Addiction and Craving Research Faculty
Kent Hutchison, PhD
Jody Tanabe, MD
Despite our best efforts over the last few decades, currently available treatments for addiction are, at best, modestly effective. Our lab has taken a two pronged approach to address the limited effectiveness of current treatments. To develop more effective pharmacotherapies, we have focused our attention on medications 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, we have focused our attention on genetic factors that might explain individual variation in the same basic neurobiological and behavioral mechanisms that influence the etiology of addiction. This focus serves two purposes. It yields valuable information about who may be most at risk for developing addiction, and it yields valuable information about who may be most likely to respond favorably to a given pharmacotherapy. Ultimately, matching individuals to pharmacotherapies based on specific biological vulnerabilities has the promise of increasing the overall effectiveness of our treatment approaches. Specific areas of research are detailed below.Integrating Genetic and Neuroimaging Approaches
One very important aspect to our research is the notion that having well defined phenotypes that are proximal to the underlying biological mechanisms is critical to the success of efforts designed to uncover genetic variation that contributes to these phenotypes. In other words, a rudimentary phenotype like whether a person smokes cigarettes (or not) is unlikely to be useful in a genetic study because of the sheer number of factors that may influence that phenotype. Much of our research to date has focused on refining the phenotype such that a given phenotype will be useful in a genetic study. To date, we have focused on acute responses to alcohol, tobacco, and marijuana, publishing papers on pharmacological and genetic factors that influence these phenotypes. While acute responses to cues or the drugs themselves are useful phenotypes, we are currently working to develop phenotypes that are even more proximal to the neurobiology of addiction. We are in the process of migrating our laboratory based phenotypes to a neuroimaging environment and integrating this approach with our recent efforts at identifying genetic variation that influences gene expression in post-mortem tissue samples taken from brain regions that are critical to the neurobiology of addiction. Thus, the genetic approach should yield valuable information about genetic variation that alters gene expression in critical brain areas. The neuroimaging approach will allow us to examine whether this genetic variation also has an impact in vivo on brain activation in response to a drug or drug-related cues. It should be noted that a number of other notable scientists have already made considerable progress in terms of combining genetic and neuroimaging (see the work of Daniel Weinberger, Jon-Kar Zubieta, Ahmed Hariri).
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 determine whether the DRD4 VNTR polymorphism (or other sources of genetic variation such as the cannabinoid receptor gene: CNR1) influences this activation, and to determine whether a medications targeting the dopamine system attenuates this activation. Two separate studies are proposed to meet the specific aims of the proposed research. In the first study, the hemodynamic activation of specific brain structures will be compared after exposure to an alcoholic stimulus versus exposure to an isocaloric control stimulus. To test the influence of the DRD4 VNTR, individuals with the risk allele will be compared to individuals without the risk allele in terms of their hemodynamic activation and subjective craving. It is expected that exposure to the alcoholic stimulus will increase subjective craving as well as increase activation of the brain structures of interest, and it is expected that the individuals with the 7 repeat allele will demonstrate the greatest craving and activation. In the second study, subjects will be randomly assigned to pretreatment with a medication that targets this receptor (e.g., aripiprazole) or an active control prior to exposure to the alcoholic and control stimuli. It is expected that olanzapine will attenuate subjective craving and hemodynamic activation associated with the alcoholic stimuli and that this effect will be significantly more pronounced among individuals with the risk allele. The proposed work should establish the influence of alcohol cues on mesocortical and mesolimbic structures and elucidate important biological mechanisms that moderate the expression of craving and loss of control over drinking. The successful completion of the proposed research is also expected to advance our understanding of the role of genetic factors in the development of craving and loss of control drinking.
Craving for alcohol has been related to loss of control drinking and is a major target of biological and behavioral interventions for alcohol dependence. Our previous research has demonstrated that a dopaminergic medication attenuates craving for alcohol, that a variant in the gene that expresses D4 receptors and a variant in the cannabinoid receptor gene influences craving for alcohol, and that a dopaminergic medication (olanzapine) is effective at reducing craving among individuals with this variant. Our current research will examine whether the effects of dopamine and cannabinoid medications on drinking outcomes are mediated by its effects on a specific putative mechanism (i.e., cue-elicited craving for alcohol) and determine whether the DRD4 VNTR polymorphism (or CNR1 variation) is a marker for the effectiveness of olanzapine. To that end, 202 alcohol dependent subjects will be randomly assigned to medication group and receive 12 weeks of medication. Subjects will complete follow-up assessments at 3 and 6 months after the end of the treatment. The successful completion of the proposed research is expected to advance medications for alcohol dependence and advance genetic markers that predict the effectiveness of these medications.
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.
Despite rapid advances in our understanding of the human genome, the identification of genetic factors that influence the etiology and treatment of alcohol and drug abuse has yet to materialize. One reason for the lack of progress is poorly defined, poorly measured, ambiguous, and/or rudimentary phenotypes (e.g., dichotomous diagnostic variables) that inherently limit our ability to detect the influence of genetic factors.
One area of substance abuse research that is especially deficient with respect to phenotypic definition, measurement, and operationalization is research on cannabis abuse. Three constructs that are clearly important in terms of the etiology and treatment of a variety of drugs of abuse are withdrawal, craving, and sensitivity to the acute effects of the drug. The current application proposes to assess these cannabis-related phenotypes in the context of both cross-sectional and longitudinal designs to advance our understanding of the genetic, biological, and behavioral determinants of cannabis use and abuse. Two separate studies are proposed to address the primary aims of the project. Study 1 will define and characterize the validity of several phenotypes, including withdrawal, cue-elicited craving, and sensitivity to the rewarding effects of cannabis in a cross-sectional sample of infrequent versus frequent cannabis smokers. Study 2 will characterize the trajectory of these phenotypes using latent growth modeling in the context of a 2 year longitudinal investigation of individuals who smoked infrequently at the beginning of the study. The proposed research will also test whether these phenotypes are moderated by single nucleotide polymorphisms (SNPs) in the cannabinoid receptor (CNR1) and fatty acid amide hydrolase (FAAH) genes. The proposed research is expected to lay the foundation for future research on the genetic factors that underlie the progression of cannabis use and abuse.
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 use a cell culture model to examine the effects of these three SNPs on CHRNA4 gene expression.
The second aim is to develop a transgenic animal model that mimics the naturally occurring 5’ promoter and 3’ UTR SNPs in the human. The third aim is to examine the function of these three SNPs on the cognitive and emotional effects of nicotine in the brain using a neuroimaging approach.