title: Repeated ketamine administration alters N-methyl-D-aspartic acid receptor subunit gene expression: implication of genetic vulnerability for ketamine abuse and ketamine psychosis in humans.
abstract: For more than 40 years following its approval by the Food and Drug Administration (FDA) as an anesthetic, ketamine, a non-competitive N-methyl-D-aspartic acid (NMDA) receptor antagonist, has been used as a tool of psychiatric research. As a psychedelic drug, ketamine induces psychotic symptoms, cognitive impairment, and mood elevation, which resemble some symptoms of schizophrenia. Recreational use of ketamine has been increasing in recent years. However, little is known of the underlying molecular mechanisms responsible for ketamine-associated psychosis. Recent animal studies have shown that repeated ketamine administration significantly increases NMDA receptor subunit gene expression, in particular subunit 1 (NR1 or GluN1) levels. This results in neurodegeneration, supporting a potential mechanism where up-regulation of NMDA receptors could produce cognitive deficits in chronic ketamine abuse patients. In other studies, NMDA receptor gene variants are associated with addictive behavior. Here, we focus on the roles of NMDA receptor gene subunits in ketamine abuse and ketamine psychosis and propose that full sequencing of NMDA receptor genes may help explain individual vulnerability to ketamine abuse and ketamine-associated psychosis.
authors.affiliation: Department of Psychiatry, Yale School of Medicine, New Haven, CT 06511, USA ke.xu@yale.edu.
authors.forename: Ke
authors.initials: K
authors.lastname: Xu
authors.affiliation: Inova Neuroscience Institute, Inova Health System, Falls Church, VA 22042, USA Department of Molecular Neuroscience, the Krasnow Institute for Advanced Study, George Mason University, Fairfax, VA 22030, USA.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Lipsky
mesh_terms: D018691:Excitatory Amino Acid Antagonists / Q000009:adverse effects*; D005786:Gene Expression Regulation / Q000187:drug effects*; D020022:Genetic Predisposition to Disease; D006801:Humans; D013287:Illicit Drugs / Q000009:adverse effects*; D007649:Ketamine / Q000009:adverse effects*; D019636:Neurodegenerative Diseases / Q000139:chemically induced / Q000378:metabolism; D011605:Psychoses, Substance-Induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016194:Receptors, N-Methyl-D-Aspartate / Q000096:biosynthesis / Q000235:genetics; D019966:Substance-Related Disorders / Q000235:genetics / Q000378:metabolism / Q000473:pathology
chemical_list: D018691:Excitatory Amino Acid Antagonists; D013287:Illicit Drugs; C409466:NR1 NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D007649:Ketamine
keywords: N-Methyl-d-aspartic acid (NMDA) receptor; gene expression; ketamine administration; ketamine-associated psychosis