Changes in hippocampal AMPA receptors and cognitive impairments in chronic ketamine addiction models: another understanding of ketamine CNS toxicity.

Runtao Ding,Ao Du,Jichuan Zhou,Bolin He,Hao Yu,Xu Wu,Guohua Zhang,Yan Lu,Lu Li,Ruipeng Shen,Yanning Li,Wen Cui

doi:10.1038/srep38771

Abstract

Ketamine has been reported to impair human cognitive function as a recreational drug of abuse. However, chronic effects of ketamine on central nervous system need to be further explored. We set out to establish chronic ketamine addiction models by giving mice a three or six month course of daily intraperitoneal injections of ketamine, then examined whether long-term ketamine administration induced cognition deficits and changed hippocampal post-synaptic protein expression in adult mice. Behavior tests results showed that mice exhibited dose- and time-dependent learning and memory deficits after long-term ketamine administration. Western blot results showed levels of GluA1, p-S845 and p-S831 proteins demonstrated significant decline with ketamine 60 mg/kg until six months administration paradigm. But levels of p-S845 and p-S831 proteins exhibited obvious increase with ketamine 60 mg/kg three months administration paradigm. NR1 protein levels significantly decrease with ketamine 60 mg/kg three and six months administration paradigm. Our results indicate that reduced expression levels and decreased phosphorylation levels of hippocampal post-synaptic membrane GluA1- containing AMPA receptors maybe involved in cognition impairment after long-term ketamine administration. These findings provide further evidence for the cognitive damage of chronic ketamine addiction as a recreational drug.

Highlights

Focusing on the acute effects of ketamine, some studies indicate that sub anesthetic doses of ketamine induced learning and memory impairment in developing rodents[10,11]
Our findings from long term ketamine administration models indicate that chronic ketamine addiction induced cognitive impairments and may significantly alter these hippocampal post-synaptic membrane proteins that are of vital importance to cognitive function
We found that mice showed dose- and time-dependent learning and memory impairments after long-term sub anesthetic ketamine administration

Summary

Introduction

Focusing on the acute effects of ketamine, some studies indicate that sub anesthetic doses of ketamine induced learning and memory impairment in developing rodents[10,11]. One study found ICR mice exposed to chronic sub anesthetic doses of ketamine (30 mg/kg) exhibited learning and memory deficits[13]. S831 and S845 are two important serine phosphorylation sites on the GluA1 subunit intracellular carboxy terminus[29,30] Both of these sites play an essential role in post-synaptic AMPA receptor regulation and synaptic plasticity[23]. We set out to establish mice chronic ketamine addiction models utilizing three and six month sub anesthetic ketamine administration, and to investigate whether mice exhibit learning and memory impairments in this model. We attempted to determine the underlying relationship between behavior performance and relevant proteins levels by analyzing the changes, with the goal of better understanding of the cognitive toxicity of this recreational drug after chronic use

Methods

Results

Conclusion