Ketamine-induced loss of phenotype of fast-spiking interneurons is mediated by NADPH-oxidase.
Abuse of the dissociative anesthetic ketamine can lead to a syndrome indistinguishable from schizophrenia. In animals, repetitive exposure to this N-methyl-d-aspartate-receptor antagonist induces the dysfunction of a subset of cortical fast-spiking inhibitory interneurons, with loss of expression of parvalbumin and the gamma-aminobutyric acid-producing enzyme GAD67. We show here that exposure of mice to ketamine induced a persistent increase in brain superoxide due to activation in neurons of reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. Decreasing superoxide production prevented the effects of ketamine on inhibitory interneurons in the prefrontal cortex. These results suggest that NADPH oxidase may represent a novel target for the treatment of ketamine-induced psychosis.
Department of Medicine, Division of Geriatric Medicine, University of California San Diego, La Jolla, CA 92093-0746, USA. mbehrens@ucsd.edu
M Margarita
MM
Behrens
Sameh S
SS
Ali
Diep N
DN
Dao
Jacinta
J
Lucero
Grigoriy
G
Shekhtman
Kevin L
KL
Quick
Laura L
LL
Dugan
D000098:Acetophenones / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D002478:Cells, Cultured; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005968:Glutamate Decarboxylase / Q000378:metabolism; D007395:Interneurons / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism*; D007649:Ketamine / Q000494:pharmacology*; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000378:metabolism*; D010084:Oxidation-Reduction; D010320:Parvalbumins / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects; D013574:Synaptosomes / Q000378:metabolism
D000098:Acetophenones; D004791:Enzyme Inhibitors; D008562:Membrane Glycoproteins; D010320:Parvalbumins; D016194:Receptors, N-Methyl-D-Aspartate; D013481:Superoxides; D007649:Ketamine; C056165:acetovanillone; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1