Ketamine meets mTOR

A team from Yale School of Medicine has found an mTOR-mediated mechanism that could help explain how the anesthetic ketamine is able to reduce depression more rapidly than standard antidepressants.1 The researchers now hope to identify new targets in the mTOR pathway that can produce the same rapid result without the psychotic side effects associated with ketamine.

Ketamine is marketed as a veterinary anesthetic and as an analgesic to treat severe or chronic pain in humans. At high doses,the drug can cause hallucinogenic and psychotic effects. As a result, ketamine is a recreational drug of abuse and was classified as a Schedule III controlled substance by the U.S. Drug Enforcement Agency (DEA) in 1999.

Ketamine antagonizes the NMDA receptor (NMDAR), which is expressed throughout the CNS and binds the neurotransmitter glutamate on inhibitory neurons. By doing this, the drug is thought to increase the overall excitatory activity of certain brain regions. This heightened activity is a double-edged sword: it can lead to schizophrenia-like cognitive and behavioral abnormalities in animals and normal human subjects2,3 but it can also reduce depression in both animals and patients4,5 (see Box 1, "NOX2-driven schizophrenia").

In pain, injury to the CNS leads to increased extracellular glutamate, which activates NMDAR on postsynaptic neurons, leading to greater intracellular calcium, more neuronal firing and the development of chronic and/or neuropathic

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