The effects of sub-anesthetic ketamine plus ethanol on behaviors and apoptosis in the prefrontal cortex and hippocampus of adolescent rats

Pharmacol Biochem Behav. 2019 Sep;184:172742. doi: 10.1016/j.pbb.2019.172742. Epub 2019 Jul 23.


Ketamine has become increasingly popular in adolescent drug abusers worldwide. Meanwhile, alcohol is usually used by ketamine users. However, little work has been conducted to examine the chronic combined effects of ketamine and ethanol on adolescent brain. Here we probed into the effects of chronic administration of ketamine at recreational doses alone or combined with ethanol on behaviors and neuron damage in an adolescent rat model. 28-day old rats were treated with either 20 or 30 mg/kg ketamine plus or not plus 10% ethanol daily for 21 days. Depressive like behaviors, anxiety like behavior and memory impairment were tested using open field test, forced swimming test, elevated plus maze and Morris water maze. Apoptosis in prefrontal cortex (PFC) and hippocampus (HIP) were determined by the TdT-mediated dUTP Nick-End Labeling (TUNEL) and protein and mRNA levels of caspase-3, Bax and Bcl-2. Results show that co-application of ketamine and ethanol significantly increased immobility time in the forced swimming test, up-regulated TUNEL positive cells and both protein and mRNA expressions of caspase-3 and Bax, compared with the control group and ketamine and ethanol use alone groups in the PFC, but not in the HIP. Our study suggests that chronic co-administration of ketamine and ethanol results in depressive-like behavior and the caspase-dependent apoptosis in the PFC of adolescent rats' brains.

Keywords: Abuse; Adolescent; Apoptosis; Hippocampus; Ketamine; Prefrontal cortex.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anesthetics, Dissociative / administration & dosage
  • Anesthetics, Dissociative / pharmacology*
  • Animals
  • Anxiety / chemically induced
  • Apoptosis / drug effects*
  • Behavior, Animal / drug effects*
  • Caspase 3 / genetics
  • Caspase 3 / metabolism
  • Central Nervous System Depressants / administration & dosage
  • Central Nervous System Depressants / pharmacology*
  • Depression / chemically induced
  • Ethanol / administration & dosage
  • Ethanol / pharmacology*
  • Hippocampus / drug effects*
  • Hippocampus / metabolism
  • Ketamine / administration & dosage
  • Ketamine / pharmacology*
  • Male
  • Memory / drug effects
  • Prefrontal Cortex / drug effects*
  • Prefrontal Cortex / metabolism
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • bcl-2-Associated X Protein / genetics
  • bcl-2-Associated X Protein / metabolism


  • Anesthetics, Dissociative
  • Bax protein, rat
  • Bcl2 protein, rat
  • Central Nervous System Depressants
  • Proto-Oncogene Proteins c-bcl-2
  • bcl-2-Associated X Protein
  • Ethanol
  • Ketamine
  • Casp3 protein, rat
  • Caspase 3