Andrea C. King - US grants

Cigarette smoking and alcohol misuse rank among the foremost public health problems facing the United States. Understanding the biological mechanisms underlying smoking and drinking is integral to designing targeted and effective treatment strategies. Given the high occurrence of heavy alcohol drinking and cigarette smoking, and the increased number of young, college- age binge drinkers, we plan to elucidate some of the opioidergic mechanisms of reinforcement of co-existing alcohol and nicotine use. Alcohol and nicotine effect hypothalamic-pituitary-adrenal (HPA) axis function, however, little is known about the possible interactions between nicotine and alcohol in these effects. Work in our laboratory and in others has shown that the endogenous opioid system has a role in the regulatory control and release of HPA axis hormones, which in turn may relate to the initiation, maintenance, and relapse to heavy use of addicting substances. Our first aim is to study HPA activity and subjective factors related to smoking behaviors in the following three groups of regular heavy smokers, with different drinking histories, while they smoke: Group 1 - recently sober alcoholics; Group 2 - binge/heavy consumption social drinkers; and Group 3 - light social drinkers. Non-smoking light social drinkers, who will not smoke, Group 4, will serve as a control group. Adjunctive treatment with opioid antagonists has been shown to reduce alcohol intake and relapse rates in alcohol-dependent persons, through parallel data in nicotine-dependant persons are mixed. Our second aim, therefore, is to study the effects of a preadministered bolus of the mu-selective but also kappa-directed opioid antagonist nalmefene on HPA activity and subjective measures in the above four groups. By elucidating the role of the stress- responsive endogenous opioid system in smokers with different drinking patterns, we may begin to understand the combined reinforcing properties of heave use and abuse of both substances, which may ultimately lead to the identification of and improved pharmacologic treatments strategies for subgroups most likely to benefit.

Clinical double-blind placebo-controlled studies have shown that naltrexone significantly reduced relapse rates and alcohol consumption in treated alcoholic patients compared to placebo-treated alcoholics. Similar preliminary results have been demonstrated with the opioid antagonist nalmefene versus placebo. At a recent symposium on the mechanisms of opioid antagonist treatment to reduce drinking, it was suggested that the identification of individuals most likely to benefit from such treatment and the development of increasingly selective pharmacological adjuncts may relate to changes in the stress responsivity axis and concomitant subjective changes. Both opioid antagonists and acute alcohol have been found to activate the hypothalamic-pituitary- adrenal axis, however subgroups at risk for alcoholism have shown differential activation and/or neuroadaptation. We propose to examine the effect of the opioid antagonists naloxone and nalmefene on both subjective report and HPA axis responsivity, which may provide the individual with an internal "cue" and precede other changes associated with subjective intoxication. The use of naloxone, a short-acting antagonist primarily acting at mu opioid receptors, and nalmefene, a mu and kappa receptor agent, will allow further analysis of receptor subtype activity. In lieu of our recent study demonstrating a differential response to naltrexone in sons of alcoholics versus sons of nonalcoholics, participants for this study will include abstinent alcoholics (greater than or equal to l month sober), and heavy consumption social drinkers at High- and Low- Risk for the future development of alcohol dependence based on family history, as well as normal low-consumption Lower-Risk control subjects. The groups will be compared on neuroendocrine (ACTH, cortisol, beta-endorphin) and subjective (POMS, Karolinska Scale) measures during baseline (saline injection) conditions and separate sessions pre- and post-administration of i.v. 30 mg naloxone and nalmefene. The High Risk model has been used previously to aid in identification of psychobiological markers and motivational implications of problematic drinking, and the paradigm may also be of benefit for the study of pharmacological agents. Our long-term objectives are to acquire a database with which to further study the mechanisms and perturbations in HPA function and subjective response to opioid antagonist treatment in alcoholics and heavy consumption drinkers at risk for the disorder.

