Antipsychotic drug action in schizophrenic patients: effect on cortical dopamine metabolism after long-term treatment.

In the brains of deceased schizophrenics who underwent long-term treatment with antipsychotic drugs, the concentration of homovanillic acid (a dopamine metabolite) was significantly increased in the orbital frontal, cingulate, and temporal tip areas of the cortex, but not in the putamen or the nucleus accumbens. The concentration of homovanillic acid was normal in the brains of schizophrenics who were not treated with drugs.

Brain monoamine oxidase activity in schizophrenics and controls.

Postmortem samples of caudate nucleus and frontal cortex from schizophrenic, schizophrenic-like, and control subjects were examined for monoamine oxidase activity using dopamine, phenylethylamine, and 5-hydroxytryptamine as substrates. There were no significant differences between the diagnostic groups with any of the three substrates. Neither was there a difference between the sexes, nor a consistent relationship of enzyme activity to age.

Increased brain dopamine and dopamine receptors in schizophrenia.

In postmortem samples of caudate nucleus and nucleus accumbens from 48 schizophrenic patients, there were significant increases in both the maximum number of binding sites (Bmax) and the apparent dissociation constant (KD) for tritiated spiperone. The increase in apparent KD probably reflects the presence of residual neuroleptic drugs, but changes in Bmax for tritiated spiperone reflect genuine changes in receptor numbers. The increases in receptors were seen only in patients in whom neuroleptic medication had been maintained until the time of death, indicating that they may be entirely iatrogenic. Dopamine measurements for a larger series of schizophrenic and control cases (n greater than 60) show significantly increased concentrations in both the nucleus accumbens and caudate nucleus. The changes in dopamine were not obviously related to neuroleptic medication and, unlike the receptor changes, were most severe in younger patients.

A 10-year study of the incidence of and factors predicting dementia in Parkinson's disease.

OBJECTIVE: To compare the incidence of dementia in PD with that of a control group without PD, and to assess the relationship between dementia and other features of PD. METHODS: The authors recruited 83 patients with PD and 50 controls, all without dementia at initial assessment, and assessed them at regular intervals over a maximum period of 122 months. Dementia was diagnosed according to objective criteria, and included a judgment by researchers masked to subject group and to variables putatively associated with dementia. RESULTS: Seventeen patients fulfilled dementia criteria; no controls did so. The cumulative proportion of PD patients becoming demented by 112 months was 0.38 (95% CI 0.20 to 0.55), or 42.6 cases per 1000 years of observation. Univariate analyses showed that incident dementia in patients with PD was associated with older age at entry into the study, greater severity of neurologic symptoms, longer duration of PD, greater disability, and male sex. The association of age at onset of PD with incident dementia was of only borderline significance. Multivariate analysis found that age at entry into the study and severity of motor symptoms were significant predictors of dementia but duration of PD and age at onset of PD were not. CONCLUSIONS: Dementia in PD is likely to reflect interaction of the neuropathology of the basal ganglia and age-related pathology. The findings do not support the division of PD into early and late-onset cases.

Angiotensin-converting enzyme in substantia nigra: reduction of activity in Huntington's disease and after intrastriatal kainic acid in rats.

The substantia nigra of Huntington's disease brains shows a 78% reduction in angiotensin-converting enzyme activity in the pars reticulata and a 48% reduction in the pars compacta. The nucleus accumbens shows a 28% reduction in converting enzyme activity. In the rat, after intrastriatal injections of kainic acid (2.5 microgram), an agent which selectively destroys neuronal cell bodies, there is a 55% reduction in angiotensin-converting enzyme activity in the ipsilateral substantia nigra. Both human and animal data suggest that a major part of the angiotensin-converting enzyme in the substantia nigra is localized in nerve terminals whose cell bodies originate in the striatum.

Multiple system atrophy with autonomic failure: clinical, histological and neurochemical observations on four cases.

Four cases of progressive autonomic failure are described, in all of which there were additional non-autonomic neurological abnormalities, including pyramidal, extra-pyramidal and cerebellar features. Histological examination revealed cell degeneration in the substantia nigra, putamen and intermediolateral columns of the spinal cord as a common pathological finding. In addition, 3 cases showed loss of Purkinje cells in the cerebellum and degeneration of pontine nuclei and inferior olivary nuclei. In one case there was cell loss from the locus coeruleus, caudate nucleus, vestibular nuclei and dorsal vagal nuclei. These were, therefore, cases of multiple system atrophy. Neurochemically, a common feature was a profound depletion in dopamine and noradrenaline from brain regions which are normally rich in these catecholamines. Central cholinergic systems appeared to be involved also, but to a variable degree.

Alterations in [3H]spiperone binding in human caudate nucleus, substantia nigra and frontal cortex in the Shy-Drager syndrome and Parkinson's disease.

[3H]Spiperone binding was investigated in the caudate nucleus, substantia nigra (s. nigra) and frontal cortex of control subjects and of patients with Parkinson's disease and the Shy-Drager syndrome. Binding sites for [3H]spiperone were interpreted as dopamine receptors in caudate and s. nigra, and as 5-hydroxytryptamine (5-HT) receptors in frontal cortex. Scatchard analysis showed that the Bmax (maximal number of binding sites) in caudate was similar in the 3 groups, whereas in s. nigra the Bmax was reduced by approximately 60% in both Parkinsons disease and Shy-Drager syndrome. The dissociation constant (Kd) for [3H]spiperone binding in s. nigra was similar in the 3 groups. In caudate nucleus, the Kd was similar in control and Parkinson groups; however, there was a significant increase in the dissociation constant in the caudate nucleus from cases of Shy-Drager syndrome. No differences in binding characteristics were observed in the frontal cortex. These results are taken to reflect a loss of dopamine receptor sites in the s. nigra in both Parkinson's disease and Shy-Drager syndrome, and a reduced affinity of dopamine receptor sites in the caudate nucleus in Shy-Drager syndrome.

Distribution of GABA in post-mortem brain tissue from control, psychotic and Huntington's chorea subjects.

Gamma-aminobutyric acid (GABA) concentrations were measured in 10 regions of post-mortem brain from control, psychotic and choreic subjects; glutamate decarboxylase (GAD) activities were estimated in substantia nigra. In agreement with earlier observations, agonal status profoundly affected GAD measurements in the substantia nigra but had no effect on GABA levels in any brain region. Although GAD and GABA levels were significantly correlated in nigral tissue from sudden death control and psychotic cases, the association was lost in patients dying slowly. In Huntington's chorea significant reduction in GABA content were observed in the nucleus accumbens, lateral pallidum, subthalamic nucleus, substantia nigra and ventrolateral thalamic nucleus. In psychotic patients there were significant decreases in GABA concentrations in the amygdala and nucleus accumbens. Division of the psychotic group into schizophrenia and schizophrenia-like categories and into early-onset and later-onset cases revealed that GABA levels in the amygdala were diminished in all 4 psychotic subgroups, whereas in the nucleus accumbens the deficit was confined to cases of early-onset schizophrenia.