ABSTRACT Membrane/lipid rafts (MLRs) are plasmalemmal microdomains that are essential for neuronal signaling and synaptic development/stabilization. Inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme-A reductase (statins) can disable the N-methyl-D-aspartate (NMDA) receptor through disruption of MLRs and, in turn, decrease NMDA-mediated anxiety. This hypothesis will contribute to understanding the critical roles of simvastatin in treating anxiety via the NMDA receptor.

Simvastatin is one of many hydroxymethylglutaryl-coenzyme-A reductase inhibitors that are prescribed to lower cholesterol. Some emerging evidence indicates that classical music can serve as an effective adjuvant in rats treated with simvastatin. Moreover, simvastatin and classical music have been shown to influence some cognitive functions. To further understand the mechanisms of action, we exposed rats to classical music for 1 month, and then treated them orally with simvastatin. The behavioral experiments suggested that exposure to subchronic simvastatin (1 or 10 mg/kg/day) reduced anxiety levels in the elevated plus-maze and open-field test in rats exposed to Mozart music. The recognition object test results indicated that simvastatin altered non-spatial working memory only at the 1 mg/kg/day dose and improved both short- and long-term object recognition. No significant differences were found between Mozart music and silence in the object recognition test, suggesting that music did not significant affect learning and memory in adult rats. We hypothesize that the anxiolytic, but not object-recognition memory, effects of simvastatin and classical music occur through similar mechanisms, providing an important foundation for future preclinical and clinical research.