hypothalamic pituitary adrenal axis; smoking; alcoholism /alcohol abuse; tobacco abuse; alcoholic beverage consumption; endogenous opioid; nicotine; social behavior; psychopharmacology; inhibitor /antagonist; drug interactions; behavioral /social science research tag; nutrition related tag; human subject; clinical research;

The candidate is a clinical and biological psychologist who seeks to acquire the skills in conducting clinical trials outcome research for nicotine, alcohol, and other drug dependencies. This award will allow the candidate to advance science-based treatment into clinical practice, by providing training, mentorship, and experience in relevant methodologies to combine pharmacotherapy and psychosocial treatment. The candidate will also expand her previous laboratory research background to study subjective, behavioral, and physiological factors involved in alcohol and drug reinforcement and their relation to clinical outcome. Throughout the award, Dr. King will engage in course work, workshops, laboratory and pilot clinical trial research, and have ongoing mentorship from experts in the field. Concurrent heavy use of alcohol and tobacco is common. However, the mechanisms of combined reinforcement and the optimal treatment strategies for heavy users of both drugs have not been delineated. The proposed study will examine the effects of combining naltrexone with standard smoking cessation treatment in heavy smokers with moderate-to-heavy drinking patterns. The rationale for this study derives from the candidate's recent preliminary data. These data indicate that naltrexone significantly reduced heavy smokers' craving for cigarettes after smoking one cigarette and a subsequent one hour rest period. Also in heavy smokers, naltrexone decreased the number of choice cigarettes smoked, lowered carbon monoxide (CO) levels, and acutely increased cortisol response to the first cigarette compared to placebo, suggesting a potential mechanism of reduced craving. We hypothesize that naltrexone will be particularly efficacious as an adjunctive treatment in moderate-to-heavy drinking smokers, an historically treatment refractory subgroup. Naltrexone might directly reduce craving or number of cigarettes smoked, or decrease alcohol intake and indirectly reduce cigarette smoking, since studies have shown that alcohol drinking enhances subsequent urge to smoke. Consumption patterns and quit rates for both substances will be monitored throughout the study. We will also investigate the relationship between response to naltrexone in the laboratory to response in a clinical trial, which will enable us to explore potential mechanisms for heightened response to opioid antagonists. Examining a targeted treatment combining pharmacotherapy and behavioral treatment for this subgroup is of great importance, as alcohol abusers show increased mortality more due to tobacco than alcohol-related illness.

DESCRIPTION (provided by applicant): Binge drinking continues to be a major problem in young adults in the United States. Persons who are chronic, heavy alcohol drinkers (i.e., consume 5+ drinks/occasion on a weekly or more frequent basis) not only incur greater consequences and adverse effects if they maintain hazardous drinking levels, but are also at increased risk for progression to Alcohol Dependence. Little is known about the individual response factors, such as acute response to ethanol, in these early-age heavy drinkers (HDs) compared to light drinkers (LDs). The majority of laboratory research in this area has examined persons at high risk by virtue of a positive family history of alcoholism (FH+), with mixed results on their relative sensitivity and/or tolerance to the effects of alcohol. Given the multiple etiologies and complexities of alcohol use disorders, it is important to broaden the range of risk factors examined in alcohol challenge paradigms. Our prior data suggest that heavy drinkers show greater sensitivity to alcohol-induced stimulation and less sensitivity to alcohol sedation compared to light drinkers. Therefore, our goal in Study 1 is to replicate and extend these findings of differential acute alcohol response in early-stage heavy binge drinkers versus light drinkers. In the proposed within-subjects study, the effects of alcohol will be measured through subjective, objective, and performance domains during two alcohol sessions (0.4 and 0.8 g/kg) and a placebo session. In addition, we will examine the role of drinking history as a risk factor, along with other potential risk factors, to develop a predictive model for acute alcohol response characteristics (subjective stimulation, sedation, and objective/performance response). Study 2 will further extend this model by conducting a prospective study in the same subjects to examine the role of acute alcohol response to future alcohol-related behaviors and consequences. We hypothesize that those persons who show increased sensitivity to alcohol reinforcement, as measured by euphoria and stimulation, and less alcohol-induced sedation during the testing session will exhibit significantly greater signs of subsequent heavy drinking, as measured by heightened alcohol quantity, frequency, binge episodes, and early alcohol-related consequences.

DESCRIPTION (provided by applicant): Although women may be particularly susceptible to the damaging effects of chronic cigarette smoking, evidence indicates that they may have more difficulty in maintaining smoking cessation than men. Given women's reduced response to nicotine replacement and other traditional treatments, habitual cigarette smoking, more targeted pharmacotherapy and intervention strategies may be necessary to improve their quit rates. Preliminary data by our group and others indicate that the opioid antagonist naltrexone may be an effective pharmacotherapy approach for female smokers. The purpose of the proposed study is to conduct a randomized clinical trial to compare adjunct treatment with 50 mg oral naltrexone vs. placebo in conjunction with standard smoking cessation treatment with nicotine patch and counseling. Participants (N=324) will be randomized to receive either naltrexone or placebo starting one week prior to the quit date (25 mg for three days; 50 mg thereafter) and continue for 12 weeks after the quit date. The effects of naltrexone will be evaluated during the pre-quit date period, initial smoking cessation, relapse prevention, and at one-year follow-up. It is hypothesized that sex will moderate the effects of naltrexone on outcome, with naltrexone improving prolonged abstinence quit rates in women but not in men. The secondary goal will be to elucidate the mechanisms underlying women's treatment response to naltrexone. Weight (relative weight gain and weight concerns) and smoking-related variables (reduced cigarette pleasure, taste, craving and relief of negative withdrawal affect) may be important factors by which naltrexone improves quit rates in women. Medication compliance, psychosocial stress and levels of naltrexone's metabolite, 6-|3-naltrexol, will also be examined. In sum, the proposed clinical trial will provide a comprehensive study of sex differences in response to adjunct treatment with naltrexone for smoking cessation. Given the public health concerns and significant health consequences of women's continued high rates of smoking, the proposed study may provide important information on a novel treatment strategy targeting the endogenous opioid system to selectively aid in women's smoking cessation.

Active Follow-up; Acute; Alcohols; Behavior; Behavioral; Blood Alcohol Content; Blood alcohol level measurement; CRISP; Chemical Class, Alcohol; Computer Retrieval of Information on Scientific Projects Database; Funding; Future; Goals; Grant; Heavy Drinking; Institution; Investigation; Investigators; Laboratory Study; Light; Measures; NIH; National Institutes of Health; National Institutes of Health (U.S.); Participant; Pattern; Performance; Phase; Photoradiation; Physiologic; Physiological; Research; Research Personnel; Research Resources; Researchers; Resources; Source; Staging; Substance abuse problem; To specify; United States National Institutes of Health; abuse of substances; alcohol response; blood alcohol concentration; blood alcohol level; drink heavily; drinking; ethanol response; excess alcohol consumption; excess alcohol ingestion; excess ethanol ingestion; excessive alcohol consumption; excessive alcohol ingestion; excessive alcohol intake; excessive drinking; excessive ethanol ingestion; extreme drinking; follow-up; heavy alcohol use; pre-clinical; preclinical; response to alcohol; response to ethanol; social; substance abuse

