Human studies examining CNS sequelae of chronic marijuana use provide evidence for increased metabolism and activation of alternate neural pathways within these regions . Further adverse effects may result from the pharmacological interaction of alcohol and marijuana, where THC has been reported to markedly enhance apoptotic properties of ethanol. In infant rats, administration of THC alone did not result in neurodegeneration; however, the combination of THC and a mildly intoxicating dose of ethanol induced significant apoptotic neuronal cell death, similar to that observed at high doses of ethanol alone . In sum, studies of adolescent alcohol and marijuana use indicate weaknesses in neuropsychological functioning in the areas of attention, speeded information processing, spatial skills, learning and memory, and complex behaviors such as planning and problem solving even after 28 days of sustained abstinence . There are also associated changes in brain structure and function that include altered prefrontal, cerebellar, and hippo campal volumes, reduced white matter microstructural integrity, and atypical brain activation patterns . There may be potential reversibility of brain structural changes with long-term abstinence , though additional studies are needed to understand the extent to which abnormalities persist or remit with time. Further, the potential interaction of alcohol and marijuana are of concern considering that comorbid use is common .It is postulated that there is an asynchronous development of reward and control systems that enhance adolescents’ responsivity to incentives and risky behaviors . Bottom-up limbic systems involved in emotional and incentive processing purportedly develop earlier than top down prefrontal systems involved in behavioral control. In situations with high emotional salience,drying cannabis the more mature limbic regions will override prefrontal regions, resulting in poor decisions.
The developmental imbalance is unique to adolescents, as children have equally immature limbic and prefrontal regions, while adults benefit from fully developed systems. Within this model, risky behaviors of adolescents is understood in light of limbic system driven choices to seek immediate gratification rather than long-term gains. Moreover, this relationship may be more pronounced in adolescents with increased emotional reactivity. Behavioral and fMRI studies show increased subcortical activation when making risky choices and less activation of prefrontal cortex, as well as immature connectivity between emotion processing and control systems overall . A more specific characterization of these patterns using comparisons of low- and high-risk gambles indicated that high-risk choices activate reward-related ventral striatum and medial prefrontal cortex, whereas low-risk choices activate control-related dorsolateral prefrontal cortex. Interestingly, activation of the ventral medial prefrontal cortex was positively associated with risk-taking propensity, whereas activation of the dorsal medial prefrontal cortex was negatively associated with risk-taking propensity , suggesting that distinct neural profiles may contribute to the inhibition or facilitation of risky behaviors.Development of effective treatments for alcohol use disorder remain a high priority area which involves screening compounds in the laboratory before proceeding to clinical trials . Within this process, there is a need to develop and understand relationships among human laboratory paradigms to assess the potential efficacy of novel AUD treatments in early-stage clinical trials. To date, reviews of the human laboratory literature in AUD pharmacotherapy development indicate significant outcome variability based on experimental paradigm parameters, population of interest, and sample size, and suggest that these myriad variables contribute to the disconnect between laboratory effect sizes and treatment outcomes . Amidst the efforts to develop translational experimental paradigms, neuroimaging tasks are increasingly used to explore potential pharmacotherapy effects on neural correlates of alcohol-induced craving . Alcohol consumption produces neuroadaptations in multiple circuits, including GABA-ergic regulation of traditional reward circuitry; alcohol craving is mediated by cortico-striatal-limbic activation, heightens relapse risk , and can be triggered through internal and external stimuli associated with alcohol consumption .
For this reason, neuroimaging techniques, such as functional magnetic resonance imaging , have been used to explore these circuits as potential medication targets. Recent qualitative reviews and meta-analyses suggested that while such fMRI tasks vary in sensory experiences and scan parameters, mesocorticolimbic areas consistently exhibit task-based neural activity and may be viable tools in understanding mechanisms of AUD pharmacotherapy . Based on this emerging literature, there is growing evidence that neural responses to alcohol cues and associated contexts are predictive of real-world consumption behavior and, potentially, clinical outcomes. For instance, among college students, alcohol cue-elicited blood oxygen level-dependent response in caudate, frontal cortex, and left insula predicted escalation to heavy drinking over a 1-year period. Further, insula and frontal gyrus activation in response to an emotion face recognition task similarly predicted alcohol related problems five years later in young adults . Regarding treatment outcomes, increased ventral striatum activation in response to alcohol cues was associated with a faster time to relapse in a sample of abstinent AUD individuals . Comparisons of AUD treatment completers and non-completers in a community sample indicated that non-completers showed stronger associations between reported alcohol craving intensity and resting state functional connectivity between striatum and insula, relative to completers . Of note, one study had contradicting results by reporting that relapsers, compared to successful alcohol abstainers and healthy controls, exhibited reduced alcohol cue-elicited activation in ventral striatum and midbrain . Several studies have examined whether AUD pharmacotherapies alter neural responses to contexts that elicit alcohol craving, including alcohol cues, exposure to reward and emotional faces, and stress exposure. While significant variability exists in sample populations, examined tasks, modified areas of activation, and molecular targets of treatments, there is some consistent evidence that AUD pharmacotherapies may reduce reward-related activation in regions such as the ventral striatum, precuneus, and anterior cingulate . Importantly, in one study of naltrexone, magnitude of reduction in alcohol cue-induced ventral striatum activation was associated with fewer instances of subsequent heavy drinking . In support, Mann and colleagues have found that individuals with high ventral striatum cue reactivity demonstrate lower relapse rates when treated with naltrexone than those with low VS reactivity. Bach and colleagues have also identified that individuals with high alcohol cue-reactivity in the left putamen exhibit longer time to relapse when treated with naltrexone, compared to those with low reactivity.
