NIH – Mechanisms of Alcohol Tolerance (R21/R33 Clinical Trial Not Allowed)

February 22, 2018 by

While many Americans imbibe in alcoholic beverages, for some, drinking becomes problematic, potentially leading to an alcohol use disorder (AUD). The response to the initial alcohol experiences, sometimes known as sensitivity, may predict AUD later in life. Low sensitivity is associated with high probability of developing an AUD. Following initial exposure, responses to alcohol change with subsequent drinking. Alcohol tolerance is 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. Stated in another way, tolerance decreases the effect of a defined alcohol dose. Alcohol sensitivity and tolerance vary in the population, yet, research on underlying mechanisms is sparse and findings are disparate. Experimental subjects vary in age, sex, previous alcohol exposure, drinking context and genetics. Response variables are often subjective, while objective measures are not comparable between studies of the same species or cross-species. The goal of this FOA is to build a framework for the systematic analysis of the factors that contribute to alcohol sensitivity and tolerance and the mechanisms that regulate tolerance and transition to alcohol dependence.

In contrast to the scarcity of studies directly addressing mechanisms of tolerance, there is an abundance of behavioral and physiological data from subjects with AUD or alcohol dependence, and thus alcohol tolerance. Clinical studies include retrospective data regarding the need to increase the number of drinks over time for the same effect. In animal models, responses to alcohol exposure paradigms (e.g., including changes in blood alcohol concentrations, and changes in behavioral and physiological measurements with subsequent alcohol intake), may vary within a cohort, representing differences in sensitivity and tolerance. The clinical studies and reports of animal models of drinking behavior usually focus on the withdrawal, relapse and re-instatement phases of AUD, but the same models and data can inform tolerance and progression to dependence.

The physiological nature of tolerance has been classified as either metabolic or functional. Metabolic tolerance describes changes in efficiency or capacity to metabolize ethanol resulting in a decrease in the blood alcohol concentration following a given dose of alcohol. Functional tolerance refers to lessened response to alcohol independent of the rate of metabolism of alcohol. Little is known about the interplay between metabolic and functional tolerance, as many of the molecules that metabolize alcohol in the liver are expressed in the nervous system.

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.

Different time frames for the forms of tolerance suggest separate underlying mechanisms. Tolerance diminishes after periods of abstinence, and thus, an individual may experience multiple episodes of tolerance. The dependence of the alcohol responses on previous periods of alcohol exposure, context(s), and abstinence has not been systematically studied under the framework of tolerance, nor have relationships between acute, rapid or chronic tolerance been well studied. It is unknown whether the common mechanisms mediate multiple forms of tolerance.

Sensitivity and tolerance are assessed by multiple methods. For human subjects, measurements include self-reported number of drinks to achieve intoxication, cortisol levels, or electrophysiological changes. Brain imaging studies have combined blood (or breath) alcohol concentration with self-reported assessment of intoxication, performance on cognitive and memory tasks with blood oxygen level-dependent response and functional connectivity measures. Recent studies of tolerance measured drinking and blood alcohol concentrations in complex motor and cognitive tasks, such as driving simulators. Animals studies focus on motor and physiological responses such as loss of righting reflex and hypothermia, but there are few reports of effects on cognition or learning and memory function.

The development of tolerance requires a compensatory response. For example, to overcome the alcohol induced hypothermia, the animal increases body temperature. Behavioral tolerance describes tolerance in response to specific cues. Thus, an individual or research subject may exhibit tolerance to alcohol in one context (i.e. bar), but not in another (i.e. workplace). The repeated pairing of the situational cues with alcohol represents Pavlovian conditioning. With behavioral tolerance, the cues alone can elicit the compensatory response, such as the increase in body temperature, and the tolerance can be extinguished after repeated presentation of cues in absence of alcohol. Behavioral tolerance contributes to the dependence, withdrawal and abstinence phases of AUD.

Alcohol responses and tolerance capacity widely vary among humans and are influenced by multiple factors, including genetics, sex, behavioral context, and age. A spectrum of responses is observed, yet the underlying mechanisms for individual variability are not known. By contrast, individual heterogeneities are rarely reported in animal studies, in part because animal experiments are often designed to minimize variance among subjects. Yet inherent variations within subjects is present in animal and human subjects. Hence drinking patterns of individual subjects within a cohort are not reported, but rather the average and variance. However, the blood alcohol concentration is often measured and correlated with alcohol intake on an individual basis, providing an indication of variability within the study population. Similarly, self-report surveys highlight drinking patterns (or maximum number of drinks per day) and analyze individual perception of intoxication but often are not accompanied by objective measurements of functional outcomes or genetic variation. In summary, individual differences in the research subjects and the measurements of response and tolerance have been overlooked, and the translation and interpretation of the results between human and animal studies do not converge into common mechanisms and neural circuits.

Specific Areas of Research Interest

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 and animal experimental paradigms leading to dependence and AUD, with the goal of developing new hypotheses and common experimental framework(s) to characterize the sensitivity and tolerance (including individual variations). For example, animal studies of dependence started with naïve animals that were administered increasing amounts of alcohol exposure and likely developed tolerance. 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 in AUDs in the R33 phase. Animal studies that specifically test the underlying molecular and cellular mechanisms of human genetic candidates that regulate sensitivity and tolerance are encouraged. Study topics include, but are not limited to, the following:

  • Studies that determine the effects of sex, age, 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), age, sex)
  • 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 dependence 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. Adaptations leading to the allostatic static within a neural circuit or across neural circuits due to tolerance is of high programmatic priority
  • Interactions of neural circuitry of the physiological responses (cortisol and temperature changes) of tolerance and the neural circuitry of alcohol dependence and relapse, including methods of electrophysiology, fMRI, whole animal imaging
  • Studies that utilize state-of-the-art multi-omics approaches in humans and animal models 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

Deadlines:  standard dates and standard AIDS dates apply


Filed Under: Funding Opportunities