PROJECT SUMMARY ABSTRACT Laboratory alcohol challenges, in which researchers assess participants? responses to alcohol administered in a controlled setting, have provided the alcohol research community with important knowledge about the associations between individual responses to alcohol and risk for drinking-related problems. In recent studies in young adult heavy drinkers, our group showed that greater sensitivity to alcohol?s stimulant and rewarding effects was more predictive of future development of alcohol use disorder (AUD) symptoms than were lower responses to sedative or intoxicating effects. While laboratory-derived alcohol challenges remain the ?gold standard? for measuring alcohol responses, the time- and resource-intensive nature of this approach has hampered efforts to extend findings of alcohol challenge studies to intervention and epidemiological research. One potential solution to this problem is to develop and validate an accessible and user-friendly method to measure alcohol responses outside of the laboratory using ecological momentary assessment (EMA). EMA methods assess individuals? behaviors and experiences in real-time and in their natural environment. Rapid advances in mobile smartphone technology and high adoption rates of these devices (86% of young adults own a smartphone) suggest that EMA alcohol response data may be collected via this portable and user- friendly method, e.g., providing data via text messaging and mobile web from one?s own smartphone. Our pre- pilot work suggests that using smartphones to measure alcohol responses in vivo is reliable, safe, and well- received by young adult heavy drinkers. The goal of this proposal is to build on this to further establish the reliability, validity, and safety of a smartphone-based EMA technique for measuring alcohol responses in drinkers? natural environments, and to examine associations with identical measures obtained via laboratory alcohol challenge. We plan to collect alcohol response data during at least 2 real-world drinking episodes from 64 young adult heavy drinkers (ages 21-29), and compare these responses with those obtained during a laboratory alcohol challenge. Safety of the smartphone procedure will be assessed by next-day and 2-week follow-up assessments of alcohol use and consequences, and by comparing those outcomes to a sample of n=20 heavy drinkers who will also complete these measures but not the smartphone/laboratory assessments. Estimated breath alcohol content (eBrAC) will be calculated during the smartphone-based assessments and actual BrAC will be measured during the laboratory challenge. Both the laboratory- and smartphone-based assessments will assess subjective alcohol stimulation, sedation, and reward (liking and wanting) using brief (~1 min), psychometrically sound measures. The results will contribute to knowledge on individual differences in alcohol responses in the natural environment. If shown to be reliable, valid, and safe, this new smartphone- based EMA technique could be used to inform future research on AUD risk assessment and treatment, as well as population-based work to examine changing patterns of drinking behavior and responses.

DESCRIPTION (provided by applicant): Adverse effects of excessive drinking are widespread in terms of the increased health care, loss of productivity, crime, accidents, and myriad emotional and personal costs. Understanding the factors that contribute to the development and persistence of excessive alcohol consumption is crucial for improved prevention, education and intervention strategies. The goal of our study is to evaluate the role of subjective and physiologi responses to alcohol in the escalation and maintenance of excessive drinking in adults. Our paradigm integrates human laboratory alcohol challenge with longitudinal assessment of drinking and related behaviors to discern whether alcohol responses predict future drinking problems in young heavy drinkers versus light drinker controls. In the last award phase, we also provided an initial laboratory re-examination of alcohol responses 5 years after initial testing to determine the stability or change in alcohol responses over time and how they relate to drinking behaviors. Thus far, findings from our carefully designed laboratory and intermediate-term follow-up investigation has advanced new discoveries and challenged existing paradigms. Compared with light drinkers, heavy social drinkers have greater sensitivity to alcohol's stimulating and rewarding (liking, wanting) effects and lower sensitivity to sedative effects. These effects predicted future binge drinking through six years of follow-up. As the sample is now aging to their thirties, a developmental period when binge drinking is less normative, we now propose several extensions of the longitudinal aspects of the study. In Aim 1, we will extend follow-up during early middle adulthood in our existing cohorts (n=290) to discern binge drinking severity, alcohol use disorder symptoms, and drinking consequences during this transitional phase and evaluate the role of early-adult stimulating, rewarding, and sedating alcohol responses in predicting these behaviors. In Aim 2, we will conduct a second re-examination testing of alcohol response one decade after initial testing. This will enable full direct and longitudinal tests of incentive-sensitization, reward sensitivity and low response models of the development of addictive behavior. In Aim 3, we propose to conduct alcohol challenge testing in a new cohort of persons with alcohol dependence who are not seeking treatment (n=104) and compare them to existing heavy and light drinker cohorts (n=290). The information from this translational laboratory and longitudinal investigation will provide an evidence-based test of the role of alcohol response to escalations and maintenance of excessive drinking. Results have already advanced our knowledge of how alcohol responses predict future course of drinking, and the proposed extensions and new directions will further elucidate new empirical insights into the propensity for excessive and harmful drinking.

PROJECT SUMMARY/ABSTRACT: Smoking is an appetitive behavior and stimuli associated with nicotine?s desirable effects have been shown to increase smoking urge and behavior. As electronic nicotine delivery systems (ENDS, electronic cigarettes, or e-cigarettes) share salient features of traditional smoking in form and function, it is possible they could generalize as a conditioned cue to elicit smoking urge and behavior. This is of critical importance as the availability and rapid adoption of ENDS has led to increased second-hand exposures to vaping that occur in similar contexts as smoking. Thus, even one occasion of e-cigarette use could conceivably result in numerous ENDS products have rapidly evolved with increased popularity for tank systems with variable-voltage/wattage settings. These devices are used in conjunction with e-liquids that include various chemical constituents, including the primary humectant vegetable glycerin (VG). E-liquids with high levels of VG are desirable for both the throat hit as well as their ability to increase exhaled aerosol (vape) production which may affect their cue salience exposures to observers. . Well-controlled, evidence-based research is needed to elucidate the role of e-liquid constituents of ENDS and their aerosols that may affect tobacco use in observers. We propose the first large-scaled controlled study to address this issue. We will examine current and former smokers? cue reactivity to the use of a tank-based ENDS device with different VG content e-liquids. Study 1 will compare subjective and behavioral responses to the use of ENDS with high vs. low VG e-liquids, relative to both a non- smoking control cue (bottled water) and a cigarette cue (active comparison) in a diverse sample of adult daily and nondaily smokers (N=320, 80/cue condition). Study 2 will examine subjective responses to the high VG e- liquid ENDS cue compared to the control and active comparison cues in a sample of former smokers (N=240, 80/cue condition). Smoking behavior and cigarette reinforcement tasks will not be assessed in Study 2 for ethical reasons as participants are not currently smokers. Cue exposures will be delivered via a trained confederate engaging in product use in the presence of the participant. Thus, this paradigm mimics real-world exposures for ecological validity while retaining standardized cue delivery, hand to mouth movements, and interaction quality . The main dependent variables will be cigarette and e-cigarette desire, smoking urge, and smoking behavior (latency to smoke, smoking choice), as well as secondary outcomes including affect, cigarette reinforcement and attentional bias. The results will contribute to our scientific knowledge on the effects of ENDS in terms of the downstream effects of product use. The proposed studies will play a critical role in determining the role of e-liquid constituents that may factor into the ongoing debate about the ENDS? potential benefit versus harm. Second-hand exposures to these devices and the salience of their exhaled aerosols may be an important part of the equation in evaluating the overall effects of ENDS use in society.