Together, these studies underscore reward circuitry as a key area in the translation of neural responses to clinical outcomes in AUD medication development . Alcohol self-administration tasks in the laboratory are thought to capture alcohol use behavior in controlled settings that approximate consumption in real world settings. Studies have tested multiple variants of self-administration paradigms,ebb flow including tasks that require participants to orally consume alcohol at the cost of monetary rewards per drink , and intravenous methods that can closely control breath alcohol concentration levels e.g. computer assisted self-infusion of ethanol.Studies have used self administration methods to test genetic, physiological, and psychological risk factors for heavy drinking .While both fMRI cue-reactivity tasks and alcohol self administration tasks are widely used in alcohol research, the extent to which cue-reactivity predicts self-administration in the laboratory remains unknown. In light of the emerging role of functional neuroimaging in predicting drinking behavior and AUD treatment outcomes, a remaining question is the nature of the relationship between neuroimaging task-induced neural activation and widely utilized laboratory paradigms considered proximal to real-world consumption, including self-administration tasks. To date, several studies have examined relationships of response across different laboratory paradigms and have consistently identified that alcohol craving during intravenous alcohol administration mediates the relationship between alcohol induced stimulatory effects and subsequent oral alcohol consumption . While relationships across human laboratory paradigms are recently delineated, no studies have yet investigated whether alcohol cue-induced BOLD response is predictive of responses within laboratory self-administration paradigms. 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. Participants for this secondary analysis of an experimental laboratory study on naltrexone a score of 8 or higher on the Alcohol Use Disorders Identification Test AUDIT; self-identification of East Asian ethnicity lifetime non-alcohol substance use disorder clinically significant levels of alcohol withdrawal (indicated by a score of 10 or higher on the Clinical Institute Withdrawal Assessment-Revised CIWA-AR for women, pregnancy.
Interested individuals completed an in-person laboratory screening visit to learn about the study, provide written informed consent, and to assess for inclusion and exclusion criteria. Of note, this study collected information on genotypes encoding endogenous opioid receptors thought to mediate the stimulating effects of alcohol , as well as those associated with metabolism of alcohol . Participants provided a saliva sample for DNA analyses and completed a medical screening that included a physical examination. Detailed information on recruitment procedures are available in the primary manuscripts from which the current study is based . A study procedure flowchart can be seen in Figure 1.Study procedures followed a double-blind, randomized, placebo-controlled and counterbalanced design.Within each medication condition, participants were titrated to the medication for 5 days . Participants completed an fMRI scan on day 4 and an alcohol self-administration session on day 5 of the medication regimen. At the start of each experimental session, participants completed a urine toxicology screening; all participants tested negative for exclusionary substances during these screening periods. There was a minimum wash-out period between medication conditions of 7 days, with a range of 7-10 days. Regarding medication adherence, naltrexone and placebo capsules were packaged with 50mg of riboflavin. A visual inspection of riboflavin content under ultraviolet light indicated that all urine samples tested positive for riboflavin content. At the start of the scanning session , participants were required to have a BrAC of 0.00 g/dL, negative urine toxicology screen for all substances except cannabis, and negative pregnancy screen. Participants who smoked cigarettes were allowed to smoke 30 minutes prior to the scan to prevent acute nicotine withdrawal and craving.Within each task trial, participants initially viewed a visual cue for 2 seconds, followed by a fixation cross . The word “Taste” then appeared, corresponding to oral delivery of the indicated liquid at the start of the trial . Participants were also instructed to press a button on a button box to indicate the point at which the bolus of liquid was swallowed and this information was used to model motion associated with swallowing. There were two runs of this task, with 50 trials per run.Red or white wine, based on participant preference, was used as the alcohol stimulus; previous work from our group has demonstrated that this paradigm has been used to effectively elicit alcohol-related neural activation . Carbonated alcohol, such as beer, could not be systematically administered with the paradigm apparatus and was not offered as a drink option to participants. Visual stimuli and response collection were programmed using MATLAB and Psychtoolbox , and visual stimuli were presented using MRIcompatible goggles. Participants completed an oral alcohol self-administration paradigm on day 5 of medication titration. At the start of this session, participants were required to test negative for substance use and to have a BrAC of 0.00 g/dl. Female participants were also required to test negative on a pregnancy test. Participants fasted for two hours prior to the session and were given a standardized meal before the alcohol administration. Participants initially completed an intravenous alcohol administration discussed in the primary manuscript . After completing the alcohol infusion paradigm and reaching a target BrAC of 0.06 g/dl, the IV was removed and, after a standardized period of five minutes, participants subsequently began an oral self-administration session at the testing center. Notably, the alcohol dose of 0.06 g/dl prior to the self-administration period was higher than the typical 0.03 g/dl priming dose implemented in self-administration tasks During the self-administration period, participants were provided 4 mini-drinks of their preferred alcoholic beverage and allowed to watch a movie over a 1-hour period.