Evaluation of the pharmacodynamic effects of Ketamine on neurotransmitter levels and CREB/BDNF expression in rat brain.

Abstract

Mental disorders contribute to 13% of the global burden of disease. With major depressive disorder (MDD) expected to be the most significant contributor by 2030, the economic and social impact of this burden will be substantial. There have been various factors linked to the underlying pathophysiology of MDD, including a deficit in individual vital neurotransmitter connections between specific neurons, and alterations in the expression of the transcription factors cyclic AMP response element-binding protein (CREB) and the brain-derived neurotrophic factor (BDNF) in the brain. Ketamine, an N-methyl-D-aspartate receptor (NMDAR) rantagonist and an 􀄮-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) stimulator has officialy been used as an anesthetic and analgesic drug since the 1970s, until recently when it was approved for the management and treatment of MDD. Ketamine works by altering and rebalancing the monoaminergic, glutamatergic and GABArgic sytems to stimulate new synaptic connections, better memory, and improved brain plasticity. However, there are limited published studies that demonstrate the direct relationship between ketamine, brain neurotransmitters levels, gene and protein expression in the management of MDD. In this study, we investigated the pharmacodynamic effects of ketamine in the brain by assessing changes in monoaminergic, glutaminergic and GABAergic neurotransmitter levels using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Furthermore, we investigated the links between ketamine and the expression of transcription factors, cyclic AMP response element-binding protein (CREB) and brain-derived neurotrophic factor (BDNF) in treatment of depression using quantitative real-time polymerase chain reaction (qPCR) analysis. Twenty-one healthy male Sprague-Dawley (SD) rats were administered 15􀯗mg/kg of ketamine via intraperitoneal administration at different time points (N = 3 per time point). Experimental animals were euthanized by decapitation post-administration of ketamine, and brain samples were harvested for analysis. As per LC-MS/MS and qPCR, the pharmacodynamic results demonstrated that ketamine􀂶s anti-depressive mechanism of action is due to alteration of the glutamatergic system which occurs via the disinhibition of glutamate release, which further boosts central nervous synaptogenesis, hence maintaining the in-balance neurotransmitters and genes associated with the pathophysiology of depression.