Alcohol and Comorbid Tobacco Use Disorders: PET Imaging of Glutamate System Effects

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 DESCRIPTION (provided by applicant): Alcohol and tobacco use disorders are serious public health problems, but only a small number of medications are approved for treatment of either disorder. There is a pressing need to identify new neurotransmitter targets for medication development. There is clear preclinical and emerging clinical evidence that the glutamate (Glu) system plays a central role in development and maintenance of regular alcohol and nicotine use, withdrawal and reinstatement after a period of abstinence. Pre-clinical studies have demonstrated a specific role for the metabotropic glutamate receptor, type 5 (mGluR5). This study will examine the mGluR5 receptor in persons with alcohol use disorder (AUD) compared with age-matched healthy controls (HC) and persons with tobacco use disorder (TUD); it also will clarify the effects of smoking and TUD in the AUD population. Positron emission tomography (PET), using the specific mGluR5 radioligand [18F]FPEB, will quantify mGluR5 binding potential (BPND), a PET-derived measure that relates to receptor availability and density. Specifically, aim 1 will compare mGluR5 BPND in non-treatment seeking AUD (N=80) versus HC participants (N=40). Additionally, among AUD subjects, smokers (AUD+TUD; N=40) will be compared with nonsmokers (AUD only; N=40) (aim 2), and TUD only participants (N=40) will be compared with AUD+TUD (N=40) and HC participants (N=40) (aim 3). All participants will complete standardized assessment procedures to characterize alcohol and tobacco use history. Eligible AUD participants will be admitted to the Clinical Research Unit (CRU) and complete a three day, unmedicated alcohol detoxification; smokers will maintain their usual quantity/frequency of cigarette use; measures of alcohol withdrawal and craving as well as mood will be obtained. On day 4, AUD subjects complete PET measurement of mGluR5 BPND. On day 5, AUD subjects participate in an alcohol-motivated progressive ratio procedure to quantify extent of responding for and consumption of alcohol. In addition to the between-group comparisons, we will examine relationships between [18F]FPEB BPND and CRU measures of alcohol withdrawal and craving (aim 4), amount of alcohol-motivated responding (aim 5), as well as baseline assessment measures of amount and frequency of alcohol and tobacco use (aim 6). To date, therapeutic benefit of clinically approved or investigational AUD medications has been modest. However, there are multiple lines of evidence indicating that the mGluR5 site is highly sensitive in animal models, and shows promise as a target for treatment. This proposal will be the first to characterize mGluR5 in living humans with AUD, to clarify the modulating role of tobacco use in this population and to examine the relationship of mGluR5 to key behavioral measures of alcohol and tobacco use. Importantly, mGluR5 negative allosteric modulators (NAMs) are in development by several drug companies and are undergoing clinical trials for several psychiatric diseases. This proposed study will set the stage for future research to directly test the therapeutic effects of mGluR5 NAMs on brain mGluR5 occupancy and behavioral outcomes in AUD clinical population.