Dr. Weeks’ Comment: This research is promising.

Ketamine can reduce harmful drinking by pharmacologically rewriting drinking memories

• Ravi K. Das, 
• Grace Gale, 
• Katie Walsh, 
• Vanessa E. Hennessy, 
• Georges Iskandar, 
• Luke A. Mordecai, 
• Brigitta Brandner, 
• Merel Kindt, 
• H. Valerie Curran & 
• Sunjeev K. Kamboj 

Nature Communications volume 10, Article number: 5187 (2019) Cite this article

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Abstract

Maladaptive reward memories (MRMs) are involved in the development and maintenance of acquired overconsumption disorders, such as harmful alcohol and drug use. The process of memory reconsolidation – where stored memories become briefly labile upon retrieval – may offer a means to disrupt MRMs and prevent relapse. However, reliable means for pharmacologically weakening MRMs in humans remain elusive. Here we demonstrate that the N-methyl D-aspartate (NMDA) antagonist ketamine is able to disrupt MRMs in hazardous drinkers when administered immediately after their retrieval. MRM retrieval + ketamine (RET + KET) effectively reduced the reinforcing effects of alcohol and long-term drinking levels, compared to ketamine or retrieval alone. Blood concentrations of ketamine and its metabolites during the critical ‘reconsolidation window’ predicted beneficial changes only following MRM reactivation. Pharmacological reconsolidation interference may provide a means to rapidly rewrite maladaptive memory and should be further pursued in alcohol and drug use disorders.

Introduction

Overconsumption disorders such as harmful drinking, alcohol and substance use disorders (AUDs, SUDs), which represent leading causes of global preventable mortality and morbidity, are fundamentally acquired or learned behaviours¹. Contemporary neuroscientific models posit that the adaptive reward learning processes that control motivated behavior can be usurped by addictive drugs² forging harmful drug-use behaviors that are encoded by maladaptive reward memories (MRMs)³. These MRMs are learned associations that encode the contingencies between drug-predictive environmental stimuli (e.g. the smell and taste of beer) and drug reward⁴. MRMs underlie the tendency of environmental trigger cues and contexts to grab attention and provoke motivated behavioral routines including craving⁵, drug-seeking and excessive consumption. They are thus a core mechanism underlying alcohol overconsumption and long-term relapsing behavior that must be “unlearned” for curative amelioration of problematic drinking.

However, effective, targeted memory rewriting currently represents an unmet clinical challenge. Critically, once stabilized- or consolidated – into long-term memory storage, MRMs were thought to become long-lasting and essentially immutable, promoting rebound/ relapse even long after successful reduction or detoxification and abstinence⁶. Current treatments such as cognitive-behavioral or cue exposure therapy do not involve unlearning of MRMs⁷, but rather, suppression by alternative learning. The continued latent existence of MRMs limits the long-term efficacy of these interventions and underlies the high relapse rates that typify AUD/SUDs^8,9.

Recent insights into long-term memory persistence and malleability may hold the key to directly rewriting maladaptive memories. Reconsolidation is a memory maintenance process whereby reactivated long-term memories temporarily destabilize in order to incorporate newly available information, and hence update their contents¹⁰. Preclinical research has shown that memory destabilization requires the right retrieval conditions. These are typically brief, cue-driven retrievals that incorporate novel information or prediction error¹¹ regarding outcomes. Once destabilized, memories rely upon an N-Methyl D-Aspartate Receptor (NMDAR) mediated—MAPK/ERK—protein synthesis cascade to reorganize the synaptic architecture encoding memory traces and restabilize or reconsolidate memories in their new form. By pharmacologically intervening with reconsolidation, it is theoretically possible to selectively target and weaken memories^12,13. The temporary reconsolidation window of memory instability following reactivation therefore offers a unique and novel mechanism to directly rewrite MRMs and strip them of their relapsogenic potential at the source¹⁴.

Reliable pharmacological MRM rewriting remains elusive, however, due to the relative difficulty in reactivating/destabilizing inherently robust MRMs in human drug users and the severely limited menu of well-tolerated reconsolidation blockers¹⁵. Indeed, most preclinical studies of reconsolidation involve experimentally generated “models” of MRMs that are orders of magnitude weaker than true human MRMs, and also employ highly toxic compounds (with highly limited human translatability) to block reconsolidation¹⁶. Thus, despite the great theoretical potential of reconsolidation as a therapeutic target and promising emergent research¹⁷, in the absence of a gold standard reconsolidation blocker, the translational feasibility and scope of pharmacological memory rewriting remains relatively untested.

Ketamine is a dissociative anesthetic that may have unique potential in this regard, since it is a high-affinity non-competitive NMDAR antagonist that is relatively well tolerated and safe in humans. Ketamine is currently experiencing a renaissance in neuroscience and psychiatry due to its rapid and novel anti-depressive action¹⁸. Further it has previously been used to successfully treat alcoholism¹⁹ and heroin addiction, via unexplored, but not explicitly reconsolidation-based mechanisms²⁰. It thus carries potential therapeutic utility for addictive disorders in its own right. Importantly, these antidepressant and anti-addictive actions may not be independent, since depression and SUDs are highly co-morbid²¹ and concomitant improvements in response to an anti-depressant intervention may be seen to the extent that the former is driving the latter. We therefore assessed for the first time whether intravenous ketamine during the ‘reconsolidation window’ would interfere with the reconsolidation of robust alcohol-MRMs in harmful drinkers by blocking NMDAR activity. To differentiate reconsolidation-dependent from non-specific affective (e.g. anti-depressive) therapeutic mechanisms, ketamine was administered following the retrieval/destabilization of maladaptive alcohol memories (retrieval + ketamine; RET + KET) or control (non-drinking) memories (No RET + KET), with placebo (saline; PBO) controlling for the effects of MRM retrieval per se (RET + PBO). We further assessed plasma ketamine and its metabolites during the critical “reconsolidation window” as potential predictive biomarkers of response to the memory-rewriting manipulation.

In RET + KET, we hypothesized that ketamine would weaken MRMs via reconsolidation interference, reducing the motivational effects of alcohol (alcohol/ cue reactivity) and drinking levels in hazardous/harmful drinkers. These changes should be negatively associated with levels of blood biomarkers of ketamine metabolism during the critical reconsolidation window, indicative of a reconsolidation-interference mechanism. We also predicted (smaller magnitude) improvement in these measures in No RET + KET, given the antidepressant and potential anti-AUD properties of ketamine alone, but that these would not be related to ketamine metabolite biomarkers following the memory retrieval and drug manipulation. No improvement was expected from MRM reactivation alone (RET + PBO). This three group design allowed us to differentiate competing mechanistic interpretations. If any effects of ketamine were purely due to anti-depressive effects and independent of memory reconsolidation, the retrieval manipulation should be inconsequential and no differential improvement trajectory should be observed between RET + KET and No RET + KET. We thus assessed reconsolidation as a novel potential therapeutic mechanism and a means for catalyzing the efficacy of ketamine in problematic drinking.

Here we report that MRM retrieval + ketamine produces a rapid reduction in the reinforcing and motivational properties of alcohol and substantial, lasting reductions in drinking levels compared to retrieval or ketamine alone. Plasma levels of ketamine and its metabolites are predictive of these beneficial effects only following MRM retrieval. These findings demonstrate MRM reconsolidation interference by ketamine and rewriting of reward structures surrounding alcohol. The subsequent, lasting clinical benefits observed suggest that this one-session intervention approach should be pursued in the future treatment of alcohol related disorders.

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