Neurotransmitters and the pathogenesis of schizophrenia

In its original form, the dopamine hypothesis of schizophrenia postulated that the positive symptoms of the illness arose as a consequence of the

Table 11.2. Risk factors for schizophrenia

1. Genetic factors - polygenic inheritance

2. Pre- and perinatal events, e.g. maternal viral infection during second trimester; toxaemia and/or hypoxia at birth

3. Environmental factors, e.g. the use of cannabis, brain trauma hyperactivity of the dopaminergic system, particularly in the mesocortico-limbic region of the brain that originated in the ventral tegmental area. It is now realized that this is a gross over-simplification and recently attempts have been made to develop the dopamine hypothesis to take into account the neurochemical changes that may underlie both the positive and negative symptoms of the condition.

It is well known that typical neuroleptics, all of which have a high affinity for dopamine receptors (particularly D2 receptors), do not effectively treat all schizophrenic patients and have only limited beneficial effects on the negative symptoms of the illness. Furthermore, neither typical nor atypical neuroleptics have an immediate effect on the positive symptoms even though it can be shown by both experimental studies in animals and by imaging methods in schizophrenic patients that neuroleptics rapidly bind to dopamine receptors. Thus factors other than an overactive dopaminergic system are probably operative in this disorder. The question is which of the numerous neurotransmitters and modulatory neuropeptides are responsible for both the negative symptoms and the delay in onset of the therapeutic effects of neuroleptics on the positive symptoms?

The deficit syndrome of schizophrenia, characterized by prominent negative symptoms, is presumed to be due to diminished prefrontal cortical activity. In experimental studies in patients, these symptoms often show response to dopaminergic agonists. As there are no dopamine autoreceptors on dopamine terminals in the cortex of the brain, it must be assumed that such agonists are acting on postsynaptic dopamine receptors to alleviate the negative symptoms. A diminished frontal cortical activity, as shown by PET studies for example, appears to be a characteristic feature of the untreated schizophrenic patient which would support the view that, at least in some patients, cortical dopaminergic activity is lower than normal and is not globally increased as was postulated by the original dopamine hypothesis.

Recently, attempts have been made to reconcile the deficiencies in the dopamine hypothesis by focusing on other neurotransmitters that may interact with dopamine in discrete cortical and subcortical neural circuits. In particular, the involvement of the glutamatergic system has received considerable attention. This possibility has arisen from the finding that dissociation anaesthetics such as ketamine and phencyclidine (PCP) can cause a schizophreniform psychosis in normal individuals. Such effects bear a much closer resemblance to the positive and negative symptoms of schizophreniform psychosis than the changes elicited by amphetamine which produced changes that more closely resemble the positive symptoms of the condition. In schizophrenic patients, PCP has also been shown to exacerbate a psychotic episode.

As will be discussed in detail later (see Chapter 15) PCP is a noncompetitive inhibitor of the N-methyl-D-aspartate (NMDA) subtype of the glutamate receptor. This has led to the suggestion that schizophrenia may be associated with a decreased glutamatergic activity particularly in cortical regions of the brain.

Glutamate is the most important excitatory neurotransmitter in the brain, probably influencing more than 50% of all synapses. The major glutamatergic system involves a projection from the cortex to the striatum. Thus the hypofunctioning of the cortex may be a reflection of the diminished glutamatergic and dopaminergic activity in that area of the brain. It has been suggested that dopamine hetero receptors may regulate the release of glutamate in the striatum which could help to verify the hypothesis implicating both glutamate and dopamine in the aetiology of schizophrenia. This forms the basis of the hypothesis proposed by Arvid Carlsson that schizophrenia arises due to an abnormality in the dopamine-glutamate systems in the corticostriatal pallido-thalamic circuit (Figure 11.2).

In addition to an abnormality in the corticostriatal system, it is also possible that a disorder in the dopamine-glutamate system occurs in other subcortical regions which could account for some of the symptoms seen in schizophrenia. The hippocampus and the associated entorhinal cortex are important areas of the brain concerned in memory formation, information

Figure 11.2. Schematic representation of ventral limbic circuits implicated in the positive symptoms of schizophrenia.
The Schizophrenia Dopamine Circuit

Increase of DA receptor activity in limbic system

Figure 11.3. Integrated model of schizophrenia.

Limbic System

High DA activity, especially

Reduced descending inhibition modulated by GAB A and NMDA pathways secondary to cortical atrophy

Increase of DA receptor activity in limbic system

Figure 11.3. Integrated model of schizophrenia.

processing and the generation of specimen-specific behaviours. Neuropsychological tests in schizophrenic patients have occasionally been shown to be abnormal and the cytoarchitecture and other morphological changes in the hippocampus and entorhinal cortex suggest that the positive symptoms of the illness may originate within the hippocampus. These regions of the brain are innervated by the dopaminergic system while glutamate is the predominant intrinsic excitatory transmitter in the hippocampus. Thus a dysfunction of the hippocampal dopamine-glutamate system in these areas could also account for the positive symptoms of the illness. This forms the basis of the integrated model of schizophrenia (Figure 11.3). The role of a dysfunctional dopaminergic system in the development of the disorder is shown in Figure 11.4.

In Chapter 15, the complexity of the glutamatergic system is briefly outlined. Four distinct families of glutamate receptors were described of which the alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA) and the NMDA glutamate receptors have been most extensively studied. Recently the cloning of both NMDA and non-NMDA (for example, AMPA) receptor genes has enabled receptor expression at the transcriptional level to be made. Such techniques are much more sensitive than those used previously that relied on the binding of a radioactive ligand to a glutamatic receptor. Using this technique of in situ hybridization it has been shown that after 2 weeks of treatment of rats with either haloperidol or clozapine (representing a typical and an atypical neuroleptic respectively) substantial alteration occurs in non-NMDA receptors in the hippocampus. It has been postulated that one of the functions of neuroleptics is to "up-regulate" some

Genes

Neurodevelopmantal abnormaliiy

Developmental insult

Deficient cortical control or subcortical DA activity

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