The effects of cognitive reappraisal following retrieval-procedures designed to destabilize alcohol memories in high-risk drinkers

RATIONALE: Addiction is a disorder of motivational learning and memory. Maladaptive motivational memories linking drug-associated stimuli to drug seeking are formed over hundreds of reinforcement trials and accompanied by aberrant neuroadaptation in the mesocorticolimbic reward system. Such memories are resistant to extinction. However, the discovery of retrieval-dependent memory plasticity has opened up the possibility of permanent modification of established (long-term) memories during 'reconsolidation'. OBJECTIVES: Here, we investigate whether reappraisal of maladaptive alcohol cognitions performed after procedures designed to destabilize alcohol memory networks affected subsequent alcohol memory, craving, drinking and attentional bias. METHODS: Forty-seven at-risk drinkers attended two sessions. On the first lab session, participants underwent one of two prediction error-generating procedures in which outcome expectancies were violated while retrieving alcohol memories (omission and value prediction error groups). Participants in a control group retrieved non-alcohol memories. Participants then reappraised personally relevant maladaptive alcohol memories and completed measures of reappraisal recall, alcohol verbal fluency and craving. Seven days later, they repeated these measures along with attentional bias assessment. RESULTS: Omission prediction error (being unexpectedly prevented from drinking beer), but not a value prediction error (drinking unexpectedly bitter-tasting beer) or control procedure (drinking unexpectedly bitter orange juice), was associated with significant reductions in verbal fluency for positive alcohol-related words. No other statistically robust outcomes were detected. CONCLUSIONS: This study provides partial preliminary support for the idea that a common psychotherapeutic strategy used in the context of putative memory retrieval-destabilization can alter accessibility of alcohol semantic networks. Further research delineating the necessary and sufficient requirements for producing alterations in alcohol memory performance based on memory destabilization is still required

The Subjective Response to Nitrous Oxide is a Potential Pharmaco-Endophenotype for Alcohol Use Disorder: A Preliminary Study with Heavy Drinkers.

BACKGROUND: Healthy people with a family history of alcohol problems show a pattern of subjective responses to alcohol that resemble those of affected probands. Studies on ketamine suggest that up-regulation of N-methyl-D-aspartate receptors (NMDARs) underlies these effects, and point to a pharmacologically-responsive endophenotype reflecting enhanced risk for alcohol-use disorders. METHODS: Subjective stimulant and sedative effects were assessed before and during nitrous oxide (N2O; 50%) inhalation in heavy drinkers who were otherwise healthy. RESULTS: Participants with an ostensible family history of alcohol-use disorders (n = 23) were distinguishable from those without such familial risk (n = 37) by an enhanced stimulation-to-sedation ratio during N2O inhalation. CONCLUSION: The pattern of subjective effects of N2O according to familial risk is remarkably similar to that previously seen with ketamine, supporting the idea of a common, NMDAR-mediated mechanism of action. N2O may prove to be a safe and accessible alternative to ketamine for probing heritable NMDAR dysregulation in neuropsychiatric disorders

Dopamine, urges to smoke, and the relative salience of drug versus non-drug reward

When addicted individuals are exposed to drug-related stimuli, dopamine release is thought to mediate incentive salience attribution, increasing attentional bias, craving and drug seeking. It is unclear whether dopamine acts specifically on drug cues versus other rewards, and if these effects correspond with craving and other forms of cognitive bias. Here, we administered the dopamine D 2 /D 3 agonist pramipexole (0.5 mg) to 16 tobacco smokers in a double-blind placebo-controlled crossover design. Visual fixations on smoking and money images were recorded alongside smoking urges and fluency tasks. Pramipexole attenuated a marked bias in initial orienting towards smoking relative to money but did not alter a maintained attentional bias towards smoking. Pramipexole decreased urges to smoke retrospectively after the task but not on a state scale. Fewer smoking words were generated after pramipexole but phonological and semantic fluency were preserved. Although these treatment effects did not correlate with each other, changes in initial orienting towards smoking and money were inversely related to baseline scores. In conclusion, pramipexole can reduce the salience of an addictive drug compared with other rewards and elicit corresponding changes in smoking urges and cognitive bias. These reward-specific and baseline-dependent effects support an ‘inverted-U’ shaped profile of dopamine in addiction

A Prediction Error-driven Retrieval Procedure for Destabilizing and Rewriting Maladaptive Reward Memories in Hazardous Drinkers

