A wide range of neurochemical systems and parameters have been investigated in schizophrenia, and a diverse collection of abnormalities reported. (1> Discussion is limited here to three areas of current interest.
The dopamine hypothesis of schizophrenia has been neurochemically pre-eminent since the 1960s. It proposes that the symptoms of schizophrenia result from dopaminergic overactivity, whether due to excess dopamine, or to an elevated sensitivity to it, for example because of increased numbers of dopamine receptors. The hypothesis originated with the discovery that effective antipsychotics were dopamine (D 2) receptor antagonists, and that dopamine-releasing agents such as amphetamine produce a paranoid psychosis. It received support from various findings of increased dopamine content and higher densities of D 2 receptors in schizophrenia/2) However, despite its longevity there is still no consensus as to precisely what the dopamine hypothesis explains, nor the nature of the supposed abnormality. There are two main difficulties. First, antipsychotics have marked effects on the dopamine system, seriously confounding most studies. Second, molecular biology has revealed an unexpected complexity of the dopamine receptor family, increasing the potential sites of dysfunction and mechanisms by which it might occur.
Striatal D2 receptor densities are increased in schizophrenia, but it is unclear what proportion, if any, is not attributable to antipsychotic medication. (3) Statistical methods have been used to argue that there is a genuine schizophrenia-associated elevation, but this must be balanced against negative positron emission tomography (PET) studies of D2 receptors in drug-naive first-episode cases. For D1 and D3 receptors there are reports of their altered expression in schizophrenia, but these are either unconfirmed or contradicted by other studies. Controversy has surrounded the D 4 receptor following a report that it was upregulated several-fold in schizophrenia, seemingly independent of medication. However, the result appears to have been due to a 'D 4-like site' not the true D4 receptor, and the status of the latter in schizophrenia is unknown.(4) Overall, the position of dopamine receptors in schizophrenia is still contentious and the case for their involvement unproven. In contrast, there is emerging evidence for a presynaptic abnormality, with three studies of drug-free subjects showing elevated dopamine release in response to amphetamine/5) This implies a dysregulation and hyper-responsiveness of dopaminergic neurones in schizophrenia, a potentially important finding needing further investigation.
Suggestions of 5-hydroxytryptamine (5-HT, serotonin) involvement in schizophrenia arose because the hallucinogen lysergic acid diethylamide ( LSD) is a 5-HT agonist. Recently, interest has focused on the 5-HT2A receptor.(4) A high affinity for the receptor may explain the therapeutic advantages of atypical antipsychotics, and variants in the gene are a minor risk factor for non-response to clozapine and for schizophrenia. Many studies have found a lowered 5-HT 2A receptor expression in the frontal cortex in schizophrenia, and there is a blunted neuroendocrine response to 5-HT 2 agonists. Elevated cortical 5-HT1A receptors are also a replicated finding. The 5-HT1A and 5-HT2A receptor abnormalities are both seen in subjects not on medication at death, but neither has been investigated in drug-naive or first-episode patients.
Hypotheses for the involvement of 5-HT in schizophrenia include the trophic role of the 5-HT system in neurodevelopment, interactions between 5-HT and dopaminergic neurones, and impaired 5-HT2A receptor-mediated activation of the prefrontal cortex.(6)
Phencyclidine and other non-competitive antagonists of the M-methyl-D-aspartate (NMDA) subtype of glutamate receptor produce a psychosis closely resembling schizophrenia. This has driven the hypothesis of glutamatergic dysfunction in schizophrenia. (7) In support, there is now considerable evidence for glutamatergic abnormalities in schizophrenia (Table !). In the medial temporal lobe, for example, glutamatergic markers are decreased and there is reduced expression of non-NMDA glutamate receptors. However, a different pattern is seen in other brain regions and affecting other glutamate receptor subtypes, precluding any simple conclusion regarding the nature of the abnormality in schizophrenia. Mechanisms proposed to explain glutamatergic involvement in schizophrenia centre on its interactions with dopamine, and subtle forms of glutamate-mediated neurotoxicity.
In addition to the three neurotransmitters mentioned above, schizophrenia is associated with alterations in many other systems, including g-aminobutyric acid (GABA), neuropeptides, adrenoreceptors, and second messengers.(!) However, there is still no clear picture as to the cardinal neurochemical deficits. One important point, relating to the neuropathology to be discussed below, is that the presence of structural abnormalities, however slight, must be taken into account. That is, a change in the level of a neurotransmitter, receptor, or any other molecule, may be due to dysfunction of the neurones producing it, or a change in the cellular constituents of the tissue, rather than being indicative of a specific abnormality. This applies to in vivo functional imaging as well to postmortem neurochemistry. While an obvious point to make, it has not always been appreciated in schizophrenia research, perhaps because of the belief that the brain is structurally normal.
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