It is well established that the psychosis-inducing effects of the dissociative anesthetics phencyclidine (PCP) and ketamine, when used at subanesthetic doses such as in drug abuse, are produced by blockade of neurotransmission at N-methyl-D-aspartate (NMDA)-type glutamate receptors. However, their mechanisms of action at the brain circuitry level are poorly understood. Behrens et al. found that exposure of mice to subanesthetic doses of ketamine triggers an early and profound increase in neuronal superoxide production that is specifically due to induction of the inflammatory enzyme complex, NADPH oxidase-2 (Nox2). This in turn leads to the loss of phenotype of a specific subset of GABAergic interneurons, the parvalbumin-positive (PV) fast-spiking interneurons. Prevention of superoxide effects in the brain using a brain-permeable superoxide dismutase mimetic, as well as apocynin, a Nox2 inhibitor, strongly attenuated the ketamine-induced loss of parvalbumin and GAD67 immunoreactivity.
M. M. Behrens, S. S. Ali, D. N. Dao, J. Lucero, G. Shekhtman, K. L. Quick, L. L. Dugan, Ketamine-induced loss of phenotype of fast-spiking interneurons is mediated by NADPH-oxidase. Science 318, 1645-1647 (2007). [Abstract] [Full Text]