Here is an article that presents a simplified outline of the basis for GLIA's glycine transporter program to identify treatments for Schizophrenia.
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John de C
Glutamate Is Likely Target for Schizophrenia Tx
Bruce Jancin, Denver Bureau [Clinical Psychiatry News 27(10):14, 1999. ¸ 1999
THOMPSONVILLE, MICH. -- The glutamate neurotransmitter system is attaining new stature in the neurobiology of schizophrenia and as a likely target for therapeutic intervention.
"Glutamate is an up-and-coming player. This is a receptor family I think we're all going to have to come to understand more and more because you're going to see a number of pharmaceutical companies targeting this system with innovative treatments in the next several years," Dr. James H. Meador-Woodruff predicted at a psychopharmacology update sponsored by the University of Michigan.
Most psychiatrists were trained in an era when dopamine was believed to be the only important neurotransmitter in schizophrenia. This is no longer thought to be true.
Excitatory glutamate receptors are widely distributed in the prefrontal cortex, the striatum, and to a lesser extent, the thalamus. The glutamate system is easily the most complicated of all neurotransmitter systems. It contains well over 100 different specific receptor types grouped into two broad families: ionotropic and metabotropic.
The ionotropic glutamate receptors are far better understood than the metabotropic. In fact, the N-methyl-D-aspartate (NMDA) subtype of ionotropic receptors provided the first evidence that abnormalities of the glutamate system are implicated in schizophrenia, according to Dr. Meador-Woodruff, a research psychiatrist at the university.
Fast-acting postsynaptic NMDA receptors control calcium ion flow. Postmortem receptor-binding studies in schizophrenic patients have demonstrated NMDA-receptor abnormalities in the prefrontal cortex and thalamus. Blocking NMDA receptors with a dissociative anesthetic such as ketamine or phencyclidine causes a normal person to become psychotic, and a schizophrenic to become more psychotic.
It therefore follows that an agent which activates NMDA receptors might be therapeutically useful in schizophrenia, Dr. Meador-Woodruff said. Glutamate is the naturally occurring agonist, but it's toxic in the high doses required to cross the blood/brain barrier.
Fortunately, the NMDA receptor contains a coagonist site for glycine. That's the rationale underlying published studies showing a therapeutic effect for very high-dose glycine.
A more practical, longer-acting alternative glycine agonist is D-cycloserine. Studies to date suggest it has a role in diminishing negative symptoms of schizophrenia and improving cognitive function when used as an adjunct to antipsychotic agents. Controversy remains, however, as to whether it works better in conjunction with typical or atypical antipsychotic drugs.
"My guess is that within a couple of years, we'll begin using D-cycloserine under specific conditions in clinical practice," the psychiatrist said.
Other subtypes of ionotropic glutamate receptors, notably the AMPA and kainate receptors, have also been implicated in schizophrenia.
On the metabotropic side, the group II receptors located on presynaptic glutamaturgic neurons and glial cells have attracted considerable interest from pharmaceutical companies.
"Look for phase II and phase III clinical trials of group II metabotropic receptors within a few years for the treatment of schizophrenia and maybe for certain forms of substance abuse," Dr. Meador-Woodruff advised |
