P01AA027473-06 (former grant P50DA033945-06)
DATES: Sept 2018- Aug 2020
TITLE: SEX-APPROPRIATE TREATMENT DEVELOPMENT FOR ALCOHOL USE DISORDERS
Dr. Clayton (ORWH Director) has stated that “accounting for sex as a biological variable (SABV) in biomedical research will produce robust and relevant new discoveries about basic biology and help to inform sex-appropriate individualized health care for women and men.”
Our P01 was funded in September 2018 to in response to RFA-OD-18-004. We were awarded P01 funds (from ORWH and NIAAA) to provide moderate support to maintain our investigative team and to support the collection of additional pilot data.
PROJECT 1: Marina Picciotto PhD & Yann Mineur PhD
GUANFACINE EFFECTS ON AUD AND NEURAL CORRELATES IN FEMALE AND MALE MICE
Alcohol use disorders (AUD) remain a significant problem for both women and men but stress and negative affect contribute to the initiation, maintenance of, and relapse to alcohol use in women, more so than for men. In Project 1, we will obtain preliminary data to 1) determine if guanfacine alters choice and stress-induced ethanol preference in male and female mice using a two-bottle choice drinking paradigm that is sensitive to stress, and 2) begin to determine the effects of α2A adrenergic receptors and GABA neuron activity on ethanol-induced microglia alteration and synaptic density in female and male mice.
PROJECT 2: Kelly Cosgrove PhD
IMAGING SEX DIFFERENCES IN THE NEUROCHEMICAL MECHANISMS OF ALCOHOL USE DISORDERS
It is increasingly clear that women are more vulnerable than men to some of the negative effects of chronic alcohol consumption, including immune system dysfunction and neurodegeneration. Project 2 will focus on identifying sex differences in biomarkers of alcohol-induced neurodegeneration that lead to neural adaptations that drive the addiction cycle. In the current study, we will collect pilot data to examine whether chronic alcohol consumption is associated with reductions in microglia (Aim 1) and synaptic density (Aim 2) and if the impairment varies by sex.
PROJECT 3: Sherry McKee PhD
EVALUATION OF GUANFACINE ON DRINKING BEHAVIOR IN WOMEN AND MEN WITH ALCOHOL USE DISORDERS
Several lines of evidence indicate that drinking behavior in women is more likely to be motivated by affect regulation and stress, whereas drinking in men is motivated by stimulation and alcohol-related positive reinforcement. Project 3 will collect preliminary data for a Phase 2b double-blind, placebo-controlled, parallel-group study to examine sex differences in guanfacine's effect on 1) counteracting stress- and stimulation-based drinking behavior in the laboratory and 2) improving clinical outcomes during a subsequent treatment phase.
We have a pending U54 application in response to RFA-OD-19-013
Our proposed Yale-Specialized Center of Research Excellence (SCORE) on sex differences in alcohol use disorder (AUD) brings together a team of leading basic and clinical science experts to pursue an interdisciplinary, translational, cross-species program of research aimed at identifying novel therapeutics to address the recent surge in rates of AUD in women.
Over the past 10 years, rates of AUD in women have increased by 84%, translating to 10.5 million women across the United States. Alcohol use is the third leading cause of preventable morbidity and mortality in the United States and women drinkers experience exacerbated health risks associated with alcohol consumption when compared to men. FDA-approved medications for AUD have relatively low efficacy, all were developed with samples of men, and none target factors that differentially maintain drinking in women.
A considerable body of data identifies that women are more likely to drink to regulate negative affect and stress, while men are more likely to drink for alcohol-related positive reinforcement. Koob & Volkow have developed a heuristic framework of the addiction cycle, where the ‘withdrawal/negative affect stage’ involves drinking motivated by stress and other negative affect states, also termed ‘the dark side of addiction’. Neuroadaptations during this stage identify reward deficits and stress surfeits, which drive compulsive drinking. Using this negative reinforcement model to guide our research, we plan to target key brain structures, neurochemical systems, HPA-axis activity, neuroimmune function, alcohol metabolism, and sex steroid hormones, which are hypothesized to differentially motivate alcohol consumption in women.
To date, there has not been a concerted effort to incorporate sex as a biological variable (SABV) into AUD medication development. Consequently, the focus of our Yale-SCORE represents a high research priority topic for both NIAAA and ORWH. We propose three Projects that will have inter-related and shared goals, with each providing unique contributions to inform and expedite the development of AUD therapeutics for women with AUD.
The Projects will be supported by three Cores and an institutional environment with exceptional resources and infrastructure to support translational science.
Our specific aims and objectives of the Yale-SCORE are to:
- AIM 1: Use a neurobiologically-informed approach focusing on the ‘dark side of addiction’ to inform and expedite the development of sex-appropriate therapeutics targeting stress and negative affect, which differentially maintain drinking in women.
- AIM 2: Mentor SCORE-Early Investigators to become the next generation of biomedical and behavioral researchers focused on alcohol and women’s health spanning the T1 to T4 translational spectrum.
- AIM 3: Be an institutional, regional, and national resource galvanizing the study of sex differences in relation to alcohol use across T1 to T4 translation by providing expert consultation, supporting faculty training awards, leveraging national data on sex and alcohol use to inform treatment and policy, and providing a program of outreach and dissemination.