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

Abstract

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 (a) rodent behavioral neuroscience on stress neuroadaptations in addiction, (b) rodent affective neuroscience on startle potentiation, and (c) 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 test bed to encourage tight translation and reverse translation between animal models and human clinical research on stress neuroadaptations. Experimental therapeutics approaches focused on unpredictable stressors hold high promise to identify, repurpose, or refine pharmacological and psychosocial interventions for addiction.

Figure 1.

The elicitation and measurement of startle potentiation in rodents and humans. This figure illustrates methods for the elicitation and measurement of startle potentiation during cued threat in rodents and humans. In this article, we review evidence that the psychological and neural mechanisms for startle potentiation are comparable across species. This evidence combines with the highly parallel methods in rodents and humans to position startle potentiation during cued threat for effective translational and reverse translational research across species. Cue (left column): Across species, cued threat is established by pairing electric shock (depicted as red lightning bolt) with a brief presentation of a distinct cue (Cue+; e.g., colored geometric shape on computer monitor in humans, light turned on in rodents). This Cue+ condition is typically contrasted with a no-threat condition (Cue-; e.g., alternative geometric shape in humans, light off in rodents). Measurement (center column): During each cue condition, the startle response is elicited across species by a sudden, intense, acoustic noise (i.e., the “startle probe” depicted by speaker image). In rodents, startle response magnitude is measured by quantifying cage movement (via accelerometer) caused by the reflexive movement of their full body to the startle probe. In humans, startle response magnitude is measured by quantifying their reflexive eye blink (via electromyography recording from the orbicularis oculi muscle under the eye) to the startle probe. Potentiation (right column): Across species, startle potentiation represents a contrast of startle response magnitude in the Cue+ versus Cue-conditions. Figure © Chris Kubiak, Drawski LLC. Reprinted with permission.

Figure 2.

No-Shock, Predictable Shock, Unpredictable Shock (NPU) task. In the NPU task, participants view a series of distinct visual cues presented briefly (e.g., 5 seconds) on a computer monitor. Cues are presented in a counterbalanced blocked design in three different conditions: No Shock, Predictable Shock, and Unpredictable Shock. The upper panel depicts an exemplar of one within-subject counterbalanced order of blocks. The lower panel displays examples of each condition. Across all conditions, cues are presented sequentially and separated by variable inter-trial intervals (ITI). In No Shock, participants are instructed that no electric shocks will be administered at any time. In Predictable Shock, participants are instructed that shocks will be administered only at the end of cues and that no shocks will ever be administered during ITIs. In Unpredictable Shock, participants are instructed that shocks can be administered at any time, during both cues and ITIs. The startle response is elicited with “startle probes” (50 ms acoustic white noise). Startle potentiation is calculated separately in Predictable and Unpredictable Shock conditions relative to No Shock and serves as the primary dependent measure of defensive reactivity to these shock threat stressors. A figure legend is provided in the left panel. Several variations of the NPU task have been used across laboratories that vary most notably on the number of cues per block, the cue-shock contingency in Predictable Shock (i.e., all vs. subset of predictable shock cues are shocked), and the placement of shock in Unpredictable Shock (i.e., during cues and ITI vs. only ITI). Figure modified with permission from Schmitz & Grillon (2012). Used with permission of Springer Nature.

Figure 3.

Alcohol effect sizes for startle potentiation to predictable and unpredictable shock. This forest plot depicts the size of the effect of alcohol administration on startle potentiation to predictable and unpredictable shock across five independent studies. These five studies tested the effect of a single administration of alcohol on distinct manipulations of unpredictability based on the timing and probability combined (i.e., the NPU task; Moberg & Curtin, 2009; n = 64), timing alone (Hefner et al., 2013; n = 68), probability (Hefner & Curtin, 2012; n = 120), intensity (Bradford et al., 2013; n = 89), and location (Bradford et al., 2017; n = 94) of the shock threat. Study effect sizes depict the difference in startle potentiation (in pV) between intoxicated (target blood alcohol concentration = .08%) and sober participants. The figure also includes the variance weighted, mean effect sizes across studies for alcohol on startle potentiation to unpredictable and predictable shock and on the difference between unpredictable and predictable shock (i.e., the Alcohol ^x Threat Type interaction). Error bars depict 95% confidence intervals surrounding each effect size. Confidence intervals that do not overlap 0 indicate significant effects of alcohol. Alcohol produced significantly greater reduction in startle potentiation to unpredictable than predictable shock in every study. The mean size of alcohol’s effect across studies was approximately three-fold greater for unpredictable than predictable shock. Figure © Jesse Kaye, Daniel Bradford, Katherine Magruder, & John Curtin. Reprinted with permission.