Project Summary: The specific aim of this project is to experimentally examine the effect of alcohol on aggressive and impulsive responding, and on social-emotional information processing (SEIP) responses to threat, in individuals as a function of Alcohol Use Disorder (AUD) and prominent history of recurrent, problematic, impulsive aggressive behavior (AGG). While alcohol use is associated with impulsive aggression, little is known about the system neuroscience nature of this association except that the link between alcohol and aggression is most clear, and strongest, in individuals who are already high in trait aggression. Recent reports suggest that history of high lifetime alcohol use, in addition to acute alcohol dosing, dampens both cortical and subcortical responses to threat. In addition, acute alcohol administration appears to reduce cortical-subcortical connectivity, which some suggest is the primary correlate of alcohol-related aggressive behavior. However, this cannot explain all cases of alcohol-related aggression because neuronal correlates of aggression in non-alcoholics include an over, rather than under-activation of subcortical structures (i.e., amygdala) in the alcohol-free state. To advance our understanding of these complex relationships, we propose to study neuronal responses to socio-emotional threat in four groups of subjects: a) AUD and AGG (AUD+AGG); b) AUD without AGG (AUD); c) IED without AUD (AGG); and d) Healthy Controls (AUD-/AGG-), to uncover behavioral and neuro-circuitry differences in impulsive aggression and in the neuronal response to threat as a function of a history of AUD. Specifically, this study proposes to test the hypothesis that alcohol intoxication (0.08 mg%) is associated with increases in aggressive responding, and impairment in measures of SEIP, and to test the hypothesis that alcohol intoxication further affects cortico-limbic function in ways to increase the risk of impulsive aggression, though, perhaps, by different neuronal mechanisms as a function of AUD. Subjects will complete two (2) study sessions, in randomized order, in which each will receive intravenous alcohol (using alcohol clamp methodology), with alcohol doses clamped to achieve steady state alcohol breath levels of 0.08 mg%. Subjects will then complete a human laboratory aggression task and then an fMRI scanning session including two social-emotional information processing tasks: a) one that taps into the processing of explicit emotional cues of threat and, b) one that taps into the processing of ambiguous social cues of threat.

Abstract Adverse effects of excessive drinking are widespread in society. Understanding the factors that contribute to excessive alcohol consumption is crucial for improved prevention, education, and intervention. The goal of the Chicago Social Drinking Project (CSDP) is to evaluate the role of subjective and physiologic responses to alcohol in the escalation and maintenance of excessive drinking in adults. Our paradigm integrates human laboratory alcohol challenge with longitudinal assessment of drinking and related behaviors to discern whether alcohol responses predict future drinking problems and alcohol use disorder (AUD) symptoms. The CSDP has demonstrated that heightened sensitivity to alcohol stimulation and reward (liking, wanting) characterize young adult heavy drinkers (HD) versus light drinkers (LD) and these responses are primary predictors of future drinking progression and development of AUD over a decade later. This alcohol response phenotype is also evident in a newly-tested cohort of young adult AUD drinkers. Contrary to prevailing models of addiction propensity, our findings show a pervasive and sustained heightened sensitivity to alcohol stimulation and reward in excessive drinkers, and not low reward and negative reinforcement. In this award phase, we propose to further advance new discoveries and challenge existing paradigms by continuing to examine our high- retention cohorts in CSDP as well as enroll new cohorts. In Aim 1, we will extend a final follow-up wave in our existing HD and LD as well as extend follow-up in our ongoing young adult AUD cohort (N=398; >98% retention) to discern binge drinking severity, AUD symptoms, and drinking consequences during middle adulthood to evaluate the role of early-adult stimulating, rewarding, and sedating alcohol responses in predicting these behaviors. In Aims 2 and 3, we will enroll two new cohorts historically excluded from alcohol challenge research to provide potentially the most robust tests on the role of alcohol responses in excessive drinking. These include young adult HD with affective disorder (n=100) and older, chronic AUD drinkers (n=100; non-treatment-seeking), and their respective control groups (n=70 each), to determine if their alcohol response phenotype is characterized primarily by stimulation and reward sensitivity or by reward insensitivity and relief of negative affect or withdrawal states, as commonly theorized. These participants will undergo similar alcohol and placebo laboratory sessions and follow-up on drinking behaviors and AUD symptoms, as in established cohorts. As well-controlled research examining biphasic alcohol responses in clinically-relevant subgroups of comorbid and older AUD drinkers is lacking, determining their alcohol response phenotype offers a unique opportunity to test current theories of incentive-sensitization, reward sensitivity, and positive/negative reinforcement models of the development and maintenance of addictive behavior.