PROJECT 2: Imaging sex differences in stress-related cellular function in alcohol use disorder

PROJECT 2 ABSTRACT It is increasingly clear that women are more vulnerable than men to some of the negative effects of chronic alcohol consumption, including stress and immune system dysfunction. We have preliminary data indicating significantly greater neuroimmune impairment in females than males with alcohol use disorder (AUD), which is in line with the idea of greater vulnerability to the neurotoxic effects of alcohol in women vs. men. This is important since the rates of problem drinking in women are rapidly increasing, and the currently available treatments are only minimally effective. There is clear evidence that women and men drink for different reasons. Women tend to drink to regulate stress and negative affect, whereas men report drinking for alcohol- related positive reinforcement and stimulatory effects. This motivates a critical need to explore sex differences in stress-related neurochemical mechanisms underlying AUD to inform treatment approaches that are effective for women. The current project will focus on identifying sex differences in phosphodiesterase 4B (PDE4B), a regulator of intracellular signaling in the immune pathway, that has a demonstrated role in AUD and is a promising medication target. PDEs are enzymes that regulate the concentration of cyclic adenosine monophosphate (cAMP), a second messenger functioning as an intracellular signal. cAMP plays a key role in neuroimmune pathways including in the induction of anti-inflammatory responses and the resolution of inflammation, and cAMP-dependent pathways are critical in medications treating immune disease. PDE4B is the main PDE subtype involved in neuroimmune signaling and mood regulation and is located in microglia that are in brain regions regulating reward and affect. However, little is known about the role of PDE4B in people with AUD. Using state-of-the-art positron emission tomography (PET) brain imaging techniques with the new PDE4B-specific radiotracer [18F]PF-06445974 ([18F]PF974), we can measure PDE4B in the living human brain. In the current project, we propose to examine, for the first time, sex differences in PDE4B in the brains of females and males with AUD compared to control groups with [18F]PF974 and PET (Aim 1). We will examine relationships between PDE4B levels and clinical outcomes (Aim 2) and determine brain penetration of a PDE4B inhibitor (Aim 3) that has potential to treat AUD. Overall, we hypothesize that females with AUD will have greater deficits in PDE4B than males with AUD that are associated with greater stress-reactivity, mood impairment, and cognitive dysfunction. These findings could significantly advance the alcohol field by indicating PDE4B as a treatment target with potentially greater benefit to women with AUD.