Mechanisms underlying the reduction in alcohol intake in response to low intensity targeting of the reward circuit

Alcohol use disorder (AUD) remains a major issue in the United States (US) despite the various laws, campaigns, and preventative efforts. Alcohol is by far the most commonly-abused drug across the lifespan. According to 2015 data from The National Survey on Drug Use and Health, there are currently 138 million alcohol users in the US, with almost half of drinkers reporting problem drinking (binge or heavy alcohol consumption), and 15.7 million reporting an AUD. A host of pharmaceutical targets have been identified, but treatment efficacy and abstinence rates both remain low due to factors such as cost, negative physiological effects, and requirements of long-term commitment to treatment. Thus, new directions for addiction treatment are needed. In one such direction, recent advances in ultrasound technology have enabled the non-invasive modulation of deep brain systems such as the reward circuit. We propose a novel combination of low intensity focused ultrasound (LIFU) with photoacoustic tomography (PAT) localization to modify the activity of the two primary components of the reward system, the ventral tegmental area and nucleus accumbens. Our preliminary work has demonstrated that this approach reduces alcohol intake and preference when administered once daily in either region. Thus, in the proposed studies, we will examine the mechanisms by which LIFU reduces alcohol intake, the longevity of this effect, and potential side effects of this treatment on the brain. We will first optimize our protocol for maximum efficacy in the deep brain regions of the reward circuit. Next, we will assess a variety of behaviors related to affect and to alcohol-seeking in order to identify the neurological processes on which LIFU is exerting its effects. Finally, we will assess the molecular effects in the brain following LIFU treatment, in order to identify those neuronal changes that may explain the behavioral shifts, and to determine whether there are any adverse effects on neuronal function following chronic LIFU treatment. For these studies, we will use male and female crossed high-alcohol-preferring mice, in order to identify whether there are sex-dependent differences in the effects of LIFU on alcohol-seeking, or in the neuronal effects of LIFU. These studies will provide an essential foundation of knowledge for the use of LIFU to reduce AUD, and will open the door to a wide spectrum of further studies examining other substance use disorders, and use of LIFU in traditionally difficult to treat populations, such as adolescents, or for disorders commonly comorbid with AUD, such as sleep disorders.