Alcohol consumption in the United States is unevenly distributed, with 64% of adults consuming alcohol but 8% meeting criteria for alcohol abuse (Grant et al., 2004). Many risk factors leading to excessive alcohol drinking have been identified, including an aggressive temperament, which can be studied in both human and non-human primate populations. Results from my laboratory have characterized aggressive temperament as a predictor of heavy ethanol (alcohol - these terms will be used interchangeably throughout the proposal) self- administration in non-human primates, and have found a positive linear relationship between the extent of aggressive behavior at baseline and average daily intake of ethanol (4% w/v) during open access to concurrent ethanol and water. Importantly, the functional neural correlates of an aggressive temperament have not been identified in human or non-human primate subjects, although a network encompassing the amygdala and prefrontal cortical areas has been identified in relation to aggression in humans. Additionally, it is not known whether atypical functional connectivity within this or other networks associate with future ethanol intake or change with chronic ethanol consumption. The goal of these studies is to identify the functional brain network modulating an aggressive temperament, to determine in-vivo neural correlates of risk for progression to heavy drinking, and to assess changes in temperament and functional connectivity following chronic ethanol consumption. Thus, Aim 1 will seek to identify the functional neural correlates of an aggressive temperament by assessing resting state functional connectivity between the amygdala and prefrontal cortical areas in aggressive and non-aggressive monkeys. Analysis will also extend beyond this network to characterize differences in modular organization in regulatory networks that may be associated with aggressive temperament. Next, monkeys will self-administer ethanol over a 12 month period, and those monkeys consuming 3.0 g/kg/d or more (heavy drinkers) will be compared monkeys consuming less than 3.0 g/kg/d of ethanol (non-heavy drinkers).
Aim 2 will assess changes in functional connectivity in the same networks identified in Aim 1, to determine whether the same atypical connectivity associated with aggression is associated with heavy drinking. Finally, Aim 3 will assess changes in aggressive behavior and functional connectivity within the networks identified in Aim 1 following chronic intake of ethanol in the same monkeys assessed at baseline. Identification of the neural mechanisms contributing to an aggressive temperament and progression to heavy drinking is important in furthering understanding of the emergence and progression of alcoholism, and could lead to improved identification and treatment of at-risk individuals.
Alcohol abuse and dependence are prevalent and detrimental disorders which can lead a variety of personal and societal problems. Although many risk factors for alcohol abuse have been identified, their neural correlates have not been well characterized, and it is generally not known if risk factors themselves are altered by the progression of alcoholic drinking. This proposal strives to establish functional neuroimaging correlates of a single risk factor, aggressive temperament, and assess changes in behavioral responses and neural circuitry in the same monkeys following ethanol intake, to improve methods to identify at-risk individuals in the human population and prevent the transition to alcohol abuse.
| McClintick, Megan N; Grant, Kathleen A (2016) Aggressive temperament predicts ethanol self-administration in late adolescent male and female rhesus macaques. Psychopharmacology (Berl) 233:3965-3976 |
