Alcohol Tolerance and Behavioral Disinhibition in Humans

Alcohol tolerance refers to a diminished intensity of response as doses are repeated. Tolerance has long been implicated as a factor contributing to alcohol abuse and dependence by encouraging the use of escalating doses to reinstate initial effects of the drug (Jellinek, 1960). Although changes in the intensity of drug effects often have a biochemical basis (Kalant et al., 1971), the role of learning also has been well- documented. Studies of laboratory animals and humans show that tolerance is often environmentally- dependent, whereby maximum tolerance is observed when the drug is taken in the presence of cues that reliably signal its administration (Siegel, 2005; Vogel-Sprott & Fillmore, 1999). However, despite well- developed laboratory methods for studying alcohol tolerance in humans, no research has applied these techniques to investigate how such tolerance can directly affect the abuse potential of the drug. Moreover, despite interest in tolerance as a phenotypic marker for alcohol use disorders (Schuckit, 1994), little research has sought to determine how differences in alcohol sensitivity and tolerance might characterize populations at- risk for alcohol abuse, such as those with externalizing disorders (e.g., attention deficit/hyperactivity disorder - ADHD). This proposal addresses these long-standing gaps in our knowledge concerning the role of tolerance in alcohol abuse. Our research program examines the acute disruptive effects of alcohol on mechanisms involved in the self-regulation of behavior. The proposed studies build on these techniques to examine the contribution of tolerance to abuse potential as measured by changes in basic mechanisms involved in the control and regulation of behavior. The proposal is based on the working hypothesis that the abuse potential of alcohol is determined by the sensitivity to its reward-enhancing effects and to its disinhibiting effects. The proposed research examines this hypothesis in a series of studies that test drinkers' sensitivity and tolerance to the acute disinhibiting effects of alcohol, the contribution of these factors to abuse potential, and the degree to which these factors characterize at-risk drinkers with ADHD. The specific aims of the project are: 1. To examine inhibitory mechanisms of control in terms of their sensitivity and tolerance to alcohol impairment There is growing evidence that inhibitory mechanisms of behavioral control play a role in risk for alcohol abuse. These mechanisms regulate behavior by suppressing inappropriate or maladaptive responses. Studies in our laboratory have employed control models of behavioral regulation to show that alcohol reduces inhibitory control over inappropriate responses, and we have obtained evidence relating this impairment to alcohol abuse potential (Fillmore, 2003b). However, little is known about how tolerance might be expressed in terms of changes in these fundamental mechanisms. Our preliminary studies (Section C) suggest that tolerance to alcohol impairment of inhibitory mechanisms might be particularly slow to develop, possibly explaining the persistent sensitivity to the disinhibiting effects of the drug, despite heavy use (Marczinski, Combs & Fillmore, 2007). No research has examined systematic changes in alcohol effects on inhibitory control over the course of repeated alcohol exposures. Studies will employ established learned tolerance training procedures to determine the extent to which inhibitory mechanisms recover from alcohol impairment over the course of repeated doses.