Preprint: Alcohol's effects during uncertain and uncontrollable stressors in the laboratory

Alcohol’s effects on reactivity to stressors depend on the nature of the stressor and the reactivity being assessed. Research identifying characteristics of stressors that modulate reactivity and clarifies the neurobehavioral, cognitive, and affective components of this reactivity may help prevent, reduce or treat the negative impacts of acute and chronic alcohol use with implications for other psychopathology involving maladaptive reactivity to stressors. We used a novel, multi-measure, cued electric shock stressor paradigm in a greater university community sample of adult recreational drinkers to test how alcohol (N=64), compared to No-alcohol (N=64), affects reactivity to stressors that vary in both their perceived certainty and controllability. Preregistered analyses suggested alcohol significantly dampened subjective anxiety (self-report) and defensive reactivity (startle potentiation) more during uncertain than during certain stressors regardless of controllability, suggesting that stressor uncertainty —but not uncontrollability— may be sufficient to enhance alcohol’s stress reactivity dampening and thus negative reinforcement potential.

Central stress allostasis among deprived and continuing marijuana users and non-users

Objective: We examined central nervous system stress allostasis (i.e., stress responses) among deprived and continuing heavy marijuana users and non-users. Method: Participants (N=210; 46.7% female; mean age=21.99; 91.4% White, 94.3% Non-Hispanic) were heavy marijuana users (N=134) and non-users (N=76). Heavy users were randomly assigned to a 3-day marijuana deprivation condition (N=68) or to continue using regularly (N=66). Participants completed 2 threat-of-shock stressor tasks that manipulated stressor predictability by varying shock probability or timing. We measured central stress allostasis via startle potentiation (stressor conditions minus matched no-stressor condition). We examined two group contrasts (heavy use: all heavy users vs. non-users; deprivation: deprived vs. continuing heavy users) on startle potentiation overall and moderated by stressor predictability (unpredictable vs. predictable). Results: Deprivation did not affect startle potentiation overall (timing task: p=0.184; probability task: p=0.328) or by stressor predictability (timing task: p=0.340; probability task: p=0.488). Heavy use did not affect startle potentiation overall (timing task: p=0.213; probability task: p=0.843) or by stressor predictability (timing task: p=0.683; probability task: p=0.348). Post-hoc analyses showed a general startle reactivity X deprivation interaction on startle potentiation overall (timing task: p=0.019; probability task: p=0.056) and by stressor predictability in the probability task (p=0.022) but not in the timing task (p=0.374). Conclusions: A history of marijuana use or acute deprivation did not alter central stress allostasis despite prominent theoretical expectations. This study adds to growing research on central stress allostasis in individuals with a history of drug use and begins to parse moderating roles of individual differences and stressor characteristics.

Preprint: Alcohol stress response dampening: Selective reduction of anxiety in the face of uncertain threat

Problematic alcohol use and stress-response dampening (SRD) are intimately interconnected. Recent evidence suggests that alcohol produces selective SRD during uncertain but not certain threat. We systematically varied shock probability in a novel task assessing alcohol SRD during low probable/uncertain threat, while holding temporal precision of threat constant. Intoxicated (0.08% target blood alcohol concentration) and placebo participants completed a cued shock threat task in which probability of shock administration at the offset of brief visual cues varied parametrically. High probability (100%) shock cues represented certain threat as used in earlier research, while lower probability (20% & 60%) shock cues provided novel uncertain threat conditions. Startle potentiation during cues and inter-trial-intervals (ITIs) served as the measure of affective response. General linear model analysis indicated that alcohol SRD magnitude increased monotonically as threat uncertainty increased. Alcohol SRD was significantly greater during 20% and 60% shock threat relative to 100% shock threat. Alcohol also significantly reduced startle potentiation during distal threat in shock-free ITIs. Alcohol SRD magnitude during distal/uncertain threat was meaningfully moderated by individual differences in negative affectivity and weekly alcohol consumption. This work advances understanding of which properties of uncertainty are relevant to anxiety and anxiolytic effects of alcohol.

Preprint: Alcohol stress response dampening: Selective reduction of anxiety in the face of uncertain threat

Problematic alcohol use and stress-response dampening (SRD) are intimately interconnected. Recent evidence suggests that alcohol produces selective SRD during uncertain but not certain threat. We systematically varied shock probability in a novel task assessing alcohol SRD during low probable/uncertain threat, while holding temporal precision of threat constant. Intoxicated (0.08% target blood alcohol concentration) and placebo participants completed a cued shock threat task in which probability of shock administration at the offset of brief visual cues varied parametrically. High probability (100%) shock cues represented certain threat as used in earlier research, while lower probability (20% & 60%) shock cues provided novel uncertain threat conditions. Startle potentiation during cues and inter-trial-intervals (ITIs) served as the measure of affective response. General linear model analysis indicated that alcohol SRD magnitude increased monotonically as threat uncertainty increased. Alcohol SRD was significantly greater during 20% and 60% shock threat relative to 100% shock threat. Alcohol also significantly reduced startle potentiation during distal threat in shock-free ITIs. Alcohol SRD magnitude during distal/uncertain threat was meaningfully moderated by individual differences in negative affectivity and weekly alcohol consumption. This work advances understanding of which properties of uncertainty are relevant to anxiety and anxiolytic effects of alcohol.