Maladaptive reward memories (MRMs) can become unstable following retrieval under certain conditions, allowing their modification by subsequent new learning. However, robust (well-rehearsed) and chronologically old MRMs, such as those underlying substance use disorders, do not destabilize easily when retrieved. A key determinate of memory destabilization during retrieval is prediction error (PE). We describe a retrieval procedure for alcohol MRMs in hazardous drinkers that specifically aims to maximize the generation of PE and therefore the likelihood of MRM destabilization. The procedure requires explicitly generating the expectancy of alcohol consumption and then violating this expectancy (withholding alcohol) following the presentation of a brief set of prototypical alcohol cue images (retrieval + PE). Control procedures involve presenting the same cue images, but allow alcohol to be consumed, generating minimal PE (retrieval-no PE) or generate PE without retrieval of alcohol MRMs, by presenting orange juice cues (no retrieval + PE). Subsequently, we describe a multisensory disgust-based counterconditioning procedure to probe MRM destabilization by re-writing alcohol cue-reward associations prior to reconsolidation. This procedure pairs alcohol cues with images invoking pathogen disgust and an extremely bitter-tasting solution (denatonium benzoate), generating gustatory disgust. Following retrieval + PE, but not no retrieval + PE or retrieval-no PE, counterconditioning produces evidence of MRM rewriting as indexed by lasting reductions in alcohol cue valuation, attentional capture, and alcohol craving

A comparison of emotion regulation strategies in response to craving cognitions: Effects on smoking behaviour, craving and affect in dependent smokers

AIM: The effects of three emotion regulation strategies that targeted smoking-related thoughts were compared on outcomes relevant to smoking cessation. METHOD: Daily smokers applied defusion (n = 25), reappraisal (n = 25) or suppression (n = 23) to thoughts associated with smoking during a cue-induced craving procedure. Smoking behaviour, approach/avoidance behavioural bias, and subjective measures of experiential avoidance, craving, and affect were assessed during the experimental session, with additional behavioural and subjective outcomes assessed at 24 h and seven day follow-up. The influence of baseline group differences in smoking level and nicotine dependence were explored statistically. RESULTS: Defusion and reappraisal were associated with greater restraint in smoking behaviour in the immediate post-session period as well as reduction in smoking at seven day follow-up compared to suppression. Relative to suppression, reduced subjective craving was seen in the reappraisal group, and reduced experiential avoidance in the defusion group. Differences in approach/avoidance responses to smoking and neutral cues were observed only between the suppression and reappraisal groups. Although suppression was rated as lower in both credibility and strategy-expectancy compared to defusion and reappraisal, neither credibility nor expectancy mediated the effect of any strategy on changes in levels of smoking. CONCLUSION: Defusion and reappraisal produced similar benefits in smoking-related behavioural outcomes but, relative to suppression, were associated with distinctive outcomes on experiential avoidance and craving. The effects appear to be independent of perceived expectancy and credibility of the different strategies. Overall, the results suggest a role for reappraisal and defusion strategies in the development of psychological treatments for addiction-related disorders

Modulation of naturalistic maladaptive memories using behavioural and pharmacological reconsolidation-interfering strategies: a systematic review and meta-analysis of clinical and 'sub-clinical' studies

BACKGROUND: Consolidated memories can undergo enduring modification through retrieval-dependent treatments that modulate reconsolidation. This represents a potentially transformative strategy for weakening or overwriting the maladaptive memories that underlie substance use and anxiety/trauma-related disorders. However, modulation of naturalistic maladaptive memories may be limited by 'boundary conditions' imposed on the reconsolidation process by the nature of these memories. METHODS: We conducted a systematic review and meta-analyses of behavioural and pharmacological studies examining retrieval-dependent modulation of reward- and threat-related memories in (sub) clinical substance use and anxiety/trauma, respectively. RESULTS: Of 4938 publications assessed for eligibility, 8 studies of substance use and 10 of anxiety (phobia)- and trauma-related symptoms were included in the meta-analyses. Overall, the findings were in the predicted direction, with most studies favouring the 'retrieval + treatment' condition. However, the magnitude of effects was dependent upon the nature of treatment, with pharmacological interventions showing a medium-sized effect (g = 0.59, p = 0.03) and behavioural treatments, a relatively small effect (g = 0.32, p = 0.10) in studies of phobia/trauma. Among studies of substance use, post-retrieval behavioural interventions yielded a larger effect (g = 0.60, p < 0.001) relative to pharmacological treatments (g = - 0.03, p = 0.91), with treatment type being a statistically significant moderator (χ2(1) = 4.20, p = 0.04). CONCLUSION: Modification of naturalistic maladaptive memories during reconsolidation appears to be a viable treatment strategy for substance use and phobias/trauma disorders. However, high levels of heterogeneity and methodological variation limit the strength of conclusions that can be drawn from the reviewed studies at this stage

Rewarding Subjective Effects of the NMDAR Antagonist Nitrous Oxide (Laughing Gas) Are Moderated by Impulsivity and Depressive Symptoms in Healthy Volunteers

BACKGROUND: Nitrous oxide (N2O) is an anaesthetic gas with both therapeutic and abuse potential. As an NMDAR antagonist, its effects are expected to resemble those of the prototypical NMDAR antagonist, ketamine. Here, we examine the subjective rewarding effects of N2O using measures previously employed in studies of ketamine. We also test for moderation of these effects by bipolar phenotype, depressive symptoms, and impulsivity. METHODS: Healthy volunteers were randomised to either 50% N2O (n=40) or medical air (n=40). Self-reported rewarding (liking and wanting), and alcohol-like effects were assessed pre-, peri- and post-inhalation. RESULTS: Effect sizes for the various rewarding/alcohol-like effects of N2O were generally similar to those reported in studies of moderate-dose ketamine. Impulsivity moderated the subjective reinforcing (liking) effects of inhaled gas, while depressive symptoms moderated motivational (wanting [more]) effects. However, depression and impulsivity had opposite directional influences, such that higher impulsivity was associated with higher N2O-liking, and higher depression, with lower N2O-wanting. CONCLUSIONS: To the extent that static (versus longitudinal) subjective rewarding effects are a reliable indicator of future problematic drug use, our findings suggests that impulsivity and depression may respectively predispose and protect against N2O abuse. Future studies should examine if these moderators are relevant for other NMDAR antagonists, including ketamine, and novel ketamine-like therapeutics and recreational drugs. Similarities between moderate-dose N2O and moderate-dose ketamine in the intensity of certain subjective effects suggest that N2O may, at least partially, substitute for ketamine as a safe and easily-implemented experimental tool for probing reward-related NMDAR function and dysfunction in humans

Long-term behavioural rewriting of maladaptive drinking memories via reconsolidation-update mechanisms

BACKGROUND: Alcohol use disorders can be conceptualised as a learned pattern of maladaptive alcohol-consumption behaviours. The memories encoding these behaviours centrally contribute to long-term excessive alcohol consumption and are therefore an important therapeutic target. The transient period of memory instability sparked during memory reconsolidation offers a therapeutic window to directly rewrite these memories using targeted behavioural interventions. However, clinically-relevant demonstrations of the efficacy of this approach are few. We examined key retrieval parameters for destabilising naturalistic drinking memories and the ability of subsequent counterconditioning to effect long-term reductions in drinking. METHODS: Hazardous/harmful beer-drinking volunteers (N = 120) were factorially randomised to retrieve (RET) or not retrieve (No RET) alcohol reward memories with (PE) or without (No PE) alcohol reward prediction error. All participants subsequently underwent disgust-based counterconditioning of drinking cues. Acute responses to alcohol were assessed pre- and post-manipulation and drinking levels were assessed up to 9 months. RESULTS: Greater long-term reductions in drinking were found when counterconditioning was conducted following retrieval (with and without PE), despite a lack of short-term group differences in motivational responding to acute alcohol. Large variability in acute levels of learning during counterconditioning was noted. 'Responsiveness' to counterconditioning predicted subsequent responses to acute alcohol in RET + PE only, consistent with reconsolidation-update mechanisms. CONCLUSIONS: The longevity of behavioural interventions designed to reduce problematic drinking levels may be enhanced by leveraging reconsolidation-update mechanisms to rewrite maladaptive memory. However, inter-individual variability in levels of corrective learning is likely to determine the efficacy of reconsolidation-updating interventions and should be considered when designing and assessing interventions

Voluntary and involuntary emotional memory following an analogue traumatic stressor: the differential effects of communality in men and women

Background: Men and women show differences in performance on emotional processing tasks. Sex also interacts with personality traits to affect information processing. Here we examine effects of sex, and two personality traits that are differentially expressed in men and women – instrumentality and communality – on voluntary and involuntary memory for distressing video-footage. / Methods: On session one, participants (n = 39 men; 40 women) completed the Bem Sex-Role Inventory, which assesses communal and instrumental traits. After viewing film-footage of death/serious injury, participants recorded daily involuntary memories (intrusions) relating to the footage on an online diary for seven days, returning on day eight for a second session to perform a voluntary memory task relating to the film. / Results: Communality interacted with sex such that men with higher levels of communality reported more frequent involuntary memories. Alternatively, a communality × sex interaction reflected a tendency for women with high levels of communality to perform more poorly on the voluntary recognition memory task. / Limitations: The study involved healthy volunteers with no history of significant psychological disorder. Future research with clinical populations will help to determine the generalizability of the current findings. / Conclusion: Communality has separate effects on voluntary and involuntary emotional memory. We suggest that high levels of communality in men and women may confer vulnerability to the negative effects of stressful events either through the over-encoding of sensory/perceptual-information in men or the reduced encoding of contextualised, verbally-based, voluntarily accessible representations in women