Molecular Imaging Studies of Alcohol Use Disorder.

Abstract

Alcohol use disorder (AUD) is a serious public health problem in many countries, bringing a gamut of health risks and impairments to individuals and a great burden to society. Despite the prevalence of a disease model of AUD, the current pharmacopeia does not present reliable treatments for AUD; approved treatments are confined to a narrow spectrum of medications engaging inhibitory γ-aminobutyric acid (GABA) neurotransmission and possibly excitatory N-methyl-D-aspartate (NMDA) receptors, and opioid receptor antagonists. Molecular imaging with positron emission tomography (PET) and single-photon emission computed tomography (SPECT) can open a window into the living brain and has provided diverse insights into the pathology of AUD. In this narrative review, we summarize the state of molecular imaging findings on the pharmacological action of ethanol and the neuropathological changes associated with AUD. Laboratory and preclinical imaging results highlight the interactions between ethanol and GABA A-type receptors (GABA_AR), but the interpretation of such results is complicated by subtype specificity. An abundance of studies with the glucose metabolism tracer fluorodeoxyglucose (FDG) concur in showing cerebral hypometabolism after ethanol challenge, but there is relatively little data on long-term changes in AUD. Alcohol toxicity evokes neuroinflammation, which can be tracked using PET with ligands for the microglial marker translocator protein (TSPO). Several PET studies show reversible increases in TSPO binding in AUD individuals, and preclinical results suggest that opioid-antagonists can rescue from these inflammatory responses. There are numerous PET/SPECT studies showing changes in dopaminergic markers, generally consistent with an impairment in dopamine synthesis and release among AUD patients, as seen in a number of other addictions; this may reflect the composite of an underlying deficiency in reward mechanisms that predisposes to AUD, in conjunction with acquired alterations in dopamine signaling. There is little evidence for altered serotonin markers in AUD, but studies with opioid receptor ligands suggest a specific up-regulation of the μ-opioid receptor subtype. Considerable heterogeneity in drinking patterns, gender differences, and the variable contributions of genetics and pre-existing vulnerability traits present great challenges for charting the landscape of molecular imaging in AUD.