Rewarding and Antidepressant Properties of Ketamine and Ethanol: Effects on the Brain-Derived Neurotrophic Factor and TrkB and p75NTR Receptors

There is a high level of comorbidity between depression and alcohol use disorder. Subanesthetic doses of ketamine induce short-acting and enduring antidepressant effects after a single or a few administrations. Considering such comorbidity, we assessed, in Swiss male mice, if ketamine-induced antidepressant-like effects would alter ethanol's rewarding effects; and, if ethanol pretreatment would alter the rewarding and antidepressant effects of ketamine. The role of the brain-derived neurotrophic factor (BDNF) and its high and low affinity receptors TrkB and p75NTR, respectively, in both reward and depression-related behaviors is well established. The present study assessed, in outbred Swiss male mice, the expression of these proteins in the prefrontal cortex and hippocampus. Ketamine did not alter the development of ethanol-induced conditioned place preference (CPP), yet ethanol inhibited the expression of CPP induced by 50 mg/kg ketamine. The antidepressant action of 50 mg/kg ketamine was attenuated after repeated treatment (i.e., developed tolerance), an effect blocked by ethanol preexposure; ethanol also inhibited the antidepressant effect of 30 mg/kg ketamine. Ketamine (50 mg/kg) and Ethanol-Ketamine (50 mg/kg) groups showed lower levels of 145 kDa TrkB in the hippocampus than Saline treated group. Ethanol-Ketamine (50 mg/kg) decreased the hippocampal expression of p75NTR compared to Saline-Saline and Saline-Ethanol groups. Ketamine (50 mg/kg) induced hippocampal downregulation of 145 kDa TrkB may contribute to ketamine-induced antidepressant tolerance. Likewise, a relationship between low hippocampal levels of p75NTR in the Ethanol-Ketamine (50 mg/kg) and ketamine-induced CPP blockade may be considered. The findings underscore potential ethanol-ketamine interactions likely to undermine ketamine putative antidepressant effects. (C) 2022 IBRO. Published by Elsevier Ltd. All rights reserved.

Automated summary

There is a high co-occurrence between depression and alcohol use disorder. Subanesthetic doses of ketamine have short-acting and long-lasting antidepressant effects. This study investigated the interaction between ketamine-induced antidepressant effects and ethanol's rewarding effects, as well as the effect of ethanol on the antidepressant actions of ketamine. The expression of brain-derived neurotrophic factor (BDNF) and its receptors TrkB and p75NTR in the prefrontal cortex and hippocampus were examined. The findings suggest that ethanol can interfere with the antidepressant effects of ketamine and highlight potential interactions between ethanol and ketamine that may undermine ketamine's putative antidepressant effects.