Ernest G. Spokes

Neurotransmitter receptor alterations in Parkinson's disease.

Abstract Neurotransmitter receptor binding for GABA, serotonin, cholinergic muscarinic and dopamine receptors and choline acetyltransferase (ChAc) activity were measured in the frontal cortex, caudate nucleus, putamen and globus pallidus from postmortem brains of 10 Parkinsonian patients and 10 controls. No changes in any of these systems were observed in the frontal cortex. In the caudaye nucleus, only the apparent dopamine receptor binding was altered with a significant 30% decrease in the Parkinsonian brain. Both cholinergic muscarinic and serotonin receptor binding were significantly altered in the putamen, the former increasing and the latter decreasing with respect to controls. In addition, ChAc activity was decreased in the putamen. In the globus pallidus, only ChAc activity was significantly changed, decreasing about 60%, with no change in neurotransmitter receptor binding. The results suggest that a progressive loss of dopaminergic receptors in the caudate nucleus may contribute to the decreased response of Parkinsonian patients to L-dopa and dopamine agonist therapy.

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.

Human brain substance P: distribution in controls and Huntington's chorea

EVIDENCE for a neurotransmitter role of the undecapeptide. substance P (SP), has accumulated from studies in the spinal cord (OTSUKA & KONISHI, 1976) and CNS (BARKER, 1976; KONISHI & OTSUKA, 1974). of laboratory mammals. This peptide has also been shown immunohistochemically in axonal processes in human spinal cord (CUELLO et al., 1976). Substance P is unevenly distributed in the rat brain, with highest concentrations in the substantia nigra (s. nigra) (KANAZAWA & JESSELL, 1976). High concentrations of SP have also been reported in the human s. nigra (DUFFY et al., 1975; KANAZAWA et al., 1977) and in animal experiments iontophoretically applied SP has been shown to excite nigral neurones (WALKER er al.. 1976). Preliminary studies indicated abnormally low levels of this transmitter in the s. nigra of post-mortem brains from patients dying with Huntingtons chorea (KANAZAWA et al., 1977). a disorder in which there is marked atrophy of the basal ganglia. We now present the results of a more extensive study on SP distribution in various regions of normal and choreic post-mortem human brain.

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 Huntingtons 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.

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

The substantia nigra of Huntingtons 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.

3H-spiperone binding in normal and schizophrenic post-mortem human brain

The neuroleptic ligand 3H-spiperone binds saturably to areas of human and rat brain which are rich in either dopamine (DA) or 5- hydroxytryptamine (5-HT). 2-Amino-6, 7-dihydroxytetralin (ADTN) and cinanserin were found to displace 3H-spiperone selectively from DA and 5-HT receptor sites respectively. An investigation of the DA and 5-HT receptor components of 3H-spiperone binding in nucleus accumbens samples from 26 post-mortem schizophrenic brains failed to reveal any abnormality.

Huntington's disease and its animal model: Alterations in kainic acid binding

The density of 3H-kainic acid (KA) binding was determined in several regions of Huntingtons Diseased (HD) and control human brains. 3H-Kainic acid binding was significantly reduced by 55% in the caudate nucleus and by 53% in the putamen of HD brains. In addition, 3H-KA binding was determined in rat striatum at various intervals following lesion with KA, a procedure which produces an animal model of HD. After KA lesion, 3H-KA binding in the rat striatum underwent a slow reduction, reaching 25% of control after 6 weeks. Several properties of 3H-KA binding to rat brain membranes were also investigated, including inhibition by ions, regional distribution and displacement by various compounds. The findings confirm the validity of the KA-lesioned model for HD and suggest a post-synaptic location for kainic acid receptors in the striatum.

Differential effects of agonal status on measurements of GABA and glutamate decarboxylase in human post-mortem brain tissue from control and Huntington's chorea subjects.

Abstract— GABA and its biosynthetic enzyme glutamic acid decarboxylase (GAD) remained remarkably stable for many hours after death in both human putamen obtained at autopsy and in mouse brain stored under conditions simulating the routine handling of human cadavers. GAD activity was profoundly influenced by agonal status in control but not in choreic subjects. Conversely, GABA concentrations were unaffected by the agonal status but showed a significant age‐related decline. GAD activity and GABA concentrations were positively correlated in sudden death control cases but not in control cases suffering a protracted terminal illness or in choreic subjects. In choreic putamen there was an approximate 50% reduction in GABA concentration and GAD activity (correcting for agonal status) consistent with the hypothesis that striatal GABA‐containing neurones degenerate in this disease. Since GABA concentrations are unaffected by agonal factors they may provide a reliable marker for the integrity of GABA systems provided that control and pathological groups are matched for age and delay in post‐mortem sampling.