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

December 06, 2007

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.
-end-
Additional contributors to the paper include Sameh S. Ali, Diep N. Dao, Jacinta Lucero, Grigoriy Shekhtman and Kevin L. Quick, Department of Medicine, UCSD Division of Geriatric Medicine. The research was funded in part by the Larry L. Hillblom Endowment and NARSAD.

University of California - San Diego

Related Schizophrenia Articles from Brightsurf:

Schizophrenia: When the thalamus misleads the ear
Scientists at the University of Geneva (UNIGE) and the Synapsy National Centre of Competence in Research (NCCR) have succeeded in linking the onset of auditory hallucinations - one of the most common symptoms of schizophrenia - with the abnormal development of certain substructures of a region deep in the brain called the thalamus.

Unlocking schizophrenia
New research, led by Prof. LIU Bing and Prof. JIANG Tianzi from the Institute of Automation of the Chinese Academy of Sciences and their collaborators have recently developed a novel imaging marker that may help in the personalized medicine of psychiatric disorders.

Researchers discover second type of schizophrenia
In a study of more than 300 patients from three continents, over one third had brains that looked similar to healthy people.

New clues into the genetic origins of schizophrenia
The first genetic analysis of schizophrenia in an ancestral African population, the South African Xhosa, appears in the Jan.

Dietary supplement may help with schizophrenia
A dietary supplement, sarcosine, may help with schizophrenia as part of a holistic approach complementing antipsychotic medication, according to a UCL researcher.

Schizophrenia: Adolescence is the game-changer
Schizophrenia may be related to the deletion syndrome. However, not everyone who has the syndrome necessarily develops psychotic symptoms.

Study suggests overdiagnosis of schizophrenia
In a small study of patients referred to the Johns Hopkins Early Psychosis Intervention Clinic (EPIC), Johns Hopkins Medicine researchers report that about half the people referred to the clinic with a schizophrenia diagnosis didn't actually have schizophrenia.

The ways of wisdom in schizophrenia
Researchers at UC San Diego School of Medicine report that persons with schizophrenia scored lower on a wisdom assessment than non-psychiatric comparison participants, but that there was considerable variability in levels of wisdom, and those with higher scores displayed fewer psychotic symptoms.

Recognizing the uniqueness of different individuals with schizophrenia
Individuals diagnosed with schizophrenia differ greatly from one another. Researchers from Radboud university medical center, along with colleagues from England and Norway, have demonstrated that very few identical brain differences are shared amongst different patients.

Resynchronizing neurons to erase schizophrenia
Today, a decisive step in understanding schizophrenia has been taken.

Read More: Schizophrenia News and Schizophrenia Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.