Biomedical subjects

R L Albin

Publications and source records attributed to R L Albin.

At least 73 records · Page 4Linked to original sources

PubMed1994

Autoradiographic quantification of muscarinic cholinergic synaptic markers in bat, shrew, and rat brain.

We employed radioligand binding autoradiography to determine the distributions of pre- and post-synaptic cholinergic radioligand binding sites in the brains of two species of bat, one species of shrew, and the rat. High affinity choline uptake sites were measured with [3H]hemicholinium, and presynaptic cholinergic vesicles were identified with [3H]vesamicol. Muscarinic cholinergic receptors were determined with [3H]scopolamine. The distribution patterns of the three cholinergic markers were similar in all species examined, and identified known major cholinergic pathways on the basis of enrichments in both pre- and postsynaptic markers. In addition, there was excellent agreement, both within and across species, in the regional distributions of the two presynaptic cholinergic markers. Our results indicate that pharmacological identifiers of cholinergic pathways and synapses, including the cholinergic vesicle transport site, and the organizations of central nervous system cholinergic pathways are phylogenetically conserved among eutherian mammals.

Animals↗

PubMed1994

Chronic intrastriatal quinolinic acid produces reversible changes in perikaryal calbindin and parvalbumin immunoreactivity.

We recently reported the use of a chronic dialytic delivery system for intrastriatal administration of quinolinic acid in the rat. This system produces neurodegeneration with some characteristics similar to post mortem brain tissue from Huntington's disease patients, including reduced cytochrome oxidase staining, a decreased number of Nissl-stained neurons, and relative sparing of striatal NADPH-diaphorase containing neurons. The present findings show that chronic dialytic delivery of quinolinic acid also produces a Huntington's disease-like pattern of reduced calbindin and parvalbumin perikaryal immunoreactivity that is reversed in rats allowed four to eight weeks' recovery after cessation of quinolinic acid. Furthermore, cytochrome oxidase staining and the number of Nissl-stained cells were unchanged in the region of transient calbindin and parvalbumin immunoreactive perikaryal staining alterations. These results suggest that changes in calbindin and parvalbumin perikaryal immunoreactivity provide a relatively sensitive measure of quinolinic acid induced neurotoxicity. The reversible nature of reduced perikaryal immunoreactivity suggests a premorbid state of neurotoxicity, possibly marked by cellular redistribution of calbindin and parvalbumin.

Animals↗

PubMed1994

Postnatal ontogeny of GABAB binding in rat brain.

The postnatal development of GABAB binding sites in rat brain was studied by quantitative receptor autoradiography using [3H]GABA under selective conditions. Binding levels peak at regionally specific times during the first three weeks of life and then decline to adult levels. GABAB binding peaked in the globus pallidus, vestibular and spinal trigeminal nuclei, and the CA3 region of the hippocampus at postnatal day 3; in the striatum, nucleus accumbens, inferior olive, septum, dentate gyrus and CA1 region of the hippocampus at postnatal day 7; in the neocortex and thalamus at postnatal day 14; and in the medial geniculate at postnatal day 21. Following these regionally specific peaks, binding decreased to postnatal day 28 levels. Further significant decreases in binding were observed in all regions examined between postnatal day 28 and adulthood. Comparisons of binding site pharmacology reveal equipotent displacement of GABAB binding by several competitive agonists and antagonists in postnatal day 7 and adult rat brain, indicating that immature and adult binding sites have similar pharmacological properties with regard to these compounds. The GABAB receptor antagonist CGP 54626A, however, inhibited binding more potently in the postnatal day 7 thalamus and neocortex than in these areas in the adult brain. The guanyl nucleotide analogue guanosine 5'-O-(3-thiotriphasphate) inhibited GABAB binding extensively in both postnatal day 7 and adult brain. The non-competitive antagonist zinc also inhibited GABAB binding at both ages and was more potent in postnatal day 7 brain than in adult brain. Saturation analyses reveal two binding sites with similar affinities in both immature and adult rat brain, indicating that postnatal modulation of GABAB binding reflects changes in binding site density rather than modulation of binding site affinity. While immature GABAB binding sites share most pharmacological characteristics with adult binding sites and appear to be coupled to G-proteins at an early age, their interactions with zinc and CGP 54626A suggest that GABAB binding sites in immature brain may have a distinct pharmacological profile. Our data suggest significant regional and pharmacological changes in GABAB binding during development. The implications of these findings are discussed with regards to a possible role of GABAB receptors in the development of the central nervous system.

Aging↗

PubMed1994

Localization of AMPA-selective excitatory amino acid receptor subunits in identified populations of striatal neurons.

Two-color immunofluorescence histochemistry and immunohistochemistry in combination with retrograde tract-tracing techniques were used to examine the relationship of alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA)-selective glutamate receptor subunits (GluR1, GluR2/3/4c and GluR4) to identified populations of striatal projection neurons and interneurons. The majority of striatonigral and striatopallidal neurons were double-labeled for GluR2/3/4c. These findings were confirmed using calbindin to label matrix projection neurons. In contrast, immunostaining of the GluR1 subunit was not observed to co-localize with any striatal projection neurons. Striatal interneurons immunostained for parvalbumin were also labeled by antibodies directed against the GluR1 subunit. Approximately 50% of parvalbumin neurons also contained GluR2/3/4c. Somatostatin immunoreactivity did not co-localize with either the GluR1 or GluR2/3/4c subunits. GluR4-immunoreactive neurons were not observed in striatum. This study demonstrates that AMPA-selective glutamate receptors are differentially localized on subpopulations of striatal neurons and interneurons. These findings suggest that discrete striatal neuron populations may express different AMPA receptor subunit combinations which may account for their functional specificity.

Animals↗

PubMed1994

Zinc inhibition of t-[3H]butylbicycloorthobenzoate binding to the GABAA receptor complex.

The effect of Zn2+ on t-[3H]butylbicycloorthobenzoate ([3H]TBOB) binding to the GABAA receptor complex was studied autoradiographically in rat brain. Zn2+ inhibited [3H]TBOB binding in a dose-dependent manner at physiological concentrations. Saturation analysis revealed noncompetitive inhibition in various brain regions. The inhibitory effect of Zn2+ had regional heterogeneity; regions showing the greatest inhibition of [3H]TBOB binding were cortical laminae I-III, most areas of hippocampus, striatum, septum, and cerebellar cortex. Regions with relatively less inhibition of [3H]TBOB binding included cortical laminae V-VI, thalamus, superior colliculus, inferior colliculus, and central gray matter. The effect of Zn2+ and those of other GABAA ligands, such as benzodiazepines, bicuculline, isoguvacine, and picrotoxin, on [3H]TBOB binding seemed to be additive. Ni2+, Cd2+, and Cu2+ also inhibited [3H]TBOB binding with a regional heterogeneity similar to that produced by Zn2+. These results are consistent with Zn2+ acting at the previously detected recognition site on the GABAA receptor complex, distinct from the picrotoxin, GABA, and benzodiazepine sites. The regional heterogeneity of the Zn2+ effect may reflect differential regional distribution of GABAA receptor subtypes among brain regions. Other divalent cations probably act at the Zn2+ binding site.

Animals↗

PubMed1994

Neurochemical studies of human narcolepsy: alpha-adrenergic receptor autoradiography of human narcoleptic brain and brainstem.

Studies of human and canine narcolepsy-cataplexy syndrome suggest that noradrenergic function may be abnormal. We used quantitative autoradiography to assess noradrenergic alpha-1 and alpha-2 receptors in several regions of seven human narcoleptic and 18 control brains using [3H]prazosin to evaluate alpha-1 receptors, and [3H]UK14304 and [3H]rauwolscine to evaluate alpha-2 receptors. Specific blocking agents were used in combination with the tritiated ligands to assess alpha-1 and alpha-2 receptor subtypes. Although we found few statistically significant differences between narcoleptic and control brains, there were a number of trends. [3H]Prazosin binding to sites in the amygdala, globus pallidus and putamen was reduced by 22-68%, whereas binding was increased by 40% to the inferior olive and by 84% to portions of the dorsal pons. Binding was similar to control values in other regions. In all seven brainstem regions that were evaluated, the ratio of alpha-1b receptor binding to alpha-1a receptor binding was increased. Binding of [3H]UK14304 was increased by 35-74% in the caudate nucleus, putamen and portions of the amygdala and pons. [3H]rauwolscine binding data suggested that increase of alpha-2 receptor binding in the dorsal pons were not due to effects at the imidazole receptor. findings suggest that noradrenergic function may be altered in specific regions of the brain and brainstem in human narcolepsy, although the absence of statistical significance indicates that these trends should be considered preliminary. The trend toward a relative increase of alpha-1b receptor binding in narcoleptic brainstem is consistent with data from studies of canine narcolepsy and suggests that altered activity at this receptor may contribute to the pathogenesis of human narcolepsy. Studies of additional brains will be required to confirm these findings.

Adult↗

PubMed1994

Quantitative autoradiography of [3H]t-butylbicycloorthobenzoate binding to the gamma-aminobutyric acid receptorA complex.