Preprint: Probing for Neuroadaptations to Unpredictable Stressors in Addiction: Translational Methods and Emerging Evidence

Stressors clearly contribute to addiction etiology and relapse in humans, but our understanding of specific mechanisms remains limited. Rodent models of addiction offer the power, flexibility, and precision necessary to delineate the causal role and specific mechanisms through which stressors influence alcohol and other drug use. This review describes a program of research using startle potentiation to unpredictable stressors that is well-positioned to translate between animal models and clinical research with humans on stress neuroadaptations in addiction. This research rests on a solid foundation provided by three separate pillars of evidence from 1) rodent behavioral neuroscience on stress neuroadaptations in addiction, 2) rodent affective neuroscience science on startle potentiation, and 3) human addiction and affective science with startle potentiation. Rodent stress neuroadaptation models implicate adaptations in corticotropin-releasing factor and norepinephrine circuits within the central extended amygdala following chronic alcohol and other drug use that mediate anxious behaviors and stress-induced reinstatement among drug-dependent rodents. Basic affective neuroscience indicates that these same neural mechanisms are involved in startle potentiation to unpredictable stressors in particular (vs predictable stressors). We believe that synthesis of these evidence bases should focus us on the role of unpredictable stressors in addiction etiology and relapse. Startle potentiation in unpredictable stressor tasks is proposed to provide an attractive and flexible testbed to encourage tight translation and reverse translation between animal models and human clinical research on stress neuroadaptations. Experimental medicine approaches focused on unpredictable stressors holds high promise to identify, repurpose, or refine pharmacological and psychosocial interventions for addiction.

Preprint: Increased startle potentiation to unpredictable stressors in alcohol dependence: Possible stress neuroadaptation in humans

Stress plays a key role in addiction etiology and relapse. Rodent models posit that following repeated periods of alcohol and other drug intoxication, compensatory allostatic changes occur in the central nervous system (CNS) circuits involved in behavioral and emotional response to stressors. We examine a predicted manifestation of this neuroadaptation in recently abstinent alcohol dependent humans. Participants completed a translational laboratory task that uses startle potentiation to unpredictable (vs. predictable) stressors implicated in the putative CNS mechanisms that mediate this neuroadaptation. Alcohol dependent participants displayed significantly greater startle potentiation to unpredictable than predictable stressors relative to nonalcoholic controls. The size of this effect covaried with alcohol-related problems and degree of withdrawal syndrome. This supports the rodent model thesis of a sensitized stress response in abstinent alcoholics. However, this effect could also represent pre-morbid risk or mark more severe and/or comorbid psychopathology. Regardless, pharmacotherapy and psychological interventions may target unpredictable stressor response to reduce stress-induced relapse.

Preprint: Using the Threat Probability Task to assess anxiety and fear during uncertain and certain threat

Fear of certain threat and anxiety about uncertain threat are distinct emotions with unique behavioral, cognitive-attentional, and neuroanatomical components. Both fear and anxiety can be studied in the laboratory by measuring the potentiation of the startle reflex. The startle reflex is a defensive reflex that is potentiated when an organism is threatened and the need for defense is high. The startle reflex is assessed via electromyography (EMG) in the orbicularis oculi muscle elicited by brief, intense, bursts of acoustic white noise (i.e., “startle probes”). Startle potentiation is calculated as the increase in startle response magnitude during presentation of sets of visual threat cues that signal delivery of mild electric shock relative to sets of matched cues that signal the absence of shock (no-threat cues). In the Threat Probability Task, fear is measured via startle potentiation to high probability (100% cue-contingent shock; certain) threat cues whereas anxiety is measured via startle potentiation to low probability (20% cue-contingent shock; uncertain) threat cues. Measurement of startle potentiation during the Threat Probability Task provides an objective and easily implemented alternative to assessment of negative affect via self-report or other methods (e.g., neuroimaging) that may be inappropriate or impractical for some researchers. Startle potentiation has been studied rigorously in both animals (e.g., rodents, non-human primate) and humans which facilitates animal-to-human translational research. Startle potentiation during certain and uncertain threat provides an objective measure of negative affective and distinct emotional states (fear, anxiety) to use in research on psychopathology, substance use/abuse and broadly in affective science. As such, it has been used extensively by clinical scientists interested in psychopathology etiology and by affective scientists interested in individual differences in emotion.