To address this gap in the literature and to further integrate neuroimaging and human laboratory paradigms for AUD, the current study examines whether alcohol taste cue-induced ventral striatum activation predicts subsequent oral alcohol self-administration in the laboratory. These secondary analyses are conducted in a within-subjects design whereby the same participants completed an fMRI cue-reactivity task followed by an alcohol-self administration task . As striatal activation is thought to underlie craving responses , we hypothesized that those with greater ventral striatum activation would consume their first drink faster than those with lower activation. Similarly, as previous research has demonstrated that mesolimbic activity predicts real-world heavy drinking, we hypothesized that ventral striatum activation would also be positively associated with the total number of drinks consumed during the self-administration paradigm. For the taste cues paradigm, information regarding image acquisition parameters and preprocessing steps are available in Supplementary Materials and are derived from the primary manuscript . The main contrast of interest was the difference in activation corresponding to alcohol taste delivery and water delivery across the two task runs , for each within-subject medication condition. Consistent with previous studies examining relationships among ventral striatum activity, subjective response to alcohol, and drinking behavior , an anatomical bilateral ventral striatum region of interest was defined using the Harvard-Oxford atlas in standard MNI space and was transformed into participants’ respective native space using FSL’s FLIRT . This ROI was selected because ventral striatum is most consistently elicited in alcohol cue and taste reactivity paradigms, as well as most frequently associated with behavioral measures and treatment response .The mean contrast estimate values were extracted from this region for each subject and used in mixed models for group-level analysis . The self-administration paradigm yielded two outcome measures: latency to first drink ,cannabis grower and total number of drinks consumed during the session . To examine the relationship between alcohol taste-induced neural activation and self-administration, multilevel mixed poisson and cox proportional hazard models were the primary analyses for total number of drinks and latency to first drink, respectively.

Frailty models were fitted using a penalized partial likelihood approach available in SAS 9.4 . Primary analyses examined effects of variables of interest, including medication condition , alcohol consumption , and OPRM1. Due to concerns of over parameterization given the limited sample size, additional covariates of interest were individually included in separate models to determine whether main effects of ventral striatum would be altered. Alpha corrections were not utilized in this exploratory study due to limited sample size and constrained power. Tests of proportional hazards are included in Supplementary Materials and Figures S1a-S1d. Survival plots for latency to first drink, controlling for covariates within the final model , were generated to further explore ventral striatum activation in predicting latency to first drink. Of note, a dichotomous median-split ventral striatum variable was created for ease of visualization of these relationships, but ventral striatum activation was included as a continuous variable in all models.The distribution of latencies to first drink was non-normal. Across medication conditions, 52% of individuals refrained from drinking throughout the paradigm, 29% consumed a drink within the first three minutes of the paradigm, and 19% of individuals consumed their first drink at some point during the remainder of the session. Cox regressions for latency to first drink indicated a significant effect of ventral striatum activation, Wald χ2 = 2.88, p = 0.05, such that those with lower ventral striatum activation exhibited longer latencies to first drink . Significant covariates included medication condition, Wald χ2 = 5.99, p = 0.01, such that naltrexone was associated with longer latency to first drink. OPRM1 was also significant, Wald χ2 = 3.31, p = 0.03, such that Asn40Asn homozygotes exhibited shorter latency to first drink. Other covariates of interest were not associated with latency to first drink . There were also no interactions of medication X gender on self-administration outcomes. This study examined the relationship between alcohol cue-induced ventral striatum activation and alcohol self-administration in the laboratory. Results from this heavy-drinking sample of East Asians indicated that higher ventral striatum activation was associated with a shorter latency to first self-administered drink. Similarly, ventral striatum activation was positively associated with the total number of drinks consumed during the self-administration paradigm in this sample.

These results remained significant after controlling for severity of drinking patterns, OPRM1, and medication condition. Overall, this is the first study to examine whether neuroimaging outcomes of interest can predict responses within laboratory paradigms commonly used in the alcohol literature. This foundational work adds important validity to the hypothesized interplay between neural bases of alcohol craving and behavioral measures of alcohol seeking, namely alcohol self-administration in the human laboratory. These associations contribute to a growing literature on the translational value of neuroimaging paradigms in alcohol treatment, particularly in elucidating potential mechanisms through which self-administration paradigms in AUD research are related to real world alcohol consumption . Such work is aligned with current efforts in behavioral treatments utilizing neuroimaging to study mechanisms of behavior change for substance use disorders; identifying those individuals with severe orbitofrontal cortex deficits, for instance, may be useful in guiding them away from treatments focused on increasing the salience of future negative consequences of substance use . In a similar fashion, adjunctive fMRI has been used to train individuals with substance use disorders through resonance-based breathing to reduce visual processing of drug cues and increase activation in areas implicated in internally directed cognition . Elucidating the translational value of these various experimental paradigms is strongly indicated, as AUD medications can exhibit differential results based on the utilized paradigm and such variability may in turn inform precision medicine efforts. Expanding the study of interexperimental paradigms may also shed light on aspects of alcohol consumption unique to individual paradigms. For instance, a greater understanding of individuals’ experiences in the transition between the first and subsequent drinks may be an important point of clinical interventions when discussing naltrexone use. While the primary aim of this study was not focused on genetic determinants of self-administration, it is notable that genotypes encoding the binding potential of mu-opioid receptors were associated with self-administration outcomes. While it is theorized that individuals with at least one copy of the G-allele for OPRM1 exhibit greater vulnerability to developing AUD, meta-analyses have been mixed, with findings that such an association may not be reliable , are population specific ,or that G-allele confers a modest protective effect on general substance dependence in European ancestry cohorts .

