Mechanisms of Alcohol Tolerance – United States

Deadline: 07-Sep-24

The National Institutes of Health has announced the applications for the Mechanisms of Alcohol Tolerance, a complex phenomenon in which increased alcohol intake is required to achieve a given effect, e.g., the feeling of intoxication, and is a defining feature of AUD.

Functional tolerance is further defined based upon the duration of alcohol exposure.

Acute tolerance develops during a single exposure to alcohol. Acute tolerance is also called within session tolerance, which is historically known as the Mellanby effect. Responses are measured minutes after alcohol administration and throughout the session.
Rapid functional tolerance, or intersessional tolerance, refers to the lessened response following a second or third exposure to alcohol at a time after the complete metabolism of an initial dose of alcohol, often within 24-36 hours.
Chronic tolerance develops after repeated episodes of alcohol intake and/or chronic exposure to alcohol over days or weeks.

Specific Areas

This FOA encourages studies that identify the mechanisms of sensitivity and tolerance in AUD in relation to other variables (e. g. sex, behavioral context, age) through an R21/R33 mechanism. The R21 phase is the first two (2) years of the application, while the R33 spans the following three (3) years.
There is little convergence of published parameters, drinking models and patterns, and assessment paradigms. The R21 phase supports re-analysis of data from human experimental paradigms leading to AUD, with the goal of developing new hypotheses and common experimental framework(s) to characterize the sensitivity and tolerance (including individual variations). While tolerance may not have been the goal of the previous research, measurements of blood alcohol concentrations, in addition to the behavioral or physiological measurements, may provide insight into the mechanisms of tolerance. Re-analysis of these data and new pilot studies, through the lens of understanding sensitivity and tolerance, have the potential to provide preliminary data to develop and test new hypotheses about the roles of sensitivity and tolerance. Topics include, but are not limited to, the following:
- Studies that determine the effects of sex, age, race/ethnicity, environmental context, metabolites, and dose on the response (sensitivity) to alcohol
- Studies that define common parameters leading to the acquisition of chronic tolerance, including factors that define response heterogeneity (genetics, epigenetic modifications, biomarkers (including metabolites), sex, race/ethnicity, and age)
- Studies that define overall exposure regimen (i.e. oral, intravenous, low dose, voluntary choice, binge drinking, self-administration, and periods of abstinence) and the effects of prediction and control (learning mechanisms) in alcohol tolerance, persistence, and extinction
- Development and testing of quantitative models describing the relationship between sensitivity and tolerance, defining relationships between acute, rapid, and chronic tolerance, and identify common and distinct mechanisms of sensitivity and forms of tolerance
- Examination of behavioral responses and neural circuitry following repeated periods of tolerance and abstinence and relationship to AUD and relapse
- Studies of adaptation of neural circuits of behavioral, emotional, and cognitive measures during acquisition and loss of tolerance, including molecular and cellular changes. The identification of adaptations leading to the allostatic state within a neural circuit or across neural circuits due to tolerance is of high programmatic priority
- Interactions of neural circuitry of the physiological responses of tolerance and the neural circuitry of AUD and relapse, including methods of electrophysiology and functional magnetic resonance imaging
- Studies that utilize state-of-the-art multi-omics approaches in humans to identify and validate molecular signaling, cellular and extracellular interactions, and epigenetic mechanisms, underlying sensitivity and tolerance to alcohol
- Studies that examine the interactions of metabolic and functional forms of tolerance, with special consideration to molecules involved in alcohol metabolism that are expressed in the brain

Objectives

The objectives for the R33 phase should be based on the findings from the R21 phase. Examples of the goals for the R33 phase include, but are not limited to:
- Generation of a quantitative model that predicts the influence of sensitivity or tolerance on the development of AUD
- Identification of the neurobiological mechanisms of sensitivity and tolerance
- Identification of points of prevention or intervention of alcohol misuse or alcohol use disorder, based on the sensitivity or tolerance criteria or mechanisms of acquisition of tolerance
- Identification of the molecular genetic bases for the individual differences in sensitivity and tolerance
- Studies of pharmacological targets or drug candidates for prevention of alcohol use disorder based on mechanisms of tolerance
Studies are encouraged to use existing data from one or more Principal Investigators to develop hypotheses of the roles of sensitivity and tolerance in AUD. Projects should include the following:
- Clear milestones for the R21 phase and related scientific goals for the R33 phase
- Identification of previous studies and data that will be used to generate or support hypotheses about sensitivity or tolerance. The heterogeneity of previous samples (i.e. subjects that did not meet criterion for AUD or relapse) should be considered
- Development of hypotheses of cellular and molecular mechanisms, signal transduction pathways, or network models for chronic tolerance

Funding Information

For the R21 phase, the combined budget for direct costs during the two-year project period may not exceed $275,000 with no more than $200,000 requested in a single year. For the R33 phase, the direct costs should not exceed $500,000 per year.
The project period is limited to 2 years for the R21 phase and up to 3 years for the R33 phase. The total project period may not exceed 5 years.

Eligibility Criteria

Higher Education Institutions
- Public/State Controlled Institutions of Higher Education
- Private Institutions of Higher Education
The following types of Higher Education Institutions are always encouraged to apply for NIH support as Public or Private Institutions of Higher Education:
- Hispanic-serving Institutions
- Historically Black Colleges and Universities (HBCUs)
- Tribally Controlled Colleges and Universities (TCCUs)
- Alaska Native and Native Hawaiian Serving Institutions
- Asian American Native American Pacific Islander Serving Institutions (AANAPISIs)
Nonprofits Other Than Institutions of Higher Education
- Nonprofits with 501(c)(3) IRS Status (Other than Institutions of Higher Education)
- Nonprofits without 501(c)(3) IRS Status (Other than Institutions of Higher Education)
For-Profit Organizations
- Small Businesses
- For-Profit Organizations (Other than Small Businesses)
Local Governments
- State Governments
- County Governments
- City or Township Governments
- Special District Governments
- Indian/Native American Tribal Governments (Federally Recognized)
- Indian/Native American Tribal Governments (Other than Federally Recognized)
Federal Governments
- Eligible Agencies of the Federal Government
- U.S. Territory or Possession
Other
- Independent School Districts
- Public Housing Authorities/Indian Housing Authorities
- Native American Tribal Organizations (other than Federally recognized tribal governments)
- Faith-based or Community-based Organizations
- Regional Organizations
- Non-domestic (non-U.S.) Entities (Foreign Institutions)