Behavioral Science Essays

The Attentional Blink
The Glutamate Theory of Schizophrenia
Non-intelligent Perception
Anxiety and the GABA-A receptor subunit
On The Theory-Ladenness of Observation
ECT in Depressed Older Adults
Dennett Indented?

The Glutamate Theory of Schizophrenia (Part 1/2)

Sten M. Andersen

Next: Part 2

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.

Next: Part 2