In this study, G-allele carriers of OPRM1 exhibited lower total consumption relative to A-allele carriers at a statistical trend level, as well as slower latency to first drink. This finding is consistent with the primary analyses for this data , which indicated that G-allele carriers of OPRM1 also reported less severe drinking history and lower AUDIT scores compared to Asn40 homozygotes and may, in turn, help to explain these findings. In sum, we accounted for genetic factors in these analyses given their theoretical and practical salience ,growing cannabis outdoors particularly in this population . And while the genetic findings are notable and largely consistent with the literature, the primary focus on the study is on the fMRI to human laboratory association. This is the area in which the present analyses make a substantive contribution to the literature by supporting a long hypothesized, yet rarely tested, association between brain and behavior. Finally, this study identified significant effects of naltrexone in increasing latency to first drink and decreasing total alcohol consumption. Notably, while these contrast the primary study results from which the data are derived the current study is a secondary analysis of a sub-sample of participants who had completed both neuroimaging sessions. While inclusion of VS activation may have helped to improve model fit, the primary study had greater power in order to test pharmacogenetic effects. For these reasons, while it is possible that consideration of neuroimaging outcomes help elucidate AUD pharmacotherapy effects, replication using larger samples is warranted. On balance, this study should be interpreted in light of its strengths and limitations. Strengths included assessment of multiple experimental procedures used in the medication development literature and consideration of multiple psychiatric and genetic predictors of self-administration in the statistical analyses. Another strength is the test of hypothesis at the within subjects level of analysis. As argued by Curran and Bauer , several psychological processes which are inherently within-person processes, such as the relationship between how one’s brain processes alcohol cues and how much s/he wants to drink in the future, are presumed to be explained in between-subjects models, when in fact, within-subject analyses provide a more representative test of the process at hand . Thus, a within-subjects approach represents a more robust, and methodologically adequate, test of the association between brain and behavior. One of the most important limitations of the current study is a constrained sample and power; given the exploratory nature of this study, alpha corrections were not implemented. A limitation of the taste cues fMRI paradigm used in this study is that it was modified to reduce trial duration in order to increase the number of trials for analysis; in contrast to the original task , a whole-brain analysis of the task did not elicit significant clusters of mesocorticolimbic, including ventral striatum, activation. Therefore, replication using other tasks that more strongly elicit ventral striatum activation are needed, both to induce significant enough variability to test medication effects and also to translate such effects into another subsequent experimental modality.

Variations of the Monetary Incentive Delay task that administer beer may be particularly useful in disentangling whether anticipation, relative to receipt, of alcohol taste are differently discriminant in predicting self-administration Relatedly, the taste cues paradigm was limited to the choice of red or white wine, which did not always correspond with participants’ drink of choice; while this correspondence was not a significant covariate in self-administration outcomes, administering drink of choice may increase external validity of the imaging task. Another potential weakness is that medication effects from the primary manuscripts were null; future studies are needed to corroborate that medication effects are consistent across paradigms, particularly in identifying significant such effects. An additional warranted question is whether such consistency of medication effects in laboratory studies would translate directly to clinical outcomes and treatment-seeking populations. Lastly, the “priming dose” that preceded the self-administration period was higher than the usual 0.03 g/dl reported in the literature. While the higher priming dose of alcohol in this study did not suppress alcohol self-administration, it may be interpreted differently in that participants were seeking to self-administer to reach high levels of BrAC, perhaps binge-like levels. If that was the case, results would remain highly relevant and consistent with recent efforts to phenotype binge-drinking in the human laboratory . Limitations notwithstanding, the present findings provide proof-of-concept that neuroimaging and laboratory paradigms may be closely linked. Further, neuroimaging may be a useful tool to explore in greater detail how different paradigms are related to real world consumption behavior. Future studies are warranted to replicate the current results and to identify, refine, and implement translational paradigms in AUD research.In the European Union and the United States, 3,4-methylenedioxymethamphetamine is currently a schedule I controlled substance . The interest in MDMA use in psychiatry has solidified and is growing following publications of results from multiple controlled trials including a Phase 3 study for MDMA assisted therapy for post-traumatic stress disorder . MDMA’s psychoactive properties are due to multiple mechanisms that modulate monoamine neurotransmission, including release and reuptake of serotonin, dopamine and norepinephrine . Proposed therapeutic mechanisms of MDMA may include increased ability to confront upsetting memories, supporting fear-extinction learning and increased interpersonal closeness . Adverse events observed in controlled trials included transient hypertension, muscle tightness, decreased appetite, nausea, hyperhidrosis and feeling cold . Serotonin syndrome is a potentially life-threatening condition resulting from serotonergic over-activity at synapses of the central and peripheral nervous systems usually involving serotonergic medications . SS manifests itself through a range of mild to severe symptoms. Mild symptoms include akathisia and tremors, and severe symptoms include hyperthermia and muscular rigidity, which can be life-threatening .