The picrotoxinin ligand [3H]t-butylbicycloorthobenzoate ([3H] TBOB) was evaluated as an autoradiographic ligand to study gamma-aminobutyric acidA (GABAA) receptors. Specific [3H]TBOB binding was approximately 80% of total binding, was saturable and identified a single population of binding sites with regional Kd approximating 30 nM. [3H]TBOB binding was inhibited by picrotoxin, isoguvacine and pregnenolone sulfate. The benzodiazepines clonazepam and zolpidem produced complex effects with concentration-dependent inhibition and enhancement of [3H] TBOB binding. [3H]TBOB binding was regionally heterogeneous with high levels of binding in globus pallidus and layer IV of neocortex, intermediate levels of binding in other neocortical laminae and the cerebellar molecular layer and low levels of binding in the striatum and septum. The regional distribution of [3H]TBOB binding correlated poorly with the regional distribution of [3H]muscimol binding, somewhat better with the regional distribution of [3H]flunitrazepam binding and [35S]t-butylbicyclophosphorothionate binding and quite well with the regional distribution of [3H]zolpidem binding. [3H]TBOB binding site autoradiography is a convenient technique for studying GABAA receptor pharmacology in a regionally specific manner.

Animals↗

PubMed1993

Unchanged [3H]MK-801 binding and increased [3H]flunitrazepam binding in turtle forebrain during anoxia.

In order to determine if functional changes in N-methyl-D-aspartate receptors and GABAA receptors play a role in the remarkable anoxia tolerance of freshwater turtle brain, we used autoradiographic techniques to assay [3H]MK-801 and [3H]flunitrazepam binding in turtle forebrain after turtles had been subjected to anoxia for 2 or 6 h. The effects of glutamate, glycine, competitive N-methyl-D-aspartate antagonists, glycine antagonists, polyamines, magnesium, and zinc on [3H]MK-801 binding were the same in anoxic and control turtle forebrains. These results indicate that NMDA receptor regulation plays no role in the adaptive responses to anoxia in turtle brain. In contrast, [3H]flunitrazepam binding was significantly increased in the anoxic dorsal cortex and striatum. The most parsimonious explanation for elevated benzodiazepine receptor binding is that the rise in extracellular GABA levels known to accompany anoxia enhances benzodiazepine receptor affinity. It is possible, however, that GABAA receptor upregulation during anoxia increases the effectiveness of the inhibitory action of released GABA and contributes to the anoxia tolerance of turtles.

Animals↗

PubMed1993

Inhibitory and excitatory amino acid neurotransmitter binding sites in cynomolgus monkey (Macaca fascicularis) cervical spinal cord.

Autoradiography of inhibitory and excitatory amino acid neurotransmitter binding sites in the cervical spinal cord of M. fascicularis spinal cord revealed inhomogeneous distribution of all binding sites in spinal gray matter. Quisqualate-sensitive [3H]glutamate binding, [3H]MK-801 binding, benzodiazepine binding, kainate binding, and GABAB binding had highest levels in the superficial layers of the dorsal horn (laminae 1 and 2) and substantially lower levels in other laminae. [3H]Strychnine binding was more uniformly distributed throughout all laminae with highest levels in the superficial layers of the dorsal horn. These results are similar to those found in other mammals.

Animals↗

PubMed1993

Chronic intrastriatal dialytic administration of quinolinic acid produces selective neural degeneration.

The excitotoxic hypothesis of Huntington's disease pathogenesis suggests that selective striatal neuronal loss results from excessive activation of striatal excitatory amino acid receptors. Using a microdialysis probe mated to an Alzet 2002 mini-osmotic pump three different concentrations of quinolinic acid or vehicle were administered to the striata of rats over a 3-week period. Animals that received a total of 3.3 mumol of quinolinic acid had significant striatal atrophy that could be attributed to two distinct areas of neuronal loss. First, an area of necrosis surrounding the probe was marked by inflammatory infiltrate and a lack of neurons. In the second region, surrounding the necrotic area, there was a significant reduction in nissl-stained cells, with relative sparing of NADPH-diaphorase-staining neurons. In addition, there was a reduction in cytochrome oxidase staining throughout both of the areas of cell loss. Beyond the area of cell loss, the striatum appeared normal in all respects. The striata of animals that received 880 nmol quinolinic acid appeared identical to those that received vehicle. The striata of animals that received 8.8 mumol quinolinic acid showed severe nonselective atrophy of the striatum and some surrounding structures. We conclude that dialytic delivery of 3.3 mumol quinolinic acid produces an area of neuronal destruction that resembles the selective neuronal loss seen in Huntington's disease. This selective neurodegeneration produced by chronic exposure to quinolinic acid simulates more closely the course of Huntington's disease than previously described methods.

