David A. Kareken - US grants

Preliminary data from our positron emission tomographic (PET) studies suggests cerebral reorganization of human olfactory processing in healthy aging. This application requests pilot funds to verify this age-related reorganization, and to elucidate mechanisms of olfactory sensation, discrimination, and identification in the aging human brain. Olfaction declines in healthy aging, affecting quality of life and the ability to detect danger. Olfaction is also severely affected by Alzheimer disease (AD), in which mesial temporal olfactory cortex shows early degeneration. Correspondingly, we reported that olfactory stimulation during PET detects functional decline in mesial temporal lobe regions of AD patients (Kareken, et al., submitted). However, no research has used functional imaging to study normal age-related changes in cerebral olfactory networks. Imaging studies of young subjects report bilateral orbital and piriform activity in young subjects. Our preliminary study of healthy elderly found robust right piriform activity, and only weak left orbital activation. Therefore, our hypotheses are that: A) Right piriform cortex is activated by olfactory sensory stimulation in young and old subjects to an equivalent degree. B) Aging results in reduced left piriform and bilateral orbital activation during olfactory stimulation. C) Orbitofrontal and left piriform regions are more closely related to higher order olfactory tasks (discrimination and identification). D) Healthy elderly show reduced activity in these association areas during odor discrimination and identification. Our specific aims are to: 1) Identify patterns of cerebral activation in young and old subjects during olfactory sensory stimulation. We will perform PET during suprathreshold olfactory stimulation in healthy young and older subjects. We will perform exploratory analyses to determine cortical regions that differ between younger and older subjects. 2) Characterize regional activation produced by odor discrimination and identification. We will study the same sample performing olfactory discrimination and identification tasks during PET. We will characterize regional activity produced by these tasks in young subjects, and compare their regional cerebral activation patterns to those of simple sensory stimulation. 3) Identify candidate regions involved in odor discrimination and identification that are affected by aging. We will compare the activation patterns of younger and older subjects during olfactory discrimination and identification tasks, and identify regions that show potential differences. These data will support application for further study through an R01 application. Findings from these studies can elucidate how the aging human brain changes its ability to process odor information. By examining these normal age related changes, we lay a foundation for understanding the early functional changes found in the temporal lobes of patients with AD.

3,4-Dihydroxyphenethylamine; 4-(2-Aminoethyl)-1,2-benzenediol; Alcohol abuse; Alcoholic; Alcoholic beverage heavy drinker; Alcoholism; Alcohols; Animals; Area; Boozer; CRISP; Cell Communication and Signaling; Cell Signaling; Cerebrum; Chemical Class, Alcohol; Computer Retrieval of Information on Scientific Projects Database; Cues; Data; Dependent drinker; Disease; Disorder; Dopamine; Dose; Drugs; Epidemiology, Family Medical History; Family Medical History; Family history of; Functional Imaging; Functional Magnetic Resonance Imaging; Funding; Goals; Grant; Heavy Drinker; Hydroxytyramine; Image; Individual; Institution; Intracellular Communication and Signaling; Investigators; Knowledge; Lead; MRI, Functional; Magnetic Resonance Imaging, Functional; Medication; NIAAA; NIH; National Institute on Alcohol Abuse and Alcoholism; National Institutes of Health; National Institutes of Health (U.S.); Nucleus Accumbens; Odors; Pb element; Pharmaceutic Preparations; Pharmaceutical Preparations; Physiologic Imaging; Placebo Control; Population; Relapse; Research; Research Personnel; Research Resources; Researchers; Resources; Risk; Signal Transduction; Signal Transduction Systems; Signaling; Source; System; System, LOINC Axis 4; United States National Institutes of Health; Ventral Tegmental Area; alcohol abuse therapy; alcohol abuse treatment; alcohol cue; alcohol exposed; alcohol exposure; alcohol problem; alcohol response; alcohol treatment; alcoholism treatment; biological signal transduction; desire; disease/disorder; drinking; drug/agent; ethanol abuse; ethanol cue; ethanol exposed; ethanol exposure; ethanol response; exposed to alcohol; exposure to alcohol; fMRI; hazardous alcohol use; heavy metal Pb; heavy metal lead; human subject; imaging; interest; mesolimbic system; problem drinker; problem drinking; response; response to alcohol; response to ethanol; ventral tegmentum

3,4-Dihydroxyphenethylamine; 4-(2-Aminoethyl)-1,2-benzenediol; Absolute ethanol; Alcohol, Ethyl; Alcoholism; Animal Model; Animal Models and Related Studies; Benzamide, 3,5-dichloro-N-((1-ethyl-2-pyrrolidinyl)-methyl)-2-hydroxy-6-methoxy-; Binding; Binding (Molecular Function); Brain Part; CRISP; Computer Retrieval of Information on Scientific Projects Database; Consumption; Corpus Striatum; Corpus striatum structure; Cues; Dopamine; ETOH; Epidemiology, Family Medical History; Ethanol; Family Medical History; Family history of; Funding; Genetic; Grain Alcohol; Grant; Hydroxytyramine; Institution; Investigators; Ligands; Medical Imaging, Positron Emission Tomography; Methylcarbinol; Molecular Interaction; NIH; National Institutes of Health; National Institutes of Health (U.S.); Nucleus Accumbens; PET; PET Scan; PET imaging; PETSCAN; PETT; Positron Emission Tomography Scan; Positron-Emission Tomography; Proton Magnetic Resonance Spectroscopic Imaging; Raclopride; Rad.-PET; Research; Research Personnel; Research Resources; Researchers; Resources; Rewards; Risk; Source; Striate Body; Striatum; United States National Institutes of Health; Ventral Tegmental Area; alcohol response; ethanol response; model organism; response to alcohol; response to ethanol; striatal; ventral tegmentum

DESCRIPTION (provided by applicant): Stimuli that become associated with alcohol by repeated pairing with drinking are thought to induce craving, shift implicit attention toward alcohol, and promote relapse. However, human neuroimaging studies of such environmentally conditioned stimuli must usually revert to proxies for the actual stimuli (e.g., pictures of a beer bottle), and are forced to side-step the problem of individual differences in conditioning history and specific stimuli. For example, a displayed visual image can only approximate the originally learned stimulus in the natural environment, and there is no way to know the precise pharmacologic conditions and frequency of the original conditioning. This application uses the R21 mechanism to test the feasibility of: 1) Classically conditioning a novel stimulus to carefully controlled, pharmacokinetically modeled intravenous alcohol infusion that targets the most rewarding phase of alcohol consumption (the ascending limb), and then 2) studying the brain systems that respond to these novel cues. Our proposed paradigm would afford considerably greater control over the exact nature of stimulus learning itself, thus permitting a more refined study of the involved neural pathways and how activity in these pathways relates to implicit attention toward alcohol cues. Such an approach would be highly useful in the study of the neural mechanisms associated with drinking behaviors and particular risk factors for alcoholism. PUBLIC HEALTH RELEVANCE: This research will use a technology called functional magnetic resonance imaging to study the human brain's pathways related to learning how certain stimuli in the environment become associated with alcohol intoxication. The project will also study the manner in which people's attention are drawn to these alcohol associated stimuli after learning. Such factors are thought to be highly important to the development and maintenance of alcoholism and other addictions. Research such as this has the potential to improve our understanding of these brain systems, which may in turn lead to better treatments.

DESCRIPTION (provided by applicant): Dopaminergic transmission in the brain's mesocorticolimbic system is thought to be a significant factor in alcohol abuse and dependence. Most research on the dopaminergic response to alcohol and its conditioned cues is nevertheless done in rodents. The extent to which these rodent models translate to human alcohol use disorders is unknown. Therefore the long term goal of our proposed work is the development of an in vivo human biomarker of striatal dopaminergic responses that can be applied to the study alcoholism and its antecedent risks. We will do this using positron emission tomography (PET) and the dopamine D2 ligand [11C]raclopride. Behavioral paradigms will be employed to study how alcohol administration, alcohol's cues, and expectations of impending alcohol-intoxication relate to dopamine function in subjects with alcoholism. PUBLIC HEALTH RELEVANCE: This research will use a technology called positron emission tomography to study the neurochemical dopamine in the human brain. Alterations in this neurochemical system are thought to be highly important to alcoholism, as well as to other addictions. Research such as this has the potential to show exactly how dopamine neurotransmission is altered in alcoholism, findings that may lead to better treatments and diagnosis.

DESCRIPTION (provided by applicant): Food aromas are powerful appetitive cues that are intrinsic to foods' flavor and hedonic qualities, and such cues can facilitate overeating. Alcohol consumption similarly primes appetite, and contributes to overeating while under alcohol's acute effects. While neuroimaging of chemosensory brain networks is a major field of inquiry, testing how such sensory cues are differentially processed in lean and obese subjects has only recently begun. Further, there are no studies of how alcohol exposure alters the brain response to food odors, or how its disinhibiting qualities could facilitate overeating. Knowing the brain loci that respond to such appetitive stimuli, and how they are modified by body fat and alcohol exposure, will provide critical insights about the neural systems that underlie loss of control of eating. Our preliminary data suggest that when smelling food odors, obese subjects show a greater blood oxygen level-dependent (BOLD) response than lean subjects in the insula and hippocampus. Therefore, the main hypotheses of this proposal are that: A) Lean and obese subjects have different limbic responses to the olfactory cues that enhance motivation to eat, and B) Acute alcohol intoxication i) potentiates the brain's reward system response to food odors, and ii) affects brain systems involved in behavioral inhibition and eating restraint. To test these hypotheses, we have modified functional magnetic resonance imaging (fMRI) paradigms successfully used to study alcoholic drink aromas in subjects at risk for alcoholism and in ongoing work of inhibitory control under alcohol exposure. Our specific aims are to: 1) Determine the effect of adiposity on food aroma-induced responses of specific limbic-frontal (orbitofrontal cortex, medial frontal cortex, amygdala, hippocampus, and insula) areas, 2) Examine the relationships between caloric intake and food aroma-induced responses, and 3) Study the apiritif effect on the response to food odors. The studies in this proposal are particularly novel because, unlike prior neuroimaging research of obesity or food-cue responsiveness, we will relate the reward system response to food cues to real world conditions, including: 1) Subjects' eating behavior at realistic meal intervals that do not disrupt or interfere with circadian rhythms, 2) The effect of a meaningful reduction in calories on brain responses to food cues (as would be experienced under dieting conditions), and 3) The effect of alcohol as consumed before meals on the brain response to food cues, inhibition, and eating behavior. To accomplish these aims we will also use food aromas, which are particularly salient stimuli that convey a more immediate presence of reward than do food images.

Functional magnetic resonance imaging (fMRI) has only recently begun to identify specific brain regions where responses to stimuli associated with dnnking (alcohol cues) vary as a function of a family history of alcoholism (Kareken et al., 2010a; Tapert et al., 2003). The long-term goal of our research is to determine how alcoholism risk factors alter the brain's reward system function. The objective of this application is to determine how genetic, behavioral, and personality trait risks alter the brain's processing of cues that have been classically conditioned to predict imminent intoxication in the experimental setting. Our rationale is that, by carefully controlling learning and contingencies in the laboratory, we can better measure brain responses to alcohol predictive cues, and do so with cues devoid of the influence from prior idiosyncratic alcohol experiences. The central hypothesis of these studies is that brain responses to cued alcohol intoxication will differ as a function of both genetic and behavioral risk factors. By identifying the brain systems affected by family history, behavioral disorders, and specific genes, we will gain a more complete understanding of the nsk pathways and associated neural vulnerabilities that help lead to alcoholism. Using fMRI, we will test three specific aims: 1) Test whether a family history of alcoholism alters brain responses to novel cues experimentally paired with the ascending limb of the blood alcohol curve. 2) Test whether brain responses to experimentally conditioned cues are modified by the presence of high externalizing behaviors. 3) Test whether GABRA2 variation affects local brain responses to cues experimentally conditioned to intoxication.

