Behavioral Science Essays The
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The Glutamate Theory of Schizophrenia (Part 2/2) Sten M. Andersen In the caudate nucleus and the putamen, commonly referred to as the striatum (Rosenzweig, 1999), NMDA receptors exert two different effects. On presynaptic DA terminals, NMDA receptors stimulate DA release, whereas NMDA receptors on g-aminobutyric acid (GABA)ergic neurons stimulate GABA-release, which again inhibits DA release (Javitt et al., 2000). These findings could shed some light on some of the conflicting evidence found in DA-focused hypothesis, that even though some patients are helped by dopamine antagonists, other seem to get better when given amphetamine, which raises dopamine levels. Goldstein and Deutch (1992) propose another unifying framework, in which prefrontal hypoactivity causes mesolimbic dopamine hyperactivity. It might be that one of these theories, or the combination of both, could explain the variety of symptoms seen in schizophrenia.
When glutamate (glu) is released into the synaptic cleft, it is broken down to glutamine (gln), before it is transported back into the presynaptic terminal and converted to glu again (Erecinska & Silver, 1990). It has therefore been thought that an increase in gln levels might reflect a decrease in glu levels (Bartha et al., 1997). Using short-echo proton magnetic resonance spectroscopy (MRS), Bartha et al. (1997) found a significant increase in gln in untreated schizophrenic patients compared with controls, but not in patients treated with neuroleptics. When the patients received neuroleptic therapy, a decrease in gln was observed. This suggests that the neuroleptics act on the glutamatergic system, and either restores the levels of glu, or in some other way restores the effects of glu. Bartha et al. (1997) found no differences in glu, and suggested that the findings might indicate “an abnormality in the cycle of conversion of gln to glutamate” (Bartha et al., 1997, p. 962), reasoning that the overall level of glu would seem to be unchanged, since this is a small “neurotransmitter pool of glutamate [, which] does not equilibrate quickly with a larger pool of cellular glutamate” (Bartha et al., p. 962). Hence, the overall levels of glutamate would be unchanged, but the levels of glutamate available for signal transduction would be decreased. Stanley et al. (1996) also reported higher glutamine levels, and noted that gln levels correlated positively with the duration of the illness. In addition, gln levels were lowered by antipsychotics. But other researchers report different findings. Deakin et al. (1989) reported finding more glutamate in the medial prefrontal cortex of schizophrenic patients compared with controls, and Moghaddam and Adams (1998) that a drug which lowers brain levels of glutamate blocks schizophrenia-like symptoms in rats. Harrison (1999) lists recent findings about glutamate in schizophrenia: “Decreased expression of hippocampal non-NMDA receptors; increased cortical expression of some NMDA receptor subunits; increased glutamate reuptake in frontal cortex; decreased cortical glutamate release; altered concentrations of glutamate and metabolites”.
In addition to being activated by glutamate, NMDA receptors are activated by glycine, that is, glycine acts as a co-agonist. Javitt et al. (2000) found that glycine inhibited NMDA-mediated dopamine release in the striatum. Javitt and Frusciante (1996) suggest that glycyldodecylamide (GDA), which blocks glycine uptake (i.e., make more glycine available) might ameliorate schizophrenic symptoms which resembles those seen in a PCP psychosis. They found that both glycine and GDA reverses PCP-induced hyperactivity in rodents, and that GDA was 80-fold more potent than glycine.
Even though much research indicates that NMDA receptors play a role in the aetiology of schizophrenia, it is yet to be determined what mechanism is actually dysfunctional. It might be the case that there is too little glutamate or too much glutamate. But the NMDA receptor is also sensitive to glycine, polyamines, and some divalent cations (Javitt & Zukin, 1991), and concentrations of any of these might lead to decreased NMDA activity. It might also be the case that NMDA receptors are not functioning correctly. Olney, Newcomer, and Farber (1999) formulated an “NMDA receptor hypofunction model of schizophrenia” (NRHypo) in which they state that a prolonged NRHypo state might lead to neurodegenerative changes, which could explain the worsening seen in some patients over time.
As we have seen, PCP gives a good model for schizophrenia. In contrast to amphetamine, which increases DA levels in the brain, and extorts symptoms that resemble the positive symptoms seen in schizophrenia, PCP induces both positive and negative symptoms, in addition to the cognitive deficits seen in many schizophrenic patients. PCP works as an NMDA antagonist, and since NMDA is a glutamate receptor, it is hypothesised that schizophrenia is due to glutamatergic underactivity in the brain. Problems with verifying the theory, stems from the fact that different researchers have found conflicting evidence about the levels of glutamate and its metabolites in the brains of schizophrenic. Whereas some researchers report increased levels of glutamine, which suggests lowered levels of glutamate, others report increased levels of glutamate, and can even show that drugs which lowers glutamate levels, can reverse PCP induced effects. On the other hand, it has also been shown that drugs that act like NMDA agonists (e.g., glycine) can reduce schizophrenic symptoms. If it is correct that there is a glutamatergic hypoactivity, alternative suggestions to the glutamate theory have been proposed. There could be anomalies in the levels of any of the chemicals that affect the NMDA receptor, or the NMDA receptor itself could be dysfunctional. It would be interesting to see more research on what difference aspects of schizophrenic symptoms the different drugs ameliorate. At this stage, it is difficult to conclude anything else but the fact that NMDA and glutamate appear to have a role in schizophrenia It might be reasonable to believe that schizophrenia is a complex disease, with more than one cause, but even this is only a transient hypothesis. References Bartha, R., Williamson, P. C., Drost, D. J., Malla, A., Carr, T. J., Cortese, L., Cananran, G., Rylett, R. J., & Neufeld, R. W. J. (1997). Measurement of glutamate and glutamine in the medial prefrontal cortex of never-treated schizophrenic patients and healthy controls by proton magnetic resonance spectroscopy. Archive of General Psychiatry (54). 959-65
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