Ketamine and Metabolites

Supporting information

Ketamine is a water soluble phencyclidine derivative with an asymmetric carbon atom; it has two enantiomers. It is lipid soluble and undergoes rapid breakdown and redistribution to peripheral tissues. Ketamine is a noncompetitive antagonist of the NMDA receptor (NMDAR), but it also interacts with opioid receptors, cholinergic (nAChR and mAChR), purinergic (P2X, P2Y and adenosine receptors), monoamine and adrenoceptor systems. Ketamine stimulates the sympathetic nervous system, which in turn stimulates the cardiovascular system, leading to increased blood pressure and elevated heart rate.

Ketamine is metabolized in the liver via N-demethylation and ring hydroxylation pathways, the main metabolites being norketamine, hydroxyketamine, dehydronorketamine and hydroxynorketamine (HNK). HNKs enantioselectively decrease levels of an NMDA co-agonist D-serine. D-serine is associated with NMDA receptor-mediated neurotoxicity and neurodegeneration.

Ketamine appears to be an attractive antidepressant treatment, because its action has rapid onset and is long-lasting. However, it also has a number of undesired side effects, including disruption of long-term potentiation (LTP) and thus memory formation. Until recently the antidepressant effects of ketamine were thought to be mediated through the NMDAR, however studies blocking ketamine binding at NMDAR did not inhibit its antidepressant effect. Research showing that lower concentrations of ketamine were needed to reduce depression-like symptoms in female mice compared male mice, led to the discovery of high concentrations of the HNK metabolite in the brains of female mice. The 2R,6R-enantiomer of HNK had a potent antidepressive effect in mice and was shown not to bind to or inhibit the NMDAR. The 2R,6R-HNK enantiomer also lacked the side effects of ketamine.

The AMPA receptor (AMPAR) has become a main prospective target for the antidepressant action of ketamine and its metabolites, because blocking the AMPAR reduced and even reversed the antidepressant effects of HNK in mice. HNKs have also been shown to enhance AMPAR currents. However, to date there has been no conclusive evidence showing that the antidepressant effects of HNKs are mediated through AMPAR activation.

Ketamine was first made commercially available in the 1970s as a general anesthetic. Ketamine has subsequently been shown to have a wide range of actions, including antidepressant, neuroprotective and anti-inflammatory effects. Due to the role of NMDA receptors in pain, Ketamine is also being investigated for its antinociceptive effects, in particular for the treatment of neuropathic pain.

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