Given the strong evidence for neurological alterations at the basis of drug dependence, functional magnetic resonance imaging (fMRI) represents an important tool in the clinical neuroscience of addiction. fMRI cue-reactivity paradigms represent an ideal platform to probe the involvement of neurobiological pathways subserving the reward/motivation system in addiction and potentially offer a translational mechanism by which interventions and behavioral predictions can be tested. Thus, this review summarizes the research that has applied fMRI cue-reactivity paradigms to the study of adult substance use disorder treatment responses. Studies utilizing fMRI cue-reactivity paradigms for the prediction of relapse, and as a means to investigate psychosocial and pharmacological treatment effects on cue-elicited brain activation are presented within four primary categories of substances: alcohol, nicotine, cocaine, and opioids. Lastly, suggestions for how to leverage fMRI technology to advance addiction science and treatment development are provided.

Current directions in medication development for alcohol use disorder (AUD) emphasize the need to identify novel molecular targets and efficiently screen new compounds aimed at those targets. Ibudilast (IBUD) is a neuroimmune modulator that inhibits phosphodiesterase-4 and -10 and macrophage migration inhibitory factor and was recently found to reduce alcohol intake in rats by ∼50%. To advance medication development for AUD, the present study consists of a randomized, crossover, double-blind, placebo-controlled laboratory study of IBUD in nontreatment-seeking individuals with current (ie, past month) mild-to-severe AUD. This study tested the safety, tolerability, and initial human laboratory efficacy of IBUD (50 mg b.i.d.) on primary measures of subjective response to alcohol as well as secondary measures of cue- and stress-induced changes in craving and mood. Participants (N=24) completed two separate 7-day intensive outpatient protocols that included daily visits for medication administration and testing. Upon reaching a stable target dose of IBUD (or matched placebo), participants completed a stress-exposure session (day 5; PM), an alcohol cue-exposure session (day 6; AM), and an i.v. alcohol administration session (day 6; PM). Participants stayed overnight after the alcohol administration, and discharge occurred on day 7 of the protocol. Medication conditions were separated by a washout period that was ⩾7 days. IBUD was well tolerated; however, there were no medication effects on primary measures of subjective response to alcohol. IBUD was associated with mood improvements on the secondary measures of stress exposure and alcohol cue exposure, as well as reductions in tonic levels of craving. Exploratory analyses revealed that among individuals with higher depressive symptomatology, IBUD attenuated the stimulant and mood-altering effects of alcohol as compared with placebo. Together, these findings extend preclinical demonstrations of the potential utility of IBUD for the treatment of AUD and suggest that depressive symptomatology should be considered as a potential moderator of efficacy for pharmacotherapies with neuroimmune effects, such as IBUD.

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The approach recommended herein is largely consistent with the Research Domain Criteria (RDoC) initiative across the National Institute of Mental Health. The defining feature of such domains is that they inform behavior yet be amenable to examination through multiple units of analysis, such as molecular, genetic, circuit-level, and behavioral measurements. To that end, we contend that subjective response to alcohol represents a behaviorally and biologically plausible phenotype upon which to build using the RDoC framework for understanding alcohol use disorder.

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Rationale While persons at risk for alcohol dependence by virtue of heavy drinking patterns or family history (FH) of alcohol use disorders have exhibited differential alcohol responses on a variety of measures, few studies have examined alcohol's effects on eye movements in these subgroups. Objectives The purpose of this study was to (1) conduct a placebo-controlled, dose-ranging study of alcohol's effects on eye movements and (2) examine the impact of these risk factors on oculomotor response to alcohol. Methods A within-subject, double-blind laboratory study was conducted in N=138 heavy (HD; n=78) and light social drinkers (LD; n=60) with self-reported positive (FH+) or negative (FH−) family history. Subjects participated in three laboratory sessions in which they consumed a beverage containing a high (0.8 g/kg) or low (0.4 g/kg) dose of alcohol or placebo. Smooth pursuit, pro-saccadic, and anti-saccadic eye movements were recorded before and at two intervals after alcohol consumption. Results Alcohol significantly impaired smooth pursuit gain and pro- and anti-saccade latency, velocity, and accuracy in a dose and time specific matter. HD and LD showed similar impairment on smooth pursuit gain and anti-saccade measures, but HD were less impaired in pro-saccade latency, velocity, and accuracy. FH+ and FH− subjects were equally impaired in nearly all pro- and anti-saccade measures, but FH+ were less impaired in smooth pursuit gain. Conclusions In sum, alcohol produced systematic impairment on oculomotor functioning, even at a non-intoxicating dose. Furthermore, high- and low-risk drinkers may be vulnerable to select performance deficits relative to eye movement task.

Background Varenicline is a partial nicotinic receptor agonist that is an effective smoking cessation medication. Preliminary evidence indicates that it may also reduce alcohol consumption but the underlying mechanism is not clear. For example, varenicline may reduce alcohol consumption by attenuating its subjectively rewarding properties or by enhancing its aversive effects. In this study, we examined the effects of an acute dose of varenicline upon subjective, physiological and objective responses to low and moderate doses of alcohol in healthy social drinkers. Methods Healthy men and women (N=15) participated in six randomized sessions; three sessions each with 2mg varenicline and placebo followed 3 hours later by a beverage containing placebo, low dose alcohol (0.4g/kg), or high dose alcohol (0.8g/kg). Subjective mood and drug effects (i.e., stimulation, drug liking), physiological measures (heart rate, blood pressure), and eye tracking tasks were administered at various intervals before and after drug and alcohol administration. Results Varenicline acutely increased blood pressure, heart rate, ratings of dysphoria and nausea, and also improved eye tracking performance. After alcohol drinking (vs placebo), varenicline increased dysphoria and tended to reduce alcohol liking ratings. It also attenuated alcohol-induced eye-tracking impairments. These effects were independent of the drug’s effects on nausea before drinking. Conclusions Our data support the theory that varenicline may reduce drinking by potentiating aversive effects of alcohol. Varenicline also offsets alcohol-induced eye movement impairment. The evidence suggests that varenicline may decrease alcohol consumption by producing effects which oppose the rewarding efficacy of alcohol.

Background Subjective responses to alcohol (SR) have been implicated in alcoholism etiology, yet less is known about the latent factor structure of alcohol responses. The aim of this study is to examine the factor structure of SR using a battery of self-report measures during a controlled alcohol challenge. Methods Non-treatment seeking drinkers (N = 242) completed an intravenous alcohol challenge including the following SR measures: Biphasic Alcohol Effects Scale, Subjective High Assessment Scale, Profile of Mood States, Alcohol Urge Questionnaire, and single items assessing alcohol ‘Liking,’ and ‘Wanting.’ Ascending limb target Breath Alcohol Concentrations were 0.02, 0.04 and 0.06, and descending limb target was 0.04 g/dl. Exploratory factor analyses were conducted separately on estimates of mean and dose responses on the ascending limb and on descending limb data. To examine the generalizability of this factor structure these analyses were repeated in heavy drinkers (≥14 drinks/week for men, ≥7 for women; n = 132) and light drinkers (i.e. non-heavy drinkers; n = 110). Results In the full sample, a 4-factor solution was supported for ascending limb mean and dose responses and descending limb data representing the following SR domains: Stimulation/Hedonia, Craving/Motivation, Sedation/Motor Intoxication, and Negative Affect. This 4-factor solution was replicated in heavy drinkers. In light drinkers however, SR was better summarized by a 3-factor solution where ascending mean and descending limb responses consisted of Stimulation/Hedonia, Craving/Motivation and a general negative valence factor, and dose responses consisted of a general positive valence factor, Sedation/Motor Intoxication and Negative Affect. Conclusions These findings suggest that SR represents a multifaceted construct with consistent factor structure across both ascending and descending limbs. Further, as drinking levels escalate more defined Craving/Motivation and negative valence dimensions may emerge. Longitudinal studies examining these constructs are needed to further our understanding of SR as potentially sensitive to alcohol-induced neuroadaptation.