DESCRIPTION (provided by applicant): A critical need remains to identify how the brain's reward system is altered by alcoholism risk. Our objective is to determine if drinking and familial alcoholism are related to the brain's associative sensory response to an intensely sweet taste- a primary reward repeatedly linked to animal and human drug use. The rationale for the approach is to allow examination of those who have yet to learn the relationship between alcohol cues and intoxication, or who are ethically precluded from drinking (e.g., abstinent alcoholics). Our central hypothesis is that associative sensory (BOLD fMRI) responses to an intensely sweet taste in posterior orbital cortex are associated with abusive drinking, alcohol self-administration (measured in the lab), and familial alcoholism. Aim 1: Test if abusive drinking and alcohol-related problems are associated with the magnitude of the posterior orbitofrontal response to a highly sweet gustatory stimulus. Hypothesis 1: (a) Heavy drinking subjects have larger orbitofrontal responses to a highly sweet sucrose solution than subjects who drink socially; (b) alcohol-related problems correlate positively with the orbitofrontal response. Aim 2: Determine if alcohol self-administration is related to the magnitude of the sweet taste response. Hypothesis 2: The magnitude of orbital responses to oral sucrose correlates positively with the preferred level of alcohol intoxication achieved in a validated laboratory paradigm of intravenous alcohol self-administration. Aim 3: Determine if a family history of alcoholism is related to the magnitude of the response to a sweet taste. Hypothesis 3: Subjects with a family history of alcoholism have larger orbitofrontal responses to sweet taste delivery than family history negative subjects. Aim 4: Compare the associations between alcoholism risks and responses to: a) sucrose and b) monetary rewards. Hypothesis 4a: Alcoholism risks are related more to the orbital sensory response to an intensely sweet taste than to responses provoked by monetary reward anticipation (ventral striatum) or receipt (medial prefrontal). Hypothesis 4b: Alcoholism risks comprise blunted ventral striatal responses to monetary reward anticipation, elevated medial prefrontal responses to monetary receipt, and elevated orbital sensory association responses to high-concentration sucrose. Exploratory Aim 5: Test for associations between ¿-opioid receptor genotype and reward system responses to a sweet gustatory stimulus. Endogenous opioids mediate central responses to both sucrose and alcohol. Hypothesis 5: 'A' (common) allele homozygotes of the ¿-opioid receptor gene (rs1799971) have lower responses to oral sucrose than 'G' allele carriers. Our proposed research advances NIAAA's goal of identifying physiological traits of endophenotypic alcoholism risk, and will validate a probe for many populations, irrespective of age or drinking history. In this way, we can obtain new insights into the cerebral risk pathways that lead to alcoholism.

PROJECT DESCRIPTION One critical diagnostic criterion of an alcohol use disorder is the disproportionate time spent seeking and obtaining alcohol. A considerable body of preclinical data in animals now suggests that ventral striatal dopamine release is associated, not only with the response to reward cues, but also with reward seeking behaviors. This leaves a critical need to determine if and how human ventral striatal dopamine is related to alcohol-seeking behaviors. The objective of this application is to determine if human ventral striatal dopamine release is related to alcohol seeking behaviors. Our rationale for examining this phenomenon is that a key feature of alcohol use disorders involves disproportionate behavioral effort directed toward gaining access to alcohol. Our central hypothesis is that the cognitive and behavioral effort expended to gain access to alcohol is linked to human ventral striatal dopamine release. Using a task that requires goal-directed behaviors to gain access to ad lib alcohol, our specific aims are to conduct two experiments using dopaminergic positron emission tomography that will: Aim 1: Determine if instrumental efforts exerted to gain access to alcohol (alcohol seeking behaviors) are associated with human ventral striatal dopaminergic release. Hypothesis 1a: Alcohol seeking behaviors increase ventral striatal dopamine release. Hypothesis 1b: Alcohol craving during alcohol- seeking behaviors is positively correlated with ventral striatal dopamine release. Aim 2: Determine if alcohol cue exposure potentiates ventral striatal dopaminergic release during alcohol seeking behaviors. Hypothesis 2a: Exposure to the sensory cues of a preferred alcoholic drink will potentiate ventral striatal dopamine release during effortful alcohol seeking behaviors. Hypothesis 2b: Cue- potentiated alcohol craving during alcohol-seeking behaviors is positively correlated with ventral striatal dopamine release. Exploratory aim: Determine if ventral striatal dopamine release during alcohol seeking is associated with variables related to alcohol use and abuse. Here we explore the extent to which the magnitude of ventral striatal dopamine release during seeking behaviors is related to subjective reinforcement from alcohol, alcohol use patterns (self-reported, and observed during intravenous self-administration), alcohol-related problems, and trait impulsivity.

