Carmen Mitchell

Statins are cholesterol lowering drugs and are the most widely prescribed class of drugs in the United States. In addition to their well-known vascular effects, statins produce a variety of unwanted neurological effects, including mood and cognitive irregularities. However, the mechanism behind the adverse neurological effects of statins are unknown despite their brainpermeability. To address this knowledge gap, this proposal examines the neuropharmacological effects of statins and more specifically, the effects of simvastatin on the serotonergic system in the brain. Serotonin neurotransmission is largely regulated by the serotonin transporter (SERT) and the regulation of SERT is the focus of the project. Results reveal a significant enhancement in the activity of SERT in neurons after statin treatment both in vitro in neuronal cell models and in vivo in rat brain tissue. Statin treatment increased SERT activity that was independent of cholesterol per se, but dependent on cholesterol biosynthetic precursor intermediates, farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP). Both FPP and GGPP are lipid signaling intermediates. These intermediates constitute the isoprenylation pathway, a biosynthetic pathway that diverges from cholesterol synthesis and is important for insertion of proteins into the plasma membrane where they act. The current role for the isoprenylation pathway in the regulation of SERT is unknown. The overall goal is to investigate isoprenylation intermediates involved in the modulation of SERT that could underlie the neurological consequences associated with statin drugs.