Long term administration of HMG-COA-reductase inhibitor [simvastatin] affects brain serotonin neurotransmission in male rats

ABSTRACT

Simvastatin, an important member of statin family is widely prescribed as cholesterol-lowering agent. Like other statins it acts by inhibiting the rate limiting enzyme 3-hydroxy-3-methylglutaryl-CoA [HMG-CoA] reductase, responsible for the endogenous production of cholesterol which forms an essential part of neuronal cell membranes. Lowering of cholesterol has been reported to alter the brain chemistry and hence neurotransmission. To understand the association between low cholesterol and brain serotonin [5-HT] we monitored the effect of oral administration of simvastatin for 4 weeks on brain serotonin levels. Drug treated rats exhibited significantly low plasma cholesterol levels. Brain serotonin and 5- HIAA[5-hydroxyindole acetic acid] levels were also decreased in drug treated rats. Plasma tryptophan [TRP] was significantly increased but brain tryptophan levels were significantly decreased in drug treated rats. Weekly food intake during the entire experimental period was comparable in control and drug treated rats. Results of the present study suggest that simvastatin induced lowering of cholesterol may be responsible for the decrease in brain 5-HT neurotransmission and hence may be a cause of depression observed in subjects taking simvastatin to lower cholesterol levels