Principal Investigators //

Kent Hutchison, PhD

Professor of Translational Neuroscience
Science Liaison: Inter-mountain Neuroimaging Consortium

Kent Hutchison

Dr. Hutchison has focused on medications and/or psychosocial interventions that target the basic neurobiological and behavioral mechanisms that are involved in the development and maintenance of addiction. To determine which individuals are most vulnerable to addiction and to determine which individuals might benefit most from a given treatment, he has focused on genetic factors that might explain individual variation in the same basic neurobiological and behavioral mechanisms that influence the etiology of addiction. These foci yield valuable information about who may be most at risk for developing addiction, and valuable information about who may be most likely to respond favorably to a given treatment approach. Ultimately, matching individuals to treatment based on specific genetic variables has the promise of increasing the overall effectiveness of treatment approaches. ​

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Selected Publications //

Effectiveness of Varenicline: Testing Individual Differences

One of the primary mechanisms underlying the addictive nature of tobacco use is the binding of nicotine to nicotinic acetycholine receptors (nAChRs). The a4 subunit of the nicotinic receptor is highly expressed in the central nervous system and plays a major role in the cognitive effects of nicotine as well as tolerance, reward, and the modulation of mesolimbic dopamine function, all of which are critical to the development of tobacco dependence. Given the importance of the a4 subunit, the gene that expresses this subunit (CHRNA4) is a prime target for research into the genetic factors that influence tobacco dependence. Our preliminary research indicates that there are three single nucleotide polymorphisms (SNPs) that alter expression in cell culture models and change subjective sensitivity to nicotine in a human laboratory paradigm. To better understand the role of this gene and to address the limitations of previous work, we will develop an integrative approach with the following specific aims and hypotheses. The first aim is to utilize a neuroimaging approach to examine activation of brain structures after exposure to alcohol cues. The second aim to determine with a medication that targets this receptor (varenicline) reduces activation of these brain structures and whether varenicline is more effective based on genetic variation at these loci.

Sensitivity to Intravenous Ethanol: Genetic Determinants

The alcohol-related phenotypes that are commonly used in genetic studies are often based on broadly defined diagnostic criteria. We have focused our previous research on the development of intermediate phenotypes, or endophenotypes, that are more proximal to the biological mechanisms that underlie the etiology of alcohol dependence (e.g., acute effects of alcohol). The extant literature as well as our own previous studies clearly suggests that m opiate receptors and the m opiate receptor gene (OPRM1) are important in terms of the acute effects of alcohol. Likewise, our preliminary data indicate that cannabinoid (CB1) receptors and the cannabinoid receptor gene (CNR1) strongly influence affective responses to alcohol. The first aim of the proposed research is to replicate and extend our previous research by testing whether a functional SNP (A118G) in the OPRM1 influences the effects of an acute infusion of alcohol, as compared to a saline infusion, on physiological and subjective measures of stimulation, sedation, and mood. The first aim will also test whether this effect is specific to alcohol dependent individuals by comparing alcohol dependent individuals with healthy, non-dependent drinkers. The second aim will replicate and extend our research on the CNR1 by testing whether a functional SNP in the CNR1 influences acute responses to alcohol and whether this effect is more pronounced among alcohol dependent individuals. Finally, the third aim will examine the additive effects of these two SNPs.  The proposed study is designed to both build on the strengths and address the limitations of our previous work by utilizing an alcohol infusion protocol (i.e., clamping protocol) to reduce unwanted pharmacokinetic and pharmacodynamic variability across individuals, thereby improving the overall power to detect the effects of the genetic variants and their interaction. In addition, the proposed research will address the limitations of our previous work by using a saline control condition and by testing both alcohol dependent and healthy non-dependent controls. These design improvements will allow us to examine whether or not the effect of genetic variants in the OPRM1 and CNR1 have an immediate effect on responses to alcohol or whether these variants interact with repeated exposure to alcohol to produce an enhanced sensitivity to the effects of alcohol (i.e., a gene by environment interaction) that is more evident in alcohol dependent individuals.

Alcohol Dependence: Integrating Genetic and fMRI Methods

Craving can be reliably elicited in the laboratory with humans, is associated with alcohol dependence, and is a primary target of biological and behavioral interventions. Activation of mesolimbic and mesocortical structures has been implicated in the development and expression of craving for alcohol and other drugs. Dopamine (D4) receptors are localized to these same structures and our preliminary work has suggested that a D4 antagonist moderates the experience of craving after exposure to alcohol. Our previous research has also suggested that the DRD4 VNTR polymorphism is a genetic factor that influences alcohol-elicited craving. The aims of this project are to determine whether exposure to alcohol increases activation of mesolimbic and prefrontal brain structures using BOLD fMRI, to determine whether this activation is correlated with the subjective experience of craving, to identify genetic variation that influences this activation, and to identify medications that attenuate this activation. The successful completion of the research is also expected to advance our understanding of the role of genetic factors and lead to the development of pharmacotherapies that can be tailored to the individual based on genetic variation.