Alcohol dependence affects 18 million Americans. Treatments for alcohol dependence show only modest efficacy, and better treatments are needed. Systemic inflammation, neuroinflammation, and microglial activation may play a role in the pathogenesis of alcoholism. Our work and that of others has shown that systemic inflammation has important effects on the brain, including effects on motivation and emotion, and activation of microglia. In rodents, chronic alcohol exposure leads to activation of microglia, which release substances that cause neuronal dysfunction and death, e.g. inflammatory cytokines. Activation of microglia by pro-inflammatory signals, which are increased systemically in alcoholism, may be a mechanism through which alcohol interferes with neuronal function, thus contributing to craving and continued drinking. Rodent and postmortem human studies suggest this activation is a consequence of chronic alcohol drinking and that it is persistent. Positron emission tomography (PET) imaging of the Translocator Protein (TSPO) is used to measure the presence of activated microglia in the human brain in vivo. We found robust, higher binding of the TSPO radiotracer [ 11C]PBR28 in an alcohol-dependent vs. control subject, suggesting that PET imaging can be used to detect microglial activation in individuals with alcoholism in vivo. We propose to extend this exciting finding and assess microglial activation in alcohol-dependent individuals using [11C]PBR28, which has the highest specificity for TSPO of currently-available TSPO tracers, and the High Resolution Research Tomograph, the highest resolution human PET camera available. Alcohol-dependent (AD) subjects (n=15) will be matched with healthy control (HC) subjects (n=15) for age, sex, race and education level. A PET scan will be performed within 24 hours of their last drink. HC subjects will be assessed and scanned as outpatients. A subset of AD subjects (n=8) will be admitted to the inpatient research unit and will have a second PET scan 7 days later to assess short-term persistence of microglial activation. Behavioral ratings (craving, cognitive function, depression and anxiety) and blood cytokine levels will be obtained. [11C]PBR28 will be injected as a bolus, and a two-hour emission scan will be acquired on the HRRT. Volume of distribution (VT) will be estimated from the model fits for each region of interest and will be correlated with behavioral measures and cytokine levels (TNFalpha, IL-6). We hypothesize that as a consequence of chronic alcohol drinking, AD subjects will have significantly higher (>15%) levels of PBR28 binding vs. controls within 24 hours of the last drink and that this higher microglial activation will persist and remai higher 7 days later. If AD subjects have higher microglial activation, and this contributes to the core behaviors of alcoholism, pharmacological interventions that reduce microglial activation and neuroinflammation may be tested for the treatment of alcoholism.
In the U.S., 18 million people abuse alcohol, and their alcohol use has devastating consequences on their health, finances, employment, relationships, and longevity, causing emotional suffering, social isolation, and even suicide. Current treatments for alcohol dependence show only modest efficacy. If inflammation and activation of microglia contribute to alcohol dependence, this study could lead to new therapeutic approaches.
| Hillmer, A T; Sandiego, C M; Hannestad, J et al. (2017) In vivo imaging of translocator protein, a marker of activated microglia, in alcohol dependence. Mol Psychiatry 22:1759-1766 |
