The Differentiator Model also suggests blunted sedative SR is an AUD risk factor, however, effect sizes for sedation are generally smaller. Both the LR and Differentiator models have garnered consider able empirical support in alcohol challenge research ; however, both models share some limitations. Human subjects research has not adequately tested whether SR represent a dynamic construct across the development of alcohol dependence and whether the motivational structure of alcohol consumption is altered in dependence vs. early non-dependent drinking. Recently, King et al. reported that the elevated stimulating and rewarding SR in heavy drinkers remained elevated over a 5-year period. Furthermore, this outcome was particularly strong among the ~10% of heavy drinking participants who showed high levels of AUD progression. In two previous alcohol challenge studies, we showed that stimulation/hedonia and craving are highly correlated among non-dependent heavy drinkers, whereas no stimulation-craving association was evidenced among alcohol dependent participants. These results were interpreted as being consistent with the Allostatic Model, insofar as the function of stimulation/ hedonia in promoting craving appeared diminished in alcohol dependence. Of note, however, neither study observed the hypothesized relationship between negative affect and craving among dependent participants. A primary limitation of these previous studies was the utilization of craving as a proxy end point for alcohol motivation and reinforcement. A recent study of young heavy drinkers found that both stimulation and sedation predicted free-access self-administration via craving. How ever,indoor cannabis grow system since this study did not include moderate–severe AUD participants, it is unclear whether the association between stimulation and self-administration is blunted in later-stage dependence.
This study was designed to test whether SR predicts motivated alcohol self-administration and whether this relationship is moderated by alcohol use severity, thus providing much needed insight about the function of SR in alcohol reinforcement and advancing an experimental framework for translational science. Heavy drinkers ranging in their severity of alcohol use and problems completed a novel intravenous alcohol administration session consisting of a standardized alcohol challenge followed by progressive-ratio alcohol reinforcement. On the basis of the Allostatic Model, we predicted a strong relationship between stimulation and self-administration at low alcohol use severity, whereas no such association would be observed at greater alcohol use severity. Conversely, it was hypothesized that negative affect would be a stronger predictor of alcohol self administration among more severe participants. These two hypotheses would thus capture dependence-related blunting of positive reinforcement and enhancement of negative reinforcement.This study was approved by the Institutional Review Board at UCLA. Non-treatment seeking drinkers were recruited between April 2015 and August 2016 from the Los Angeles community through fliers and online advertisements. Initial eligibility screening was conducted via online and telephone surveys followed by an in-person screening session. After providing written informed consent, participants were breathalyzed, provided urine for toxicology screening, and completed a battery of self-report questionnaires and interviews. All participants were required to have a BrAC of 0 mg% and to test negative on a urine drug screen. Female participants were required to test negative on a urine pregnancy test. Inclusion criteria were as follows: age between 21 and 45, caucasian ethnicity , fluency in English, current heavy alcohol use of 14+ drinks per week for men or 7+ for women, if female, not pregnant or lactating, and using a reliable method of birth control , and body weight of less than 265lbs to reduce the likelihood of exhausting the alcohol supply during the infusion.
Exclusion criteria were as follows: treatment seeking for AUD, current diagnosis of substance use disorder other than nicotine or alcohol, lifetime diagnosis of moderate-to-severe substance use disorder other than nicotine, alcohol, or cannabis, a diagnosis of bipolar disorder or any psychotic disorder, current suicidal ideation, current use of non-prescription drugs, other than cannabis, use of cannabis more than twice weekly, clinically significant physical abnormalities as indicated by physical examination and liver functioning labs, history of chronic medical conditions, such as hepatitis, or a chronic liver disease, current use of any psychoactive medications, such as antidepressants, mood stabilizers, sedatives, or stimulants, score ≥ 10 on the Clinical Institute Withdrawal Assessment for Alcohol-Revised indicating clinically significant alcohol withdrawal requiring medical management, and fear of, or adverse reactions to needle puncture.The aim of this study was to develop a clinical neuroscience laboratory paradigm to test predictions emerging from preclinical research. A key tenet of the Allostatic Model is that prolonged drinking produces neurobiological adaptations that diminish the salience of positive reinforcement while simultaneously producing abstinence-related dysphoria and potentiating negative reinforcement. In this study, we developed a novel IV alcohol administration paradigm in humans that combines standardized alcohol challenge methods with progressive ratio self-administration, providing a reliable assessment of subjective responses and a translational measure of motivation to consume alcohol, respectively. SR was measured in terms of positive dimensions , negative dimensions , sedation, and craving. Through integrating measures of subjective effects and behavioral reinforcement, we could test whether SR predicted self-administration behavior, thus capturing the relationships between reward and reinforcement central to allostatic processes. As expected, severity of alcohol use predicted greater overall alcohol craving and greater self-administration.
