Knowing how ketamine impairs brain circuitry may lead to new therapies for schizophrenia

Scientists know that the drug ketamine – street name “Special K” – can induce schizophrenia-like symptoms in drug abusers. Ketamine is also used as an anesthetic and, more recently, as an antidepressant – raising concerns by researchers at the University of California, San Diego (UCSD) School of Medicine, who have found that ketamine leads to the impairments in brain circuitry observed in both drug abusers and schizophrenic patients by causing increased production of a toxic free radical called “superoxide.” Their findings, which could point the way to novel treatments for schizophrenia, will be published in the December 7 issue of the journal Science.

A research team led by Laura Dugan, M.D., Larry L. Hillblom Professor of Geriatrics and research scholar with the UCSD Stein Institute for Research on Aging, discovered an unexpected link between the inflammatory enzyme complex NADPH oxidase and the dysfunction of certain brain neurons exposed to ketamine. NADPH oxidase is normally found in white blood cells circulating outside the brain, where it helps kill bacterial and fungal infections by producing superoxide, a compound that can cause substantial damage to cells.

“Because of NADPH oxidase’s protective role in fighting infection, it was very surprising to find that the complex wears a second hat – it is also critical for modulating signaling in the brain,” said first author M. Margarita Behrens, Ph.D., Division of Geriatric Medicine, UCSD School of Medicine.

According to Behrens, it was known that ketamine initially impairs the inhibitory circuitry in the brain’s cortex and hippocampus by blocking the NMDA receptor, a molecule on the cell surface that controls the activity of neurons. But the UCSD researchers discovered that, as a result of blocking the receptor, ketamine also substantially increased the activity of NADPH oxidase, causing further disruption of neuronal signaling.

“Ketamine causes a ‘disinhibition’ of brain circuitry, taking the brakes off the system and causing overexcitation of the brain in response to a stimulus,” said Behrens. “This overexcitation activates NADPH oxidase, which then produces superoxide – resulting in detrimental changes in key synaptic proteins and profoundly affecting nervous system function.”

The result is impairment of the brain circuitry involved in memory, attention and other key functions related to learning. Loss of such functions sets up individuals for psychosis and deficits in information processing, resulting in symptoms such as hallucinations and delusions, as well as social withdrawal and cognitive problems, according to Behrens.

Using ketamine, Behrens and Dugan mimicked features of schizophrenia in mice, and then analyzed neurons in a region of the mouse brain that corresponds to the prefrontal cortex in humans where profound changes occur in patients with schizophrenia. The researchers found a substantial increase in the activity of NADPH oxidase, and that this activity made some neurons in this inhibitory circuitry “disappear.” When the researchers blocked the activity of NADPH oxidase with an inhibitor, or with a compound that annihilates superoxide, these neurons were protected.

“Our findings suggest that compounds that inhibit NADPH oxidase in the brain, without totally blocking its protective function of killing bacteria, could provide future therapies for schizophrenia or other diseases in humans that exhibit similar changes in neural circuitry,” said Behrens.

Source: University of California - San Diego

Related stories:

Scientists go chatting to hear kids' drug concerns
(AP) -- It's nothing to LOL about. Students these days often have ready access to marijuana, alcohol and tobacco but they don't feel comfortable talking about the ramifications. So, some of the nation's government scientists went to the computer chat room Tuesday to make it a little easier for them.
Millisecond brain signals predict response to fast-acting antidepressant
Images of the brain's fastest signals reveal an electromagnetic marker that predicts a patient's response to a fast-acting antidepressant, researchers have discovered.
Patterns of normal brain activity may predispose individuals to different symptoms of psychosis
A new study released today offers a potential predictive technique to anticipate how individuals might behave during a psychotic episode. The study, in the June 18 issue of The Journal of Neuroscience, related the brain activity of healthy participants to how they behaved after exposure to ketamine (a psychosis-inducing drug that mimics schizophrenia symptoms). The findings help explain why schizophrenia symptoms vary greatly from person to person and may ultimately help personalize diagnosis and intervention.
Study shows how 'horse tranquiliser' stops depression
Researchers have shown exactly how the anaesthetic ketamine helps depression with images that show the orbitofrontal cortex – the part of the brain that is overactive in depression – being ‘switched off’.
Immune deficiency and balance disorder result from single gene defect
A genetic defect that causes a severe immune deficiency in humans may also produce balance disorders, according to a new study by researchers at the University of Iowa, The Jackson Laboratory and East Carolina University.
Faster-acting antidepressants closer to becoming a reality
A new study has revealed more about how the medication ketamine, when used experimentally for depression, relieves symptoms of the disorder in hours instead of the weeks or months it takes for current antidepressants to work. While ketamine itself probably won’t come into use as an antidepressant because of its side effects, the new finding moves scientists considerably closer to understanding how to develop faster-acting antidepressant medications – among the priorities of the National Institute of Mental Health (NIMH), part of the National Institutes of Health.
A breakthrough, then a surge, in stem cell research
Less than a year after a Wisconsin team helped discover a major alternative to human embryonic stem cells, the Madison scientists say more than 800 labs have begun using the approach, suggesting that many stem-cell researchers are starting to move beyond controversial embryonic sources for their work.
Lack of vitamin D linked to Parkinson's disease
A majority of Parkinson's disease patients had insufficient levels of vitamin D in a new study from Emory University School of Medicine.

News discussion:

Medicine & Health news