Neural Mechanisms Underlying the Rewarding and Therapeutic Effects of Ketamine as a Treatment for Alcohol Use Disorder

Abstract

Alcohol use disorder (AUD) is the most prevalent substance use disorder and causes a significant global burden. Relapse rates remain incredibly high after decades of attempting to develop novel treatment options that have failed to produce increased rates of sobriety. Ketamine has emerged as a potential treatment for AUD following its success as a therapeutic agent for depression, demonstrated by several preclinical studies showing that acute administration reduced alcohol intake in rodents. As such, ketamine's therapeutic effects for AUD are now being investigated in clinical trials with the hope of it being efficacious in prolonging sobriety from alcohol in humans (ClinicalTrials.gov, Identifier: NCT01558063). Importantly, ketamine's antidepressant effects only last for about 1-week and because AUD is a lifelong disorder, repeated treatment regimens would be necessary to maintain sobriety. This raises questions regarding its safety for AUD treatment since ketamine itself has the potential for addiction. Therefore, this review aims to summarize the neuroadaptations related to alcohol's addictive properties as well as ketamine's therapeutic and addictive properties. To do this, the focus will be on reward-related brain regions such as the nucleus accumbens (NAc), dorsal striatum, prefrontal cortex (PFC), hippocampus, and ventral tegmental area (VTA) to understand how acute vs. chronic exposure will alter reward signaling over time. Additionally, evidence from these studies will be summarized in both male and female subjects. Accordingly, this review aims to address the safety of repeated ketamine infusions for the treatment of AUD. Although more work about the safety of ketamine to treat AUD is warranted, we hope this review sheds light on some answers about the safety of repeated ketamine infusions.

Keywords: addiction; alcohol use disorder (AUD); depression; ketamine; mechanisms.

Figure 1

Neural circuitry and dopamine receptor-containing cells are impacted by chronic alcohol intake in rodents. (A) Neural circuits impacted by chronic alcohol consumption. SN, substantia nigra; VTA, ventral tegmental area; vHPC and dHPC, ventral and dorsal hippocampus; Amyg, amygdala; DS, dorsal striatum; NAc, nucleus accumbens; PFC, prefrontal cortex; MSN, medium spiny neuron. (B,C) Schematics showing changes in cell-type-specific excitability following chronic alcohol consumption in D1R- and D2R-MSNs in striatum and D1R- and D2R-containing pyramidal neurons in PFC and HPC. (B) In dorsomedial striatum (DMS) and NAc, D1R-MSNs show enhanced excitability following chronic alcohol. Alcohol increases inhibition of D2R-MSNs in DMS and does not alter them in NAc; DLS, dorsolateral striatum. (C) In PFC, chronic alcohol reduces the excitability of pyramidal neurons with D1Rs and does not impact cells with D2Rs. (D) In vHPC, chronic alcohol leads to increased excitability of pyramidal neurons containing D1Rs and increased inhibition of pyramidal neurons with D2Rs.