Further validating the paradigm,cannabis grow equipment we observed a robust relationship between self reported craving for alcohol during the challenge and subsequent reinforcement behavior. Interestingly, alcohol-induced increases in craving predicted self-administration independent of alcohol use severity suggesting that reactivity to a priming dose of alcohol may represent an independent risk factor for escalated alcohol consumption. Similar reactivity effects have been observed with respect to alcohol and stress. These results suggest that craving is a proximal predictor of alcohol consumption and thus is an appropriate target for intervention research. Our hypotheses regarding blunted positive reinforcement in severe alcoholism were not supported by these data. Alcohol use severity did not affect stimulation in the challenge, and stimulation did not robustly predict self-administration regardless of alcohol use severity. These results stand in contrast to our previous reports, which found diminished associations between stimulation/hedonia and craving in dependence, as compared to non-dependent heavy drinking. However, our previous studies used craving as a proxy end point for reinforcement, and thus, those results may not generalize to actual motivated alcohol consumption. Several recent CAIS studies have observed significant relationships between stimulation and self-administration; however, multiple study factors, including sample drinking intensity and alcohol use disorder severity, target BrAC, and free-access vs. progressive ratio schedules of reinforcement may explain these discrepancies. Our hypothesis that negative reinforcement would be stronger among more severe participants were only partially supported. Alcohol use severity was associated with greater levels of depressive symptomatology and basal negative affect, but alcohol use severity did not predict alcohol-induced alleviation of negative affect. Furthermore, negative affect did not robustly predict reinforcement behavior. While these negative affect findings are consistent with our previous studies on craving , they appear inconsistent with a body of literature that has demonstrated relationships between negative affect and naturalistic alcohol use. Most studies that have observed a relationship between negative affect and drinking behavior assess negative affectivity as a trait-like variable whereas this study assessed state negative affect immediately prior to the self administration paradigm. It is possible that participants completing a laboratory paradigm such as this are in an atypically positive mood since they are going to be compensated for their participation are anticipating receiving alcohol, and do not have to deal with daily life hassles during their participation. Secondly, it is possible that the predictors of alcohol self administration in a controlled laboratory setting are dissociable from predictors of naturalistic drinking which is more susceptible to exogenous factors such as drinking cues, peer influence, drinking habits/patterns, and life stressors. Future studies are necessary to examine these multiple possible explanations. In terms of sedation, these results were partially consistent with the Differentiator and Low Level of Response Models that advance sedation as a protective factor against excessive alcohol use.
Although alcohol use severity was associated with greater overall sedation, this effect represented a baseline difference that was carried forward rather than a difference in the acute responses to alcohol and greater sedation during the challenge did predict lower levels of self-administration. The lack of light-to-moderate drinkers in our sample may explain these counter intuitive challenge results, as most other studies compare lighter drinkers to heavy drinkers. This study should be interpreted in light of its strengths and weaknesses. The study benefits chiefly from a novel, highly controlled, and translational alcohol administration paradigm that measures alcohol reward and reinforcement and isolates reactivity to alcohol-related cues. The primary limitation was the relatively small sample of participants with severe AUD per DSM-5. The fact that, for ethical reasons, participants were required to be non treatment seeking and able to produce a zero on a breathalyzer test at each visit may have impeded recruitment of severe AUD participants. While severe AUD participants were enrolled, this subgroup was smaller and generally represented the lower range of severe AUD. Allostatic neuroadaptations may occur chiefly at higher levels of dependence severity, such as those induced by the ethanol vapor paradigm and participants at this level of severity would likely have been excluded from this study for safety reasons. The relatively scarcity of severe AUD participants also reduces statistical power to detect effects that are expected to arise at this severe range. That said, our sample is comparable to other “severe” samples recruited in alcohol challenge studies. A substantial self-administration ceiling effect, where 36% of participants reached the BrAC safety threshold, may also have affected our results. Additionally, the sample restriction to Caucasian ethnicity limits the generalizability of these results. Lastly, though this study was cross-sectional, allostatic processes are necessarily longitudinal. In these analyses, alcohol use severity was used as a proxy for this longitudinal process capturing multiple facets of alcohol use and problems; However, this approach assumes a relatively linear and progressive course of alcoholism, which may not represent many AUD patients. In conclusion, this study represents a novel approach to translating preclinical theories of addiction to human-subjects research. In these data subjective craving strongly predicted reinforcement behavior and sedation was moderately protective. Conversely, we observed relatively little evidence for the allostatic processes of diminished positive reinforcement and enhanced negative reinforcement in participants with relatively severe alcohol use and problems. Further studies refining and enhancing this translational paradigm, for example by including affective manipulations to test the role of stress in reward and reinforcement are warranted. Interestingly, ecological research has high lighted the role of acute stress events in predicting drug use as opposed to basal negative affect which was measured in this study. Furthermore, given the severity of dependence induced by preclinical paradigms, recruitment of more severe AUD samples may be necessary for a robust translational examination.Our perceptions of what other people do often affect what we do. In these situations, biases in perceptions can affect what everyone does. By combing the psychology of bias and the economics of equilibrium, we construct a model to predict how individual biases affect aggregate behavior.Empirical studies often find a general tendency to over-estimate the violation of social norms by other people. Over-estimating how badly other people behave is a form of moral pessimism that psychologists call the “uniqueness bias.”We show that persistence of this bias causes more people to violate the norm than if the bias were corrected. In addition, this bias increases the probability that behavior will settle into a “bad” equilibrium with many wrongdoers, instead of settling into a “good” one with few wrongdoers. Our results suggest that researchers who found false pessimism with respect to protection of trade secrets, tax compliance, alcohol abuse, and water conservation are right to predict that this bias will cause more people to do wrong. Empirical studies also find that a person often over-estimates how many other people act the same as he does, Over-estimating how other people behave like yourself is a form of social projection that psychologists call the “false-consensus bias” or “pluralistic ignorance.”We show that persistence of this bias does not change the number of people who violate the norm. According to our model, researchers who found social projection with respect to water conservation, smoking, and drugs are wrong to predict that this bias will cause more people to do wrong.