Biomedical subjects

J W Olney

Publications and source records attributed to J W Olney.

At least 19 recordsLinked to original sources

PubMed1997

Multifocal brain damage induced by phencyclidine is augmented by pilocarpine.

Phencyclidine and other antagonists of the N-methyl-D-aspartate subtype of glutamate receptor cause psychosis in humans. In low doses these agents induce a reversible neurotoxic reaction in the rat brain that is limited to the retrosplenial granular cortex. Some investigators have reported that phencyclidine at higher doses or by more prolonged treatment causes a more disseminated pattern of damage. However, it has not been clearly demonstrated whether the disseminated damage is reversible or irreversible and whether it is consistently reproducible, nor is it known how many and which neurons are at risk. In the present study we addressed these questions using several histological approaches (plastic-embedded thin sections for light microscopy and ultrathin plastic sections for electron microscopy, paraffin-embedded haematoxylin and eosin sections, 72 kDa heat shock protein immunocytochemistry and de Olmos silver impregnation) to study the lesions induced in rat brain by phencyclidine (alone or when augmented with pilocarpine). We found that phencyclidine can kill a relatively large number of neurons distributed over many cerebrocortical and limbic brain regions, but the multifocal pattern of damage occurred in only a small percentage of treated rats. The addition of a low dose of pilocarpine to phencyclidine caused the widespread pattern of damage to manifest on a much more consistent basis. Available evidence suggests that disinhibition of multiple converging excitatory pathways is the mechanism by which phencyclidine triggers widespread neuronal degeneration; however, the specific combination of excitatory inputs that contributes to the pathological process may differ from region to region.

Animals↗

PubMed1997

Isoflurane and propofol block neurotoxicity caused by MK-801 in the rat posterior cingulate/retrosplenial cortex.

In acute brain injury syndromes, the potent N-methyl-D-aspartate (NMDA) antagonist, MK-801, can prevent neuronal degeneration, and the general anesthetics, isoflurane and propofol, may also provide neuroprotective benefits. An obstacle to the use of NMDA antagonists for neuroprotective purposes is that they can cause a neurotoxic vacuole reaction in cerebrocortical neurons. This study demonstrates the ability of isoflurane and propofol to prevent the neurotoxic vacuole reaction induced by MK-801. Low sedative doses of inhaled isoflurane (1%) or intravenous (i.v.) propofol (7.5 mg/kg/h) were as effective as higher general anesthetic doses. Thus, in the clinical management of acute brain injury conditions such as stroke and brain trauma, administration of one of these anesthetic agents together with an NMDA antagonist may be an excellent formula for obtaining optimal neuroprotection while eliminating serious side effects.

Anesthetics, Inhalation↗

PubMed1996

MK-801 neurotoxicity in male mice: histologic effects and chronic impairment in spatial learning.

Several histological and behavioral experiments were conducted to investigate the neurotoxic effects of MK-801 in male mice. Moderate subcutaneous (s.c.) doses of MK-801 (0.5 and 1.0 mg/kg) induced the formation of intracytoplasmic vacuoles in pyramidal neurons in layers III and IV of the posterior cingulate/retrosplenial (PC/RS) cortex in 50% and 100% of the mice from the two respective treatment groups. Electron microscopic analysis of the vacuoles indicated that mitochondria and endoplasmic reticulum are the cellular organelles most prominently involved in this pathomorphological change. Treating mice with a high systemic dose of MK-801 (10 mg/kg s.c. or intraperitoneal (i.p.)) caused selective, irreversible degeneration of a small number of PC/RS cortical neurons. Compared to saline controls, the acquisition performance of mice treated i.p. with 10 mg/kg MK-801 was chronically impaired on a spatial learning task (modified hole board food search task) when tested at several posttreatment intervals (up to at least 5 months), although the groups did not differ on activity or sensorimotor tests conducted 2 weeks posttreatment. In summary, MK-801 caused histopathological changes in the mouse brain similar to those observed in the rat. Furthermore, high dose MK-801 treatment that killed a small number of mouse PC/RS cortical neurons resulted in a chronic acquisition impairment in spatial learning, an effect not previously demonstrated in any species.

Animals↗

PubMed1996

Swelling of Müller cells induced by AP3 and glutamate transport substrates in rat retina.

Previous studies have shown that a single systemic injection of 2-amino-3-phosphonopropionate (AP3), an agonist/antagonist at metabotropic glutamate receptors, produces marked swelling of rodent Müller cells. To investigate the effects of AP3 on Müller cells, we used in vitro retinal segments prepared from 30 day old rats. Incubation with AP3 for 1 h or more caused severe swelling of Müller cells with the appearance of mitotic cellular profiles in the outer nuclear layer. The Müller cell swelling was mimicked by substrates for glutamate transporters, suggesting that AP3 may produce its effects via transport into glial cells. To determine whether AP3 is a substrate for glutamate transporters, we studied cultured rat hippocampal astrocytes using whole-cell patch clamp recordings. In hippocampal astrocytes, AP3 activated currents via an Na(+)-dependent glutamate transporter. Consistent with this, substitution of extracellular sodium with choline blocked Müller cell swelling in the rat retina. These results indicate that the acute glial swelling produced by AP3 results primarily from a fluid shift that accompanies the transport of AP3 and sodium into Müller cells.

