The glutamate theory of schizophrenia

 

Schizophrenia is a complex disease, which shows itself through what are called positive (Type I) and negative (Type II) symptoms. Type I symptoms include paranoia, hallucinations, thought disorders, and delusions (Carlson, 2001; Egan & Weinberger, 1997). Amongst the type II symptoms, we find flattened emotional response, social withdrawal, and reduced initiative (Carlson, 2001). In short, positive symptoms are recognisable through their presence, and negative symptoms by the absence of normal behaviours (Carlson, 2001). In addition, schizophrenic patients often show cognitive deficits (Kay & Sevy, 1990; as cited in Javitt & Zukin, 1991). It is estimated that about a half to one percent of the world’s population has schizophrenia (Carlson, 2001; Javitt, Sershen, Hashim, & Lajtha, 2000).

 

The dopamine (DA) theory of schizophrenia has dominated the attempts to explain the behaviours seen in schizophrenic patients. It is based somewhat upon the observation that amphetamine induces behaviours that resemble the positive symptoms in schizophrenia, and the fact that amphetamine raises dopamine levels in the brain. The DA theory has relatively good explanatory power when it comes to the positive symptoms, but at least in its classical form, it does not provide an explanation for the negative symptoms. Another theory of schizophrenia is the glutamate theory, which seems to give an explanation for both positive and negative symptoms, and also for the cognitive deficits seen in many patients. The idea stems from observations of phencyclidine hydrochloride (PCP) induced psychosis, which closely resembles schizophrenia (Javitt & Zukin, 1991). N-methyl-D-aspartate (NMDA) is a glutamate receptor, and PCP inhibits neurotransmitter-release mediated by NMDA (Javitt & Zukin, 1990; as cited in Javitt & Zukin 1991). This may imply that there is an underactivity of glutamate in schizophrenic patients. The findings that glycine, an NMDA agonist, reverse PCP-induced symptoms in rodents and makes patients with schizophrenia better (Javitt et al., 2000) might be seen as further support for the glutamate theory of schizophrenia. But many of the findings contradict each other, and caution should be applied when interpreting these results.

 

Glutamate is an excitatory neurotransmitter, and N-methyl-D-aspartate (NMDA) is a type of glutamate receptor (Rosenzweig, Leiman, & Breedlove, 1999). Phencyclidine (PCP) and its analogues, like ketamine and MK-801, are non-competitive antagonists of the NMDA receptor (Javitt & Zukin, 1991; Tsai et al., 1995). That is, when PCP or one of its analogues binds to an NMDA receptor, it inhibits that receptor from responding correctly to glutamate. PCP induces all the symptoms seen in schizophrenia (Javitt & Frusciante, 1996). The so-called positive symptoms are hallucinations, particularly auditory, hostility, agitation, and paranoid delusions (Carlson, 2001; Egan & Weinberger, 1997). The negative symptoms are such as flattened emotional response, social withdrawal, anhedonia, and reduced initiative (Carlson, 2001; Tsai et al., 1995). PCP also induces cognitive deficits, such as impaired learning and memory (Kay & Sevy, 1990; as cited in Javitt & Zukin, 1991). The dopamine theory of schizophrenia only has strong explanatory power for the positive symptoms, which are induced by an overactivity of dopamine, as seen in amphetamine-induced psychosis. PCP psychosis gives us a better model of schizophrenia. It has been stated that it is hard to tell PCP psychosis from schizophrenia (Yesavage & Freeman, 1978; as cited in Olney, Newcomer, & Farber, 1999), and that no other drug can mimic the state of schizophrenia as faithfully (Javitt & Zukin, 1991). Since NMDA is a glutamate receptor, and PCP is an NMDA antagonist that induces schizophrenia-like symptoms, it has been hypothesised that schizophrenia is due to glutamatergic underactivity (Bartha et al., 1997; Kim, Kornhuber, Schmid-Burgk, & Holzmuller, 1980; as cited in Tsai et al., 1995). It is interesting to notice that most PCP responses are not inhibited by typical dopamine (DA) antagonists (Javitt & Zukin, 1991); but Jentsch et al. (1997) reported that monkeys who had been treated with PCP twice a day for 14 days, and who showed deficits on a task that required frontal cortex function, where helped by clozapine, an atypical DA antagonist. Clozapine is a somewhat weak blocker of DA receptors, but is an effective antipsychotic (Torrey, 1995). Still, the findings of Jentsch et al. might suggest a connection between the glutamate and the dopamine theory of schizophrenia. But then again, in a follow up study, Jentsch et al. (1999) found that the degree of impairment seen after PCP exposure was positively correlated with a decrease in dopamine levels.

 

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

 

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            Carlson, N. R. (2001). Physiology of behaviour. Sydney: Allyn and Bacon.

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Javitt, D. C., & Frusciante, M. (1997). Glycyldodecylamide, a phencyclidine behavioral antagonist, blocks cortical glycine uptake: Implications for schizophrenia and substance abuse. Psychopharmacology (129), 96-98.

Javitt, D. C., Sershen, H., Hashim, A., & Lajtha, A. (2000). Inhibition of striatal dopamine release by glycine and glycyldodecylamide. Brain Research Bulletin, 52(3), 213-216.

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Jentsch, J. D., Redmond, D. E. Jr, Elsworth, J. D., Taylor, J. R., Youngren, K. D., & Roth, H. R. (1997). Enduring cognitive deficits and cortical dopamine dysfunction in monekys after long-term administration of phencyclidine. Science, 22(5328), 953-955. Abstract

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