Amphetamine↗

PubMed1993

mnd2: a new mouse model of inherited motor neuron disease.

The autosomal recessive mutation mnd2 results in early onset motor neuron disease with rapidly progressive paralysis, severe muscle wasting, regression of thymus and spleen, and death before 40 days of age. mnd2 has been mapped to mouse chromosome 6 with the gene order: centromere-Tcrb-Ly-2-Sftp-3-D6Mit4-mnd2-D6Mit 6, D6Mit9-D6Rck132-Raf-1, D6Mit11-D6Mit12-D6Mit14, mnd2 is located within a conserved linkage group with homologs on human chromosome 2p12-p13. Spinal motor neurons of homozygous affected animals are swollen and stain weakly, and electromyography revealed spontaneous activity characteristic of muscle denervation. Myelin staining was normal throughout the neuraxis. The clinical observations are consistent with a primary abnormality of lower motor neuron function. This new animal model will be of value for identification of a genetic defect responsible for motor neuron disease and for evaluation of new therapies.

Animals↗

PubMed1993

Antagonistic pleiotropy, mutation accumulation, and human genetic disease.

The antagonistic pleiotropy theory of senescence is the most convincing theoretical explanation of the existence of aging. As yet, no locus or allele has been identified in a wild population with the features predicted by the pleiotropic theory. Human genetic diseases offer the opportunity to identify potentially pleiotropic alleles/loci. Four human genetic diseases--Huntington's disease, idiopathic hemochromatosis, myotonic dystrophy, and Alzheimer's disease--may exhibit pleiotropic effects and further study of these diseases might result in the identification of pleiotropic genes causing aging. Inability to find an early life selective benefit associated with these disease-causing alleles would favor the major alternative genetic explanation for aging, the mutation accumulation theory.

Aging↗

PubMed1993

Pharmacology, distribution, cellular localization, and development of GABAB binding in rodent cerebellum.

Quantitative receptor autoradiography using [3H]GABA under selective conditions was used to characterize the pharmacology, distribution, cellular localization, and development of GABAB binding sites in rodent cerebellum. Pharmacologic analysis of [3H]GABA binding showed that drugs active at GABAB receptors displaced [3H]GABA with the following order of potency: 3-aminopropylphosphonous acid > CGP 35348 = 2-hydroxysaclofen > phaclofen. GTP-gamma-S and GDP-beta-S also diminished potently [3H]GABA binding in a dose-dependent manner. The pattern of [3H]GABA binding to GABAB binding sites was systematically mapped throughout the rat cerebellum. GABAB binding was greatest in the molecular layer and a pattern of parasagittal zonation was observed in the molecular layer of lobules VII-X in adult rats. The cellular localization of GABAB binding was investigated using lesion techniques. Neither methyl azoxymethanol lesions of cerebellar granule cells nor 3-acetylpyridine lesions of climbing fibers resulted in a decrease in [3H]GABA binding. Homozygote stumbler mutant mice, deficient in Purkinje cell dendrites, had a significant decrease in [3H]GABA binding in the molecular layer. These results suggest that the majority of cerebellar molecular layer GABAB binding sites detected by [3H]GABA autoradiography are located on Purkinje cell dendrites. Examination of [3H]GABA binding to GABAB binding sites during development revealed that binding in the molecular layer peaks between postnatal day 14 and postnatal day 28 and then decreases to adult levels. Transient expression of high levels of GABAB binding was observed in the deep cerebellar nuclei, peaking at postnatal day 3 and decreasing to adult levels by postnatal day 21. Our investigation of GABAB pharmacology yielded data in agreement with previously reported results. We have described a parasagittal pattern of GABAB binding in the cerebellar molecular layer and assigned the majority of cerebellar GABAB binding sites to Purkinje cell dendrites. Finally, development studies reveal transient peaks in GABAB binding in the cerebellar molecular layer and deep cerebellar nuclei.

Adenosine Triphosphate↗

PubMed1993

Expression of NMDA-receptor mRNA in the rat cochlea.

While there is considerable evidence that an excitatory amino acid and excitatory amino acid receptors are involved in the synapse between inner hair cells and the auditory nerve, evidence for the specific involvement of the N-methyl-D-aspartate (NMDA) receptor is more ambiguous. With the cloning of the NMDA receptor, probes are now available that can determine in which neurons the receptor is being expressed. In situ hybridization histochemical techniques were therefore utilized to examine the expression of NMDA receptor messenger ribonucleic acid (mRNA) in the rat cochlea. Expression of NMDA receptor mRNA was seen in spiral ganglion cells. These results suggest that NMDA receptor is a component of excitatory amino acid synapses in the cochlea.