Alanine↗

PubMed1996

Acute behavioral effects of MK-801 in the mouse.

The acute effects of 0.05 mg/kg MK-801 on spatial learning and memory in male mice were studied using a modified hole board food search task. Dose-response sensorimotor and activity tests suggested that this dose of MK-801 did not induce significant nonassociative effects. Mice were trained on the hole board using a massed trials protocol to learn the location of a hole baited with a food reward among four corner holes. Retention was tested 24 h later. Mice were split into two groups matched according to acquisition scores. The following week, mice injected with 0.05 mg/kg MK-801 30 min before being trained to a different baited hole were significantly impaired in acquiring a new baited hole location compared to saline-treated mice, although retention performance was unaffected. The same result was found in another experiment in which treatments were crossed over, and a different version of the task was used. However, in another experiment, 0.05 mg/kg MK-801 did not impair performance when the hole board task was well learned.

Animals↗

PubMed1996

Olanzapine and fluperlapine mimic clozapine in preventing MK-801 neurotoxicity.

Antagonists of the N-methyl-D-Aspartate (NMDA) subtype of glutamate receptor (e.g., phencyclidine, ketamine, MK-801) cause a schizophrenia-like psychosis in humans and neurotoxicity in the adult rat brain. We report here that clozapine and structurally related agents (olanzapine, fluperlapine, loxapine, amoxapine) can prevent NMDA antagonist neurotoxicity in the rat with a rank order corresponding to their ability to mimic the antipsychotic properties of clozapine.

Animals↗

PubMed1996

Motor neuron degeneration induced by excitotoxin agonists has features in common with those seen in the SOD-1 transgenic mouse model of amyotrophic lateral sclerosis.

A superoxide dismutase 1 (SOD-1)genetic defect has been identified in familial amyotrophic lateral sclerosis (ALS) and motor neuron degeneration has been described in SOD-1 transgenic mice. Because an excitotoxic mechanism has been implicated in ALS, we undertook studies to provide a description of excitotoxic degeneration of spinal motor neurons for comparison with the degenerative process observed in SOD-1 transgenic mice. Excitotoxin agonists selective for each of the three major types of inotropic glutamate receptors were applied directly onto the lumbar spinal cord of 21-day old rats following posterior laminectomy. N-methyl-D-aspartate (NMDA) preferentially affected dorsal horn neurons, whereas the non-NMDA agonist, kainic acid, preferentially affected motor neurons. Cytopathological changes in motor neurons closely resembled those described in SOD-1 mice. These changes consist of massively swollen dendritic processes in the presence of well-preserved presynaptic axon terminals; cell bodies of motor neurons filled with vacuoles that originate both from endoplasmic reticulum and mitochondria; pleomorphic changes in mitochondria; axons of motor neuron becoming swollen proximally with accumulation of vacuoles, organelles, filaments, and degeneration products in the swollen segment. The observed changes in motor axons resemble changes described in the spinal cord of ALS patients. These findings are consistent with the proposal that motor neuron degeneration in ALS may be mediated by an excitotoxic process involving hyperactivation with non-NMDA glutamate receptors.

Amyotrophic Lateral Sclerosis↗

PubMed1996

Increasing brain tumor rates: is there a link to aspartame?

In the past two decades brain tumor rates have risen in several industrialized countries, including the United States. During this time, brain tumor data have been gathered by the National Cancer Institute from catchment areas representing 10% of the United States population. In the present study, we analyzed these data from 1975 to 1992 and found that the brain tumor increases in the United States occurred in two distinct phases, an early modest increase that may primarily reflect improved diagnostic technology, and a more recent sustained increase in the incidence and shift toward greater malignancy that must be explained by some other factor(s). Compared to other environmental factors putatively linked to brain tumors, the artificial sweetener aspartame is a promising candidate to explain the recent increase in incidence and degree of malignancy of brain tumors. Evidence potentially implicating aspartame includes an early animal study revealing an exceedingly high incidence of brain tumors in aspartame-fed rats compared to no brain tumors in concurrent controls, the recent finding that the aspartame molecule has mutagenic potential, and the close temporal association (aspartame was introduced into US food and beverage markets several years prior to the sharp increase in brain tumor incidence and malignancy). We conclude that there is need for reassessing the carcinogenic potential of aspartame.

Animals↗

PubMed1996

Prevention of trauma-induced neurodegeneration in infant rat brain.

Recent evidence implicates the endogenous excitatory neurotransmitters, glutamate (Glu) and aspartate, in the pathophysiology of traumatic injury in the adult CNS, but it is not known whether similar excitotoxic mechanisms mediate traumatic injury in the immature CNS. Therefore, we developed a model of brain contusion injury in infant rats and used this model to study the nature and evolution of the acute cytopathologic changes and to evaluate the ability of Glu receptor antagonists to protect the immature brain against such changes. Seven-day-old rat pups were subjected to contusion injury and were killed 0, 0.5, 1, 2, 4, and 6 h later for histologic evaluation of the brain. Physical tearing of the dura and minor disruption of underlying brain tissue was noted at 0 h. At 30 min a discrete zone of neuronal necrosis began to appear at the border of the trauma site; this zone progressively expanded over a period of 4 h. The cytopathologic changes closely resembled the type of changes Glu is known to cause; these changes consisted of swollen dendