treatment — anti-depressant effect?

Simvastatin and other statins (HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase inhibitors) are extensively used in clinical practices and are very effective in decreasing serum low-density lipoprotein cholesterol. However, their effect on cholesterol synthesis in central nervous system and its behavioral consequences have not been fully understood yet. We have studied selected biologic traits potentially affected by statin treatment — serotonin (5-HT) uptake in platelets, membrane microviscosity in erythrocytes, cholesterol level in the brain (amygdala; hippocampus and prefrontal cortex), as well as behavioral changes in an elevated plus maze and open field test in male Long-Evans rats, which were treated by simvastatin (30 mg/kg per day) for 2 or 4 weeks.We demonstrated: 1) a decrease in both serotonin transporter (SERT) activity and membrane microviscosity after treatment with simvastatin, 2) lower cholesterol content in all tested brain regions in animals from the simvastatin treated group, and 3) longer time spent in the open arms and a higher number of entrances to the closed arms in the elevated plus maze by animals from the simvastatin group compared to animals from the control group, but no differences in behavior in the open field test.Taken together, our results confirmed complex alterations, including behavioral changes, after the cholesterol lowering treatment. Furthermore, we discuss the possibility that the behavioral changes, traditionally interpreted as an anxiolytic effect, may be interpreted as increased impulsivity. We also confirmed that such behavioral changes may be attributed to changes in serotonergic neurotransmission.