The mission of the Indiana Alcohol Research Center is to reduce the suffering related to alcohol use disorders. We approach this through studies on the genetic basis of addiction, using animal models, human investigation, and participating in epidemiological research. In addition, we are bolstering the education of health professionals, social workers, and members of the justice system in the science of alcohol addiction and treatment as well as prevention measures such as screening and brief intervention.
The major research focus of the Center is the Genetic Determinants of Alcohol Ingestion and Responses to Alcohol. The rationale for investing in this multidisciplinary effort is the convincing body of evidence that genetic factors influence individual susceptibility to alcoholism over the life span. Indeed, manyspecific genes have now been implicated in the genetic risk of alcoholism. The ultimate goal of this research center is to further characterize the genes and the pathways through which they act. A model of alcoholism pathogenesis proposes that genetic factors contribute to both alcohol-specific and non-specific differences in the nervous system. When individual animals or humans are exposed to alcohol in the proper environment, these factors contribute to impaired regulation of alcohol consumption, and the development of tolerance and dependence. This combination leads to uncontrolled consumption, accompanied by physical and psychological craving when consumption is interrupted. Evidence from animal experiments shows that CNS mRNA and protein phenotypes differ in animals genetically predisposed to drink in the alcohol naïve-state vs following alcohol drinking or cycles of alcohol and drinking and deprivation, suggesting very complex interactions between genetics and environment. Expression of these traits is influenced by both familial and non-familial environmental factors during the development of alcohol abuse. Studies from IARC investigators have supported the view that genetic factors become increasingly important in the development of alcoholism as one moves from initiation of drinking to alcohol dependence.
Rat and mouse lines selectively bred for alcohol preference and nonpreference are a cornerstone of alcohol research at IU. They have helped researchers to identify neurotransmitters and neuromodulators such as serotonin, dopamine, opioid peptides and neuropeptide Y that underlie alcohol seeking, alcohol craving, alcohol dependence and alcohol tolerance. An obvious advantage of animal models of alcohol abuse is that they permit analysis of the effects of genotype on specific neural pathways while controlling both environment and genetic background, which cannot be achieved in human populations.
Human drinking behavior is influenced by social and cultural factors, personality traits, and physiological responses to alcohol. Several genetically determined risk factors such as personality traits (e.g., antisocial personality, conduct disorder, harm avoidance, novelty seeking, negative affect, and behavioral disinhibition), and neuronal dynamics (e.g., amplitude and power of EEG recordings) have been recently been linked with genetic loci for risk for alcoholism, specifically the GABRA2 genotype. Other phenotypes of risk emerge in response to an alcohol challenge such as alterations in alcohol pharmacokinetics (e.g., deficiency in ALDH2 activity, or variants of ADH), changes in release of opioid peptides, neuropsychological performance, saccadic eye movements, subjective measures of intoxication, and changes in EEG and brain activation as seen with functional neuroimaging. Since these quantitative traits are influenced by alcoholism risk genes, they can be used as endophenotypes to improve the power to identify these genes, and potentially to test pharmacologic agents for their ability to modify the phenotype, namely alcohol drinking.
Methodological and Collaborative Research
A major strength of the IARC is its application of new genomics and proteomics technologies, alcohol clamping paradigms, and neuroimaging capabilities across species to extend our understanding of what determines responses to alcohol. Such studies are ideally suited to be undertaken within a center since the center facilitates the interaction of behavioral scientists, neuroanatomists, molecular biologists and geneticists, biochemists, neurobiologists, bioinformaticians, electroneuro-physiologists, and neuroimaging experts as they assess the relationship between behavior, sensations, genotype, and functional changes in the CNS in response to alcohol. Many of the center investigators have been interacting with each other over the entire lifetime of the center and have extended their interactions through other external funding mechanisms, such as individual investigator-initiated grants, training grants, and multicenter research collaborations. The Indiana Alcohol Research center is ideally situated to integrate the results of functional genomics studies and to facilitate the rapid transfer of research findings in animals to the bedside and the clinic.