Neurosteroids and Alcohol Use Disorder - PROJECT ABSTRACT Expanding pharmacotherapeutic options and finding treatment response biomarkers for existing medications are both important for facilitating personalized medicine in alcohol use disorder (AUD). Accordingly, NIAAA advocates for research exploring the neurobiological mechanisms of AUD and recovery. Acamprosate, an FDA-approved antidipsotropic, has been suggested to modulate various neurotransmission systems including glutamate and GABA, yet its exact efficacy mechanisms remain speculative. Neuroactive steroids, including allopregnanolone (ALLO), play crucial roles in modulating GABAergic inhibition by binding to GABAA receptors. Given the disruption of GABAergic neurotransmission in AUD development and withdrawal, ALLO, acting as a positive allosteric modulator on GABAA receptors, may assist in restoring the balance between inhibition and excitatory neurotransmissions. ALLO, known for its anxiolytic, antidepressant, sedative, and anticonvulsant properties, experiences disrupted biosynthesis due to chronic alcohol consumption. Pregnenolone, its precursor, was shown to reduce craving and normalize autonomic arousal in AUD individuals, hinting at the potential contribution of ALLO and related neurosteroids to AUD development and recovery. However, clinical evidence regarding associations between ALLO, its GABAergic isomers, and precursors with AUD, including craving and treatment response to acamprosate, remains unknown. This project aims to explore the relationships between circulating neuroactive steroid levels and AUD, as well as AUD-related phenotypes, using existing AUD cohorts recruited for two NIAAA-funded clinical trials, including a discovery cohort (n = 297) and a validation cohort (n = 126). We will measure the serum levels of ALLO, its precursors, and its isomers by sensitive gas chromatography coupled with mass spectrometry. This neuroactive steroid panel will enable the evaluation of ALLO biosynthesis capacity and the excitation-inhibition balance on GABAA receptors. Specifically, we will investigate the association of serum ALLO and related neuroactive steroids with AUD by comparing these neuroactive steroid levels and their ratios between the discovery AUD cohort and age-and- sex-matched controls (Specific Aim 1). Focusing on the AUD cohort, we will examine the association of these neuroactive steroid levels and their ratios, with AUD-related phenotypes, including recent alcohol consumption, withdrawal symptoms, alcohol craving, sleep quality, and depression and anxiety levels, which were collected by widely used standardized questionnaires (Specific Aim 2). Finally, leveraging the follow-up clinical data and biospecimens collected, we will explore the associations of these neuroactive steroid levels and their ratios with treatment outcomes in individuals with AUD treated with acamprosate versus placebo (Specific Aim 3). This project will deepen the understanding of the effects of AUD and prolonged abstinence on the regulation of ALLO and related neuroactive steroids, thereby laying the groundwork for utilizing neuroactive steroids as biomarkers for treatment response and uncovering novel therapeutic mechanisms in AUD management.
