A possible mechanism of action of ketamine in the treatment of depression
Possible rapid and lasting antidepressant mechanisms of action of ketamine.
Depression is suggested to be associated with altered plasticity of excitatory synapses, those which use glutamate as neurotransmitter. In several clinical trials, a low dose of the anesthetic compound ketamine, which is known to block a type of glutamate receptor, the NMDA receptor, was found to exert a rapid and lasting antidepressant effect in formerly treatment resistant patients after one injection. Unfortunately, the usefulness of ketamine for the treatment of depression is limited because of the dissociative, psychedelic and abuse properties of this drug.
Recent findings have shown that the antidepressant efficacy of ketamine is actually due to an action of a metabolite of ketamine, (2R,6R)-HNK, through another type of glutamate receptors, the AMPA receptor. The mechanism remained incompletely identified and the brain regions involved in the antidepressant action of ketamine are poorly delineated.
Researchers at Karolinska Institutet have identified a potential mechanism of action of ketamine in the mesolimbic dopamine circuit, brain regions involved in motivational behaviors and reward. In their paper, published online in Molecular Psychiatry, they show that a single, low dose of ketamine induces lasting (7 days) impairment of a form of synaptic plasticity, long-term potentiation, in the nucleus accumbens. The mechanism involves an altered phosphorylation of AMPA receptors. They found that ketamine induces a novel form of long-term depression of glutamatergic transmission mediated by AMPA receptors in dopaminergic neurons of the ventral tegmental area.
The research team also demonstrates that the function of NMDA receptors in these two brain regions is not altered following ketamine injection. The metabolite of ketamine (2R,6R)-HNK, induces the same changes as ketamine.
The study shows that a single, low dose of ketamine and its metabolite induce enduring synaptic changes and alterations in the function of AMPA receptors in the brain reward circuit. These changes are potential mechanisms by which ketamine mediates rapid and lasting antidepressant action. The results might be useful for the development of improved pharmacological agents for the treatment of major depression.
Authors:
Ning Yao, Section of Molecular Neurophysiology, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
Olga Skiteva, Section of Molecular Neurophysiology, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
Xiaoqun Zhang, Section of Translational Neuropharmacology and Center for Molecular Medicine, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
Per Svenningsson, Section of Translational Neuropharmacology and Center for Molecular Medicine, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
Karima Chergui, Section of Molecular Neurophysiology, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden