Adrenal size is increased in multiple sclerosis.

OBJECTIVE: To determine if adrenal glands are enlarged in multiple sclerosis (MS). Patients with MS and major depression are insensitive to glucocorticoid feedback regulation. Depressed patients have excessively high glucocorticoid levels and enlarged adrenal glands. To our knowledge, this is the first study of adrenal size in MS. Chronic high levels of adrenal glucocorticoid in MS may downregulate responses to exogenous or endogenous steroids. DESIGN: Retrospective postmortem analysis compared adrenal size in MS with that in other neurologic and non-neurologic diseases. SETTING: Autopsy cases were obtained from the records of a tertiary care hospital. PATIENTS: Ten patients had definite MS; 13, amyotrophic lateral sclerosis; and 14, acute myocardial infarction. MAIN OUTCOME MEASURES: Adrenal and body weight at autopsy. RESULTS: At postmortem examination, the adrenal glands of patients with MS were enlarged in comparison with the adrenal glands of patients who died of acute myocardial infarction or amyotrophic lateral sclerosis. The adrenal glands of the patients with MS were 36% larger than those of the patients with amyotrophic lateral sclerosis who had comparable body weights. The adrenal-body weight ratio was 40% greater in patients with MS than in patients who died of acute myocardial infarction. CONCLUSIONS: The increased adrenal size in patients with MS may allow excessive glucocorticoid secretion in response to stress and affect immune regulation.

Multiple states of rat brain (RS)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors as revealed by quantitative autoradiography.

The binding of (RS)-alpha-[3H]amino-3-hydroxy-5-methylisoxazole-4-propionic acid ([3H]AMPA), a selective ligand for non-N-methyl-D-aspartate excitatory amino acid receptors, was investigated in rat brain using an autoradiographic receptor binding technique. [3H]AMPA binding sites were widely distributed throughout the rat central nervous system, and the rank order of potency of displacers of [3H]AMPA binding was quisqualate greater than AMPA greater than 6,7-dinitroquinoxaline-2,3-dione = 6-cyano-7-nitroquinoxaline-2,3-dione greater than beta-N-oxalylamino-L-alanine greater than glutamate greater than kainate. Potassium thiocyanate (0-100 mM) exerted a 4-fold stimulation of [3H]AMPA binding, without changing the relative regional distribution of [3H]AMPA binding densities among rat brain regions. Scatchard analysis of equilibrium saturation binding revealed high affinity and low affinity components of [3H]AMPA binding, even in the absence of potassium thiocyanate. Addition of potassium thiocyanate increased the number of high affinity [3H]AMPA binding sites without a change in affinity. In addition, the number of low affinity [3H]AMPA binding sites was unchanged in the presence of potassium thiocyanate, but the affinity of low affinity [3H]AMPA binding was greatly increased. [3H]AMPA thus binds specifically to two affinity conformations of postsynaptic binding sites that appear to be interconverted with potassium thiocyanate. The pharmacologic profile of these sites is consistent with that of the ion channel-linked ("ionotropic") quisqualate/AMPA class of excitatory amino acid receptor in the rat central nervous system.

Excitatory amino acid binding sites in the basal ganglia of the rat: a quantitative autoradiographic study.

Quantitative receptor autoradiography was used to determine the distribution of excitatory amino acid binding sites in the basal ganglia of rat brain. alpha-Amino-3-hydroxy-5-methylisoxazole-4-propionic acid, N-methyl-D-aspartate, kainate, quisqualate-sensitive metabotropic and non-N-methyl-D-aspartate, non-kainate, non-quisqualate glutamate binding sites had their highest density in striatum, nucleus accumbens, and olfactory tubercle. Kainate binding was higher in the lateral striatum but there was no medial-lateral striatal gradient for other binding sites. N-Methyl-D-aspartate and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid binding sites were most dense in the nucleus accumbens and olfactory tubercle. There was no dorsal-ventral gradient within the striatal complex for the other binding sites. Other regions of the basal ganglia had lower densities of ligand binding. To compare binding site density within non-striatal regions, binding for each ligand was normalized to the striatal binding density. When compared to the striatal complex, alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid and metabotropic binding sites had higher relative density in the globus pallidus, ventral pallidum, and subthalamic nucleus than other binding sites. Metabotropic binding also had a high relative density in the substantia nigra. Non-N-methyl-D-aspartate, non-kainate, non-quisqualate glutamate binding sites had a high relative density in globus pallidus, ventral pallidum, and substantia nigra. N-Methyl-D-aspartate binding sites had a low relative density in pallidum, subthalamic nucleus, substantia nigra and ventral tegmental area. Our data indicate heterogeneous distribution of excitatory amino acid binding sites within rat basal ganglia and suggest that the character of excitatory amino acid-mediated neurotransmission within the basal ganglia is also heterogeneous.

Excitatory amino acid, GABA(A), and GABA(B) binding sites in human striate cortex.

Receptor autoradiography was used to study the laminar distribution of excitatory amino acid, GABA(A), and GABA(B) binding sites in human striate cortex. Binding sites for all these receptor subtypes were found within striate cortex, but there were marked differences in the laminar distribution of binding sites. NMDA binding sites were most dense in layers 1-4C, with highest density in layer 4C and lower levels in layers 5 and 6. Among non-NMDA binding sites, alpha-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid binding sites had highest levels in layers 1-3, intermediate levels in layers 5 and 6, and lowest levels in layers 4B and 4C. Kainate and metabotropic binding sites were more uniformly distributed across cortical laminae, with a trend toward highest kainate binding in layers 5 and 6. GABA(A)/benzodiazepine binding sites had highest levels in layers 2, 3, and 4C, with intermediate levels in 4B and lowest levels in layers 1, 5, and 6. GABA(B) binding sites were uniformly distributed across laminae. There was no evidence of a "columnar" or "blob" pattern of any binding site within any of the laminae. With the exception of kainate, metabotropic excitatory amino acid, and GABA(B) binding sites, the laminar distribution of binding sites within striate cortex was different than that seen in adjacent visual cortex.

Excitatory and inhibitory amino acid neurotransmitter binding sites in the cerebellar cortex of the pigeon (Columba livia).

We used receptor autoradiography to determine the distribution of excitatory and inhibitory amino acid neurotransmitter binding sites in the cerebellar cortex of the pigeon (Columba livia). alpha-Amino-3-hydroxy-5-methylisoxazole-4-propionic acid, kainate and metabotropic binding sites had highest levels in the molecular layer. N-methyl-D-aspartate binding sites, assayed with both [3H]glutamate under selective conditions and with [3H]glycine binding to the associated strychnine-insensitive glycine site, had highest levels in the granule cell layer. There was little specific binding of the non-competitive N-methyl-D-aspartate antagonist, [3H]MK-801. The level of gamma-aminobutyric acid (GABA)-A binding sites was higher than GABA-B binding sites in both molecular and granule cell layers with the highest level of GABA-A sites in the granule cell layer. The highest level of GABA-B binding sites was in the molecular layer. [3H]Flunitrazepam binding levels were approximately the same in both molecular and granule cell layers. With the exception of kainate binding sites, the distribution of binding sites was identical to that seen in the cerebellar cortex of mammals. Our results support the concept that the chemoarchitecture of the cerebellar cortex has been conserved in the course of vertebrate evolution.

Cerebellar excitatory amino acid binding sites in normal, granuloprival, and Purkinje cell-deficient mice.

Using quantitative autoradiography, the cellular localization and characterization of cerebellar excitatory amino acid binding sites in normal, Purkinje cell-deficient and granuloprival (granule cell-deficient) mouse cerebella were investigated. In the molecular layer of normal mouse cerebellum, the quisqualate subtype of excitatory amino acid receptor (assayed by [3H](RS)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate, quisqualate-sensitive L-[3H]glutamate, and [3H]6-cyano-7-nitroquinoxaline-2,3-dione binding) predominated. In the granule cell layer of the cerebellum, N-methyl-D-aspartate-sensitive L-[3H]glutamate and [3H]glycine binding sites were predominant. In the molecular layer of Purkinje cell-deficient mutant mice, [3H](RS)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate binding sites and [3H]6-cyano-7-nitro-quinoxaline-2,3-dione binding were reduced to 24% (P less than 0.01) and 36% (P less than 0.001) of control, respectively, while quisqualate-sensitive [3H]glutamate binding sites were reduced to 54% of control (P less than 0.01). N-Methyl-D-aspartate-sensitive [3H]glutamate and [3H]glycine binding were unchanged. In the granule cell layer of these mouse cerebella, there was no change in excitatory amino acid receptor binding. In the molecular layer of granuloprival mouse cerebella, [3H](RS)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate binding was increased to 205% of control (P less than 0.01), [3H]6-cyano-7-nitro-quinoxaline-2,3-dione binding was increased to 136% of control (P less than 0.02), and quisqualate-sensitive [3H]glutamate binding was increased to 152% of control (P less than 0.01). N-Methyl-D-aspartate-sensitive [3H]glutamate and [3H]glycine binding were unchanged. In areas of granule cell depletion N-methyl-D-aspartate-sensitive [3H]glutamate and [3H]glycine binding were reduced to 68% (P less than 0.01) and 59% (P less than 0.01) of control, respectively. In the granule cell layer, binding to quisqualate receptors was not significantly different from binding in controls with any of the ligands tested. These results suggest that three different receptor assays: [3H](RS)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate, quisqualate-sensitive L-[3H]glutamate, and [3H]6-cyano-7-nitro-quinoxaline-2,3-dione binding can be used to demonstrate that quisqualate receptor specific binding sites are located on Purkinje cell dendrites in the molecular layer of cerebellum, and that these binding sites apparently up-regulate in response to granule cell ablation and Purkinje cell deafferentation.

Excitatory amino acidergic pathways and receptors in the basal ganglia.

The striatum receives the majority of excitatory amino acidergic input to the basal ganglia from neocortical and allocortical sources. The subthalamic nucleus and the substantia nigra also receive excitatory amino acidergic inputs from neocortex. The subthalamic nucleus, which has prominent projections to the pallidum and nigra, is the only known intrinsic excitatory amino acidergic component of the basal ganglia. Possible excitatory amino acidergic inputs reach the basal ganglia from the intralaminar thalamic nuclei and the pedunculo-pontine nucleus. The striatum is richly endowed with all subtypes of excitatory amino acid receptors and these appear to be inhomogeneously distributed within the striatal complex. The non-striatal nuclei contain lesser levels of excitatory amino acid receptors and the relative proportion of these receptors varies between nuclei. The presence of high densities of excitatory amino acid receptors is a phylogenetically conserved feature of the striatum and its non-mammalian homologues. In Huntington's disease, there is substantial depletion ofα-amino-3-hydroxy-5-methylisoxazole-4-propionic acid, N-methyl-D-aspartate, and kainate receptors within the striatum. In Parkinson's disease substantia nigra, there is significant loss of N-methyl-D-aspartate andα-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors.

Excitatory amino acid binding sites in the periaqueductal gray of the rat.

We used receptor autoradiography to determine the distribution of excitatory amino acid (EAA) binding site subtypes in the periaqueductal gray (PAG) of the rat. N-Methyl-D-aspartate (NMDA), kainate, quisqualate-ionotropic, and quisqualate-metabotropic binding sites were all present in the PAG. Distribution was inhomogeneous with greatest density of all binding site subtypes in the dorsolateral subdivision and lowest density in the ventrolateral subdivision. Relative to regions of brain with high densities of EAA binding site subtypes, quisqualate-metabotropic binding sites had the highest relative density and NMDA binding sites the least. The presence of all subtypes of EAA binding sites in the PAG suggests that EAA action within the PAG is likely to be complex.

Two types of quisqualate receptors are decreased in human olivopontocerebellar atrophy cerebellar cortex.

We used receptor autoradiography to study the distribution of ionotropic and metabotropic quisqualate (QA) receptors in normal human cerebellar cortex and cerebellar cortex from 7 cases of olivopontocerebellar atrophy (OPCA). In normal human cerebellar cortex, both types of QA receptors were densest in the molecular layer. Both ionotropic and metabotropic QA receptors were significantly diminished in the molecular layer of OPCA specimens. These results suggest that both ionotropic and metabotropic QA receptors are localized on Purkinje cell dendrites.

L-[3H]glutamate labels the metabotropic excitatory amino acid receptor in rodent brain.

A quantitative autoradiographic assay for a novel L-[3H]glutamate binding site in rodent brain has been developed. Binding to this site was distinguished by its high affinity for quisqualate (QA), ibotenate, glutamate and trans-1-amino-cyclopentyl-1,3-dicarboxylic acid (trans-ACPD), but low affinity for [RS]-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), kainate and N-methyl-D-aspartate (NMDA). 'AMPA-insensitive, QA-sensitive [3H]glutamate binding' (AiQsGB) had a heterogeneous distribution in rat brain with high levels observed in molecular layer of cerebellum, striatum, and lateral septum. AiQsGB was reduced in molecular layer of cerebellum in mice lacking Purkinje cells. AiQsGB appears to represent binding to the 'metabotropic' neuronal excitatory amino acid receptor linked to phosphoinositide metabolism.