Project Summary: Administrative Core The Administrative Core of the Indiana Alcohol Research Center (IARC) serves to coordinate and optimize the synergy of the interacting components and cores, as well as to provide financial oversight and administrative support. It is also a central source of statistical support. It satisfies the critical need for the central management of a complex budget spanning two Schools (Medicine at IU and Science at IUPUI), and several different departments. The objective and long term goal of the Administrative Core is the smooth financial management of the grant budget as proposed in this application, in addition to the coordination and integration of the scientific activities of the participants and our collaborators. The rationale for including administrative support from the Center Director in the Department of Neurology is to link the activities of the Center with the broader resources and financial management from Neuroscience Administration. The expected outcomes of the activities of this Core are the continued excellence of the science and collaborative activities of the Center. The specific aims of the Administrative Core are therefore to: (1) Provide the scientific leadership, administrative support, and ongoing annual financial oversight for the Alcohol Research Center (2) a) Assist in the identification, recruitment, and development of new investigators in alcoholism research, b) aide new investigators and their applications for grants, c) provide support for medical students to perform summer research in Center laboratories, and d) maintain the Web site to serve as a source of information for alcoholism researchers, patients and practitioners, and as a link to the Information Dissemination Component. (3) Provide leadership in organizing seminars, conferences, and workshops, and in the dissemination of new research findings to the academic and lay communities. (4) Foster collaborative research ventures between the IARC and other ARCs and investigators in this country and abroad. The impact of performing these functions well will be the effective use of the resources of the Center in a synergistic manner, and furtherance of the mission of the NIAAA Center grants program.

Project Summary: Overall Indiana Alcohol Research Center (IARC) The Indiana Alcohol Research Center (IARC) has devoted three decades to understanding how genetic factors and responses to alcohol contribute to the risk of developing an alcohol use disorder (AUD). We continue these efforts by now examining why certain immoderate drinkers transition into a stage in which they become insensitive to the aversive outcomes associated with heavy drinking. The IARC will therefore address the critical need to understand the genetic, behavioral, and neurobiological paths by which ?aversion-resistant drinking? develops. The rationale for our centered approach is that working in close association across several scientific disciplines and spheres of expertise permits our investigators to achieve insights that are not possible when working in isolation. The IARC's central hypothesis is that aversion-resistant drinking arises through a combination of inherited behavioral and neurobiological vulnerabilities, as well as progressive changes in fronto-striatal neurotransmission in response to drinking history.  The objective of this next IARC cycle is to therefore apply coordinated, multi-disciplinary efforts to understand the brain and behavioral mechanisms through which aversion-resistant drinking arises. Using the IARC's selected animal lines, our specific aims are to determine how aversion resistant drinking may arise through: (1) Changes in medial prefrontal glutamate systems, (2) unique impulsive endophenotypic behaviors and associated differential functioning in medial prefrontal cortex, (3) forms of cognitive inflexibility and alterations in glutamate receptors in the brain's dorsal striatum, and (4) drinking history and genetic influences on the corticostriatal encoding of alcohol-paired cues. Accompanying these preclinical animal studies will be (5) a novel translational paradigm in humans to determine how aversion-resistant alcohol seeking behaviors relate to drinking history, alcohol use disorder symptoms, and brain physiology. The IARC will also (6) provide a pilot mechanism to develop new investigators and research directions, and support promising directions related to the IARC's research components. Finally, the IARC will expand existing educational, implementation, and outreach for primary care providers and the legal profession. The IARC will thus function in a coordinated way to integrate human and animal research on how genetic risk, alcohol exposure, and endophenotypic behaviors contribute to the important problem of compulsive drinking.