Alcohol use disorder (AUD) is a chronic relapsing disease with a major public health impact. The development of efficacious medications to treat AUD is a crucial research priority. The identification of novel molecular targets and the development of compounds for these targets represents a critical goal in medications development. One promising treatment target is the modulation of neuroimmune function. Chronic alcohol consumption induces a proinflammatory state, such that individuals with AUD have increased neuroinflammation. Stress exposure also induces an inflammatory response in the brain and sensitizes behavioral responses to alcohol. This proposal is based on recent indications that ibudilast (IBUD), a neuroimmune modulator that targets neurotrophin signaling and neuroimmune function, represents a potentially efficacious medication for the treatment of AUD. In rodents, IBUD reduced alcohol intake and attenuated stress-induced relapse. In a human laboratory study, IBUD improved mood resilience during alcohol cue and stress exposure and decreased tonic levels of alcohol craving. These results indicate the IBUD is a promising alcohol addiction pharmacotherapy. However, the mechanisms of IBUD?s actions are not fully understood. The objective of this NRSA application is to foster my development as a clinical neuroscientist with a focus on medications development for AUD. This application proposes to add a novel neuroimaging protocol to the Sponsor?s (Dr. Lara Ray) newly funded R01, a 12-week, double-blind, placebo-controlled randomized clinical trial of ibudilast for AUD. The proposed study will investigate the effect of neuroimmune modulation through IBUD on neural response to alcohol cues and psychosocial stress in treatment-seeking individuals with AUD. Sixty-four treatment seeking participants with current AUD will complete 1 neuroimaging visit as part of the Week 4 follow-up visit for the R01 trial. During this visit participants will complete two neuroimaging paradigms evaluating neural responses to visual alcohol cues and psychosocial stress. Participants will complete bi-weekly reports of their drinking during the 12-week trial. Specifically, Aim 1 tests the hypothesis that IBUD will attenuate neural response to alcohol cues in reward circuitry compared to placebo.
Aim 2 tests the hypothesis that IBUD will reduce neural activation in the extended amygdala and prefrontal cortex to psychosocial stress compared to placebo. The Exploratory Aim tests the hypothesis that in IBUD-treated individuals, participants with lower neural ventral striatal activation to alcohol cues will have better drinking outcomes. The present study represents an important step in: 1) identifying the neural mechanisms underlying IBUD?s actions as an AUD treatment and 2) my scientific development and maturity as an independent clinical and translational alcohol researcher with an interest in medications development.
Chronic alcohol use and stress exposure both induce a pro-inflammatory response in the brain. Ibudilast, a neuroimmune modulator thought to reduce inflammation, has been proposed as a novel alcohol addiction pharmacotherapy. This proposal seeks to elucidate the effect of neuroimmune modulation through ibudilast on neural alcohol cue and stress reactivity in individuals with alcohol use disorder.
