Objective: The initial hypothesis that schizophrenia is a manifestation of hyperdopaminergia has recently been faulted. However, several new findings suggest that abnormal, although not necessarily excessive, dopamine activity is an important factor in schizophrenia. The authors discuss these findings and their implications. Method: All published studies regarding dopamine and schizophrenia and all studies on the role of dopamine in cognition were reviewed. Attention has focused on post-mortem studies, positron emission tomography, neuroleptic drug actions, plasma levels of the dopamine metabolite homovanillic acid (HVA), and cerebral blood flow. Results: Evidence, particularly from intracellular recording studies in animals and plasma HVA measurements, suggests that neuroleptics act by reducing dopamine activity in mesolimbic dopamine neurons. Post-mortem studies have shown high dopamine and HVA concentrations in various subcortical brain regions and greater than normal dopamine receptor densities in the brains of schizophrenic patients. On the other hand, the negative/deficit symptom complex of schizophrenia may be associated with low dopamine activity in the prefrontal cortex. Recent animal and human studies suggest that prefrontal dopamine neurons inhibit subcortical dopamine activity. The authors hypothesize that schizophrenia is characterized by abnormally low prefrontal dopamine activity (causing deficit symptoms) leading to excessive dopamine activity in mesolimbic dopamine neurons (causing positive symptoms). Conclusions: The possible co-occurrence of high and low dopamine activity in schizophrenia has implications for the conceptualization of dopamine ‘s role in schizophrenia. It would explain the concurrent presence of negative and positive symptoms. This hypothesis is testable and has important implications for treatment of schizophrenia and schizophrenia spectrum disorders.

Dopamine in Schizophrenia: A Review and Reconceptualization

This review critically summarizes the neuropathology and genetics of schizophrenia, the relationship between them, and speculates on their functional convergence. The morphological correlates of schizophrenia are subtle, and range from a slight reduction in brain size to localized alterations in the morphology and molecular composition of specific neuronal, synaptic, and glial populations in the hippocampus, dorsolateral prefrontal cortex, and dorsal thalamus. These findings have fostered the view of schizophrenia as a disorder of connectivity and of the synapse. Although attractive, such concepts are vague, and differentiating primary events from epiphenomena has been difficult. A way forward is provided by the recent identification of several putative susceptibility genes (including neuregulin, dysbindin, COMT, DISC1, RGS4, GRM3, and G72). We discuss the evidence for these and other genes, along with what is known of their expression profiles and biological roles in brain and how these may be altered in schizophrenia. The evidence for several of the genes is now strong. However, for none, with the likely exception of COMT, has a causative allele or the mechanism by which it predisposes to schizophrenia been identified. Nevertheless, we speculate that the genes may all converge functionally upon schizophrenia risk via an influence upon synaptic plasticity and the development and stabilization of cortical microcircuitry. NMDA receptor-mediated glutamate transmission may be especially implicated, though there are also direct and indirect links to dopamine and GABA signalling. Hence, there is a correspondence between the putative roles of the genes at the molecular and synaptic levels and the existing understanding of the disorder at the neural systems level. Characterization of a core molecular pathway and a 'genetic cytoarchitecture' would be a profound advance in understanding schizophrenia, and may have equally significant therapeutic implications.

Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence.

Quantitative autoradiographic mapping of serotonin receptors in the rat brain. I. Serotonin-1 receptors.

in Florence showed some symptomatic improvement with only minor side effects, but this requires confirmation in a controlled trial. Cyclosporin A does not cause bone marrow depression; but reports of the development of lymphoma in patients treated with the drug after transplantation,6 and indeed in patients treated with other immunosuppressive drugs,7 mean that immunosuppression should be used circumspectly. Another approach is based on the finding that suppressor lymphocyte activity is depressed during acute relapses in multiple sclerosis.8 This has raised the possibility of enhancing suppressor cell activity therapeutically, and is yet another potentially promising line of investigation.

https://www.bmj.com/content/bmj/280/6207/66.full.pdf

Molecular pathology of schizophrenia: more than one disease process?

A model is proposed for integrating the neural and cognitive aspects of the positive symptoms of acute schizophrenia, using evidence from postmortem neuropathology and neurochemistry, clinical and preclinical studies of dopaminergic neurotransmission, anatomical connections between the limbic system and basal ganglia, attentional and other cognitive abnormalities underlying the positive symptoms of schizophrenia, specific animal models of some of these abnormalities, and previous attempts to model the cognitive functions of the septohippocampal system and the motor functions of the basal ganglia Anatomically, the model emphasises the projections from the septohippocampal system, via the subiculum, and the amygdala to nucleus accumbens, and their interaction with the ascending dopaminergic projection to the accumbens Psychologically, the model emphasises a failure in acute schizophrenia to integrate stored memories of past regularities of perceptual input with ongoing motor programs in the control of current perception A number of recent experiments that offer support for the model are briefly described, including anatomical studies of limbic-striatal connections, studies in the rat of the effects of damage to these connections, and of the effects of amphetamine and neuroleptics, on the partial reinforcement extinction effect, latent inhibition and the Kamin blocking effect; and studies of the latter two phenomena in acute and chronic schizophrenics

The neuropsychology of schizophrenia.

Increased dopamine-receptor sensitivity in schizophrenia

DURING the past decade, the central neurotransmitter, dopamine (DA), has been much studied for it is known to be involved in certain human disease states, Parkinsonism1 preeminently, and rather more inferentially, schizophrenia2. DA is metabolised by monoamine oxidase (MAO)3, which catalyses the oxidative deamination of a wide range of monoamines4,5, including the neurotransmitters noradrenaline (NA) and 5-hydroxytryptamine (5-HT), and other amines such as tyramine, tryptamine and phenylethylamine (PEA). On the basis of animal studies with the inhibitors, clorgyline6, and later deprenil7, MAO has been classified into two types, A and B. By definition, type A is selectively inhibited by clorgyline and type B by deprenil. In general, type A acts on 5-HT6 while type B prefers PEA8. In the rat, DA is preferentially deaminated by MAOA9–11. It thus seemed paradoxical that, in the treatment of Parkinsonism, addition of the MAOB inhibitor, deprenil, to a DA-generating drug combination should produce further therapeutic benefit12. In this report, we reconcile these apparently conflicting observations by demonstrating that, as far as DA oxidation is concerned, man may be different from rat: in two sites we have investigated, platelet and brain, DA is preferentially deaminated by an enzyme with the characteristics of MAOB.

Dopamine is a monoamine oxidase B substrate in man

Dopamine and its metabolites homovanillic acid and dihydroxyphenylacetic acid, noradrenaline, serotonin and its metabolite 5-hydroxyindoleacetic acid, and tryptophan and its metabolite kynurenine have been assayed in 9 schizophrenic and 10 control brains, together with the monoamine-related enzymes tyrosine hydroxylase monoamine oxidase, dopamine-beta-hydroxylase, and catechol-o-methyl-transferase. In schizophrenic brains dopamine, noradrenaline and serotonin were significantly increased in some areas of corpus striatum, but there were no significant changes in enzyme activity or monoamine metabolite concentrations in any of the brain areas examined. The findings are not consistent with theories that serotonin or noradrenaline stores are grossly depleted or noradrenaline neurones have degenerated, or that monoamine oxidase activity is abnormal, in schizophrenia, and provide no direct support for the hypothesis that dopamine neurones are overactive.

Monoamine mechanisms in chronic schizophrenia: post-mortem neurochemical findings.

It has been suggested that deterioration of central noradrenergic pathways may be responsible for the production of certain schizophrenic symptoms, and that such a degeneration might be reflected in lowered dopamine-β-hydroxylase (DBH) activity in the brains of schizophrenics. The present study revealed that in rats lowered DBH activity was a sensitive index of noradrenergic degeneration. In the postmortem brains of 12 controls and 12 schizophrenics, however, no significant difference in DBH activity between controls and schizophrenics was found. DBH activity was relatively unstable postmortem and adversely affected by neuroleptic drugs, and these factors may have contributed to the previous finding of lowered DBH activity in the brains of schizophrenics. The activity of catechol-O-methyl transferase, which has also been previously reported as low in the brains of schizophrenics, was found to be no different in the controls of the present study.

The activities of brain dopamine-beta-hydroxylase and catechol-O-methyl transferase in schizophrenics and controls.

Serotonin (5HT), its chief metabolite 5-hydroxyindoleacetic acid (5 HIAA), its precursor tryptophan, and kynurenine, another metabolite of tryptophan, have been measured in post mortem human brain samples. Concentrations of these metabolites were not found to be significantly different in putamen, hippocampus or temporal cortex from 23 normal subjects compared with 15 subjects in whom a diagnosis of schizophrenia could be restrospectively confirmed. The results have been analysed with respect to cause of death, medication and post mortem changes. Post mortem increases in tryptophan and kynurenine were observed. Some interrelationships between the variables measured within and between the different areas studied are discussed. It is concluded that there is no evidence for a generalised deficit of 5HT in the brain in schizophrenia, nor for gross changes in turnover along the serotonin or kynurenine pathways of tryptophan metabolism in brain.

Brain tryptophan metabolism in schizophrenia: a post mortem study of metabolites of the serotonin and kynurenine pathways in schizophrenic and control subjects.

G. J. Riley

Papers

Increased dopamine-receptor sensitivity in schizophrenia

Dopamine is a monoamine oxidase B substrate in man

Monoamine mechanisms in chronic schizophrenia: post-mortem neurochemical findings.

The activities of brain dopamine-beta-hydroxylase and catechol-O-methyl transferase in schizophrenics and controls.

Brain tryptophan metabolism in schizophrenia: a post mortem study of metabolites of the serotonin and kynurenine pathways in schizophrenic and control subjects.