Alcohol amplifies ketamine-induced apoptosis in primary cultured cortical neurons and PC12 cells through down-regulating CREB-related signaling pathways

Sci Rep. 2017 Sep 5;7(1):10523. doi: 10.1038/s41598-017-10868-z.


Recreational use of ketamine (KET) has been increasing worldwide. Previous studies have demonstrated that KET induced neurotoxicity; however, few studies have examined how alcohol (ALC) affects KET-induced neurotoxicity. In light of the fact that some KET abusers combine KET with ALC, the present study was aimed to investigate the effects of ALC on KET-induced neurotoxicity and the underlying mechanism in vitro. Our data revealed that co-treatment with ALC and KET was more detrimental to cell viability than KET single treatment in both PC12 cells and primary cultured rat cortical neurons. Furthermore, ALC exacerbated KET-induced apoptosis characterized by morphological changes and the sub-G1 phase increase, which were mitigated by the pretreatment of CNQX, a known alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA)/kainite (KA) receptor antagonist. In addition, ALC and KET co-treatment led to intracellular Ca2+ overload, down-regulation of p-Akt, p-CREB, PKA, CaMK-IV, Bcl-2 and BDNF expression and up-regulation of cleaved caspase-3 and Bax expression, which can be attenuated by CNQX pretreatment. These results indicate that the potentiation of ALC on KET-induced neurotoxicity was related to the down-regulation of CREB-related pathways. Our present study also indicates that ALC and KET co-abuse might cause serious neurotoxicity which should be conveyed to the public and drew enough attention.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis*
  • Brain-Derived Neurotrophic Factor / metabolism
  • Calcium / metabolism
  • Calcium-Calmodulin-Dependent Protein Kinase Type 4 / metabolism
  • Cells, Cultured
  • Cyclic AMP Response Element-Binding Protein / metabolism*
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Down-Regulation
  • Ethanol / pharmacology*
  • Ketamine / toxicity
  • Neurons / drug effects*
  • Neurons / metabolism
  • PC12 Cells
  • Rats
  • Rats, Sprague-Dawley
  • Signal Transduction*


  • Brain-Derived Neurotrophic Factor
  • Cyclic AMP Response Element-Binding Protein
  • Ethanol
  • Ketamine
  • Cyclic AMP-Dependent Protein Kinases
  • Calcium-Calmodulin-Dependent Protein Kinase Type 4
  • Calcium