Post-mortem neurochemistry of schizophrenia

There is little doubt that brain tissue taken at autopsy has provided a valuable means to investigatethe various neurochemical hypotheses of schizophrenia. This approach to the study of neurologicaland psychiatric disease has received increasing attention over the past three decades as its potentialhas become recognized. The observation that dopamine was severely depleted in the striatum ofParkinson's disease patients led directly to the initial trial of the highly successful L-dopa therapy.More recently, important if less dramatic advances in our understanding of Huntington's diseaseand senile dementia have been gained from post-mortem studies. However, the search for abiochemical abnormality in schizophrenia has classically involved the analysis of body fluids. Thesestudies have been disappointing; the literature on the biochemistry of schizophrenia is littered withinconsistent findings and artefactual results. Two notable examples are the stor thy oe endogenouf spsychotogenic 'pink spot' and investigations of platelet monoamine oxidase, each of which wasfounded on insecure premises and consumed many man-years of research effort in the pursuit ofartefactual results.It was the search for endogenous psychotogens which first focused interest on tryptophanmetabolism and 5-hydroxytryptamine (5HT) function. Studies of post-mortem brain tissue fromschizophrenic patients have, however, provided no indication of abnormalities in concentrations oftryptophan metabolites in either the 5HT or kynurenine pathways (Josep al. 1979)h. et Reports ofa decrease in frontal cortical 5HT-2 receptors, as measured using the binding of radiolabelled LSDto a cell membrane preparation from post-mortem tissue al. (Bennet 1979),t renewe et d interest in5HT function in schizophrenia, but no confirmation of these findings resulted from further studiesemploying LSD (Whitake al.r et 1981) or the more specific ligand, ketanserin (Reynolds et al.1983). The possibility of abnormal noradrenergic function in schizophrenia was originally proposed byStein & Wise (1971) after consideration of the role of noradrenergic pathways in rewardmechanisms in animals, and finding a reduced activity of dopamine /? -hydroxylase (the specificsynthetic enzyme for noradrenaline) in various brain regions, including the brainstem, inschizophrenic patients (Wise & Stein, 1973). Further studies were unable to repeat this finding(Crow et al. 1981). Nevertheless, the hypothesis was modified and developed by Hornykiewicz(1982) on the basis of an increase in noradrenaline concentrations in the nucleus accumbens inschizophrenia (Farley al. et 1978). Again, however, other groups could not repeat these results,although an increase in the noradrenergic metabolite, MHPG, in this region has been reported(Kleinman et al. 1981) Ther. e has been criticism of this evidence for the involvement of noradrenalinein schizophrenia (Iverse al. 1983)n et, and the influence of neuroleptic medication on the post-mortem findings has not been excluded.It is the common action of the antipsychotic drugs in blocking dopamine neurotransmissionwhich has enabled the 'dopamine hypothesis' to remain the major theory of schizophrenic aetiology.In investigating whether there is a hyperactivity of dopamine function in schizophrenia, much efforthas been expended measuring concentrations of the transmitter, its metabolites and associatedenzymes in post-mortem brain tissue, albeit with few conclusive results. Recently, attention hasfocused on a more consistently reported finding. Since the first report (Owe al. 1978n et ) there hasbeen substantial confirmation that dopamine D2 receptors are increased above control values in