Animals↗

PubMed1993

Widespread expression of the human and rat Huntington's disease gene in brain and nonneural tissues.

We have used RNA in situ hybridization to study the regional expression of the Huntington's disease gene (HD) and its rat homologue in brain and selected nonneural tissues. The HD transcript was expressed throughout the brain in both rat and human, especially in the neurons of the dentate gyrus and pyramidal neurons of the hippocampal formation, cerebellar granule cell layer, cerebellar Purkinje cells and pontine nuclei. Other brain areas expressed lower levels of the HD transcript without pronounced regional differences. Neuronal expression predominated over glial expression in all regions. HD mRNA was also expressed in colon, liver, pancreas and testes. The regional specificity of neuropathology in HD, which is most prominent in the basal ganglia, thus cannot be accounted for by the pattern of expression of HD.

Amino Acid Sequence↗

PubMed1993

Cerebellar excitatory and inhibitory amino acid receptors in multiple system atrophy.

We studied excitatory and inhibitory amino acid binding sites autoradiographically in control and multiple system atrophy (MSA) cerebella. Within the dentate nucleus (DN) of MSA specimens, we found a significant increase in the level of GABAA, benzodiazepine, and metabotropic binding sites compared with controls. In the granule cell layer, kainate, N-methyl-D-aspartate, and GABAA binding sites were all decreased significantly in MSA specimens compared with controls. In the molecular layer of MSA cerebellum, alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate binding sites were decreased significantly compared with controls. Cerebellar cortical binding site decreases are likely due to Purkinje and granule cell loss. The increase of binding site levels in DN of MSA specimens may represent receptor up-regulation reflecting loss of descending inhibitory Purkinje cell and ascending excitatory afferents to the DN.

Adult↗

PubMed1993

AMPA and NMDA binding sites in the hypothalamic lateral tuberal nucleus: implications for Huntington's disease.

The excitatory amino acid (EAA) hypothesis of neuronal loss in Huntington's disease predicts that structures that show neuronal loss and gliosis will contain receptor-bearing neurons. In accordance with this hypothesis, the hypothalamic lateral tuberal nucleus, severely affected in Huntington's disease, showed a high density of NMDA and AMPA binding sites in four normal subjects.

Aged↗

PubMed1993

Adrenal medulla grafts in the hemiparkinsonian rat: profile of behavioral recovery predicts restoration of the symmetry between the two striata in measures of pre- and postsynaptic dopamine function.

Following unilateral striatal dopamine depletion, the hemiparkinsonian rat exhibits rotational behavior in response to amphetamine and apomorphine. The rotational behaviors induced by these drugs are thought to reflect an asymmetry in presynaptic striatal dopamine release and an asymmetry in postsynaptic striatal dopamine receptor function, respectively. Grafts of adrenal medulla cells in the lateral ventricle of hemiparkinsonian rats have been reported to reduce behavioral asymmetry. More than one profile of behavioral recovery, however, is observed. Some animals show a graft-induced decrease only in the response to apomorphine, but others show a decrease in the response to amphetamine, and still others show a decrease in the behavioral responses to amphetamine and apomorphine. In this report, amphetamine- and apomorphine-induced turning behaviors were determined in hemiparkinsonian rats prior to and following intraventricular grafts of adrenal medulla or control tissue. Both bilateral intrastriatal microdialysis in freely moving animals and quantitative dopamine receptor autoradiography procedures were conducted in each animal so as to determine the relations between pre- and postsynaptic dopaminergic measures as well as the association between these measures and the different profiles of behavioral recovery after adrenal medulla grafts. We report here that in animals with an adrenal medulla graft-induced decrease in the behavioral response to amphetamine, the balance between the two striata in extracellular striatal dopamine concentrations and D2 dopamine receptor binding was restored. Furthermore, enhanced extracellular striatal dopamine concentrations were highly correlated with the graft-induced symmetry in striatal D2 dopamine receptor binding. In contrast to animals with decreased amphetamine-induced turning, in animals with a graft-induced decrease exclusively in response to apomorphine, the presynaptic symmetry was not restored and there was a significantly smaller effect on D2 receptor binding. We conclude that those animals that show decreased amphetamine-induced turning after adrenal medulla grafts had the most effective grafts, and suggest that methods designed to optimize this behavioral profile are most likely to lead to enhanced clinical efficacy with this procedure.

Adrenal Medulla↗