The street drug ketamine—already known to cause
schizophrenia-like symptoms by blocking the NMDA receptor—appears also
to disrupt brain circuitry by overexcitation of an inflammatory enzyme in the
The drug has been found to increase the activity of the nicotinamide
adenine dinucleotide phosphate (NADPH) oxidase enzyme complex, which is
naturally found in white blood cells circulating outside the brain. The enzyme
helps to kill bacterial and fungal infections by producing"
superoxide," a toxic, free radical that causes substantial damage
But overexcitation of the enzyme by ketamine causes it to attack neurons
critical to signaling in the brain, according to a report published in the
December 7, 2007, Science.
The lead author of the report was M. Margarita Behrens, Ph.D., associate
project scientist in the Department of Medicine at the University of
California, San Diego School of Medicine (UCSD).
The result is impairment of the brain circuitry involved in memory,
attention, and other key functions related to learning. Loss of such functions
is believed to lead to symptoms that are indistinguishable from
schizophrenia—deficits in information processing, hallucinations,
delusions, social withdrawal, and cognitive problems.
Using ketamine, Behrens and colleagues elicited schizophrenia-like features
in mice and then analyzed neurons in a region of the mouse brain that
corresponds to the prefrontal cortex in humans. The researchers found a
substantial increase in the activity of NADPH oxidase and that this activity
caused a decrease in critical neurons, known as parvalbumin interneurons.
The latter are involved in the temporal encoding and storage or recall of
information required for working memory, according to the report in
When the researchers blocked the activity of NADPH oxidase with an
inhibitor or with a compound that annihilates superoxide, these neurons were
Behrens and colleagues suggested that if compounds could be developed that
inhibit NADPH oxidase without affecting its natural protective function of
killing bacteria, it could open the door to new therapies for
"We hypothesize that NADPH oxidase may be a contributor to oxidative
mechanisms involved not only in the psychotomimetic effects of NMDA-R
antagonists, but also in schizophrenia and other processes involving increased
oxidative stress in the brain," Behrens and colleagues wrote."
Further understanding of mechanisms underlying activation or induction
of brain NADPH oxidase may provide a completely new avenue for drug discovery
aimed at the treatment of psychosis and cognitive deficits."
The research was funded by a private endowment to UCSD and by NARSAD.
"Ketamine-Induced Loss of Phenotype of Fast-Spiking
Interneurons Is Mediated by NADPH-Oxidase" is posted at<www.sciencemag.org/cgi/content/full/318/5856/1645>.▪