Recent insights into the mode of action of memantine and ketamine

Abstract

The clinical benefits of the glutamate receptor antagonists memantine and ketamine have helped sustain optimism that glutamate receptors represent viable targets for development of therapeutic drugs. Both memantine and ketamine antagonize N-methyl-d-aspartate receptors (NMDARs), a glutamate receptor subfamily, by blocking the receptor-associated ion channel. Although many of the basic characteristics of NMDAR inhibition by memantine and ketamine appear similar, their effects on humans and to a lesser extent on rodents are strongly divergent. Some recent research suggests that preferential inhibition by memantine and ketamine of distinct NMDAR subpopulations may contribute to the drugs' differential clinical effects. Here we review studies that shed light on possible explanations for differences between the effects of memantine and ketamine.

Inhibition of in vivo [3H]MK-801 binding by NMDA receptor open channel blockers and GluN2B antagonists in rats and mice

“…Furthermore, a recent study (Louderback et al, 2013) showed that ketamine and Ro 25-6981 increased food consumption in the novelty-induced hypophagia test, a model of anhedonia, which was mimicked by targeted knockdown of GluN2B receptors in the forebrain, bed nucleus of the stria terminalis, suggesting that ketamine might exert its antidepressant-like effects by acting at GluN2B receptors. In this study, we compared the where the ambient glutamate level could also have an impact on NMDA receptor functions (Machado-Vieira et al, 2009, Johnson et al, 2015. Additionally, it has recently been reported that triheteromeric (GluN1/GluN2A/GluN2B) and diheteromeric (GluN1/GluN2B or GluN1/GluN2A) NMDA receptors are differentially expressed in terms of the regional distribution and density in the brain, and exhibit distinct pharmacology (Tovar et al, 2013, Hansen et al, 2014.…”

Memantine Effects On Sensorimotor Gating and Mismatch Negativity in Patients with Chronic Psychosis

“…Although it is clear that memantine has a very distinct clinical profile compared with the dissociative and cognitively impairing properties of NMDA antagonists such as ketamine, the precise neurochemical basis for these differences in not known. At the level of NMDA receptors, memantine has lower affinity and faster kinetics compared with ketamine, and the two drugs may act on different populations of NMDA receptors (see, for example, Johnson et al, 2015). At a systemic level, memantine does not stimulate cortisol release, whereas ketamine does (Hergovich et al, 2001).…”

Amyotrophic Lateral Sclerosis, 2016: existing therapies and the ongoing search for neuroprotection

“…Memantine, initially registered in Germany for a variety of neurological indications, 112 is now widely approved for dementia, 113-119 particularly Alzheimer's disease 120 Some neuroprotective effects of memantine in cultured rat embryo motor cortex may be antagonized by riluzole 129 . Memantine reduces excitotoxicity and delays progression in animal models of neurodegenerative disease 130,131 ; it delays motor deterioration and extends life in G93A mSOD1 ALS mice 132 .…”