Ketamine can reduce harmful drinking by pharmacologically rewriting drinking memories

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.

Targeting the Reconsolidation of Licit Drug Memories to Prevent Relapse: Focus on Alcohol and Nicotine

“…To date, the pharmacological manipulations aimed to disrupt the reconsolidation of alcohol-associated memories have focused on protein synthesis inhibition [ 14 , 26 , 27 ], NMDA receptor blockade [ 26 , 28 , 29 , 30 , 31 , 32 ], and β-adrenergic receptor blockade [ 28 , 32 , 33 , 34 , 35 , 36 ].…”

“…In humans, ketamine administration following the retrieval of the alcohol-associated memories in hazardous drinkers reduced the reinforcing effects of alcohol and long-term drinking levels, compared to ketamine or retrieval alone [ 29 ]. Blood concentrations of ketamine and its metabolites during the critical “reconsolidation window” predicted beneficial changes only following memory retrieval.…”

“…Interference with memory reconsolidation by post-retrieval counterconditioning has also been successfully tested in humans [ 56 ], showing particularly promising results in modulating craving and drinking patterns in hazardous alcohol drinkers [ 54 , 74 , 75 ]. As in other reconsolidation studies from this group, alcohol-associated memories were retrieved by presenting abstinent participants with a glass of beer and then taking it away unexpectedly before the first sip [ 29 , 54 , 74 , 76 ]. Immediately after memory retrieval, alcohol cues were re-associated with gustatory disgust, leading to subsequent reduction in alcohol cue valuation, attentional capture, and alcohol craving [ 54 , 74 ].…”

Pharmakotherapie der Alkoholentwöhnung: Update und neue Entwicklungen

“…Zu den interessanten neuen Ansätzen gehört der nichtkompetitive glutamaterge NMDA-Rezeptor-Antagonist Ketamin [ 18 ]. Hier konnte experimentell gezeigt werden, dass Ketamin verstärkende Effekte von Alkohol vermindern kann [ 19 ]. Kontrollierte klinische Studien stehen noch aus.…”

Amygdala Allostasis and Early Life Adversity: Considering Excitotoxicity and Inescapability in the Sequelae of Stress

“…While much had to be learned in the process, which was traced to synapsespecific protein synthesis triggered by calcium influx primarily from NMDA receptors (Nader et al, 2000;Debiec et al, 2006) and ultimately yielding promising candidates from medicationassisted exposure therapy. This work progressed to identify NMDA-antagonistic agents (Dcycloserine, ketamine) (Guastella et al, 2008;Kalisch et al, 2009;Otto et al, 2010;Das et al, 2019), a mitochondrial enhancer (methylene blue) (Telch et al, 2014;Zoellner et al, 2017) and the original anti-adrenergic propranolol as having potential to erase the fight-or-flight component of fear learning (Kindt et al, 2009;Soeter and Kindt, 2015;Brunet et al, 2018). Several caveats were discovered including: 1) the memories must be reactivated or the treatment adds nothing 2) the medication exposure must end well, with relative safety achieved by the end or treatment could worsen the fear and 3) conveniently, the medication need not be administered prior to the exposure but does need to be administered in a 4-6 hour window of neuroplasticity 4) in the case of propranolol a much higher dose is required (40mg acute dose) than would typically be prescribed for situational phobia.…”