Abstract
Ketamine is a non-competitive antagonist of NMDA (N-methyl-D-aspartate) receptor, which has been in clinical practice for over a half century. Despite recent data suggesting its harmful side effects, such as neuronal loss, synapse dysfunction or disturbed neural network formation, the drug is still applied in veterinary medicine and specialist anesthesia. Several lines of evidence indicate that structural and functional abnormalities in the nervous system caused by ketamine are crosslinked with the imbalanced activity of multiple Ca2+-regulated signaling pathways. Due to its ubiquitous nature, Ca2+ is also frequently located in the center of ketamine action, although the precise mechanisms underlying drug’s negative or therapeutic properties remain mysterious for the large part. This review seeks to delineate the relationship between ketamine-triggered imbalance in Ca2+ homeostasis and functional consequences for downstream processes regulating key aspects of neuronal function.
Highlights
Ketamine is a well-established anesthetic drug that has been in use for more than 50 years
The current findings indicate that endogenous overactivation of NMDA receptors and massive Ca2+ influx are expected to interfere with the incorporation of newly born neurons into functional brain circuits
These studies, together with the most recent one [109], point out that AMPA receptors may be another synaptic target for ketamine, and support the hypothesis that their activation is required for antidepressant effect of ketamine, which is largely mediated by brain-derived neurotrophic factor (BDNF)
Summary
Ketamine is a well-established anesthetic drug that has been in use for more than 50 years. The ongoing studies are perpetually identifying new molecular targets for the drug (reviewed in [3,5,8,9]), and currently, the contribution of GABA(γ-aminobutyric acid)ergic, dopaminergic, serotonergic, cholinergic, aminergic and opioid systems to positive and negative modulatory role of ketamine has been confirmed. These studies disclosed, broader than was previously considered, the clinical relevance of ketamine metabolites and the differential potency of ketamine’s racemic forms. We focus on the interaction of ketamine with neuronal calcium toolkit and discuss the potential consequences of drug-induced Ca2+ imbalance on neuronal development and synaptic transmission
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