mGluR5 binding as a specific biomarker for nicotine dependence and relapse in humans

Nicotine addiction is a major public health problem and increases the risk for various psychiatric conditions, including depression and schizophrenia. On a neurophysiological level, it is associated with aberrant glutamate activity. We recently showed marked global reductions in metabotropic glutamate receptor subtype 5 (mGluR5) binding in smokers and short-term ex-smokers. Now, we examined mGluR5 in long-term ex-smokers (abstinence>1.5y). In addition, we investigated the effects of chronic nicotine exposure (35 weeks in two groups using 4 and 8 mg/l nicotine) on mGluR5 binding in rats. In humans mGluR5 receptor binding was measured with the highly selective mGluR5 radioligand [11C]ABP688. In male Dark Agouti rats we used PET with the novel mGluR5 radiotracer [18F]PSS232. Long-term ex-smokers and individuals who had never smoked showed no differences in mGluR5 binding in any of the brain regions examined. Long-term ex-smokers showed significantly higher mGluR5 binding than recent ex-smokers, most prominently in the frontal cortex (42%) and the thalamus (57%). At follow-up we found a tendency for lower mGluR5 binding in relapsed vs. abstinent ex-smokers. In rats, we demonstrated that nicotine consumption reduces mGluR5 binding, although this effect did not follow a linear dose-response-type relationship. In a series of studies we provided evidence for a downregulation of mGluR5 as a pathological mechanism involved in nicotine dependence and the relapse to smoking. Altogether, these findings suggest that mGluR5 binding is a clinically relevant biomarker for the course of nicotine addiction and a promising target for the discovery of novel drugs against nicotine dependence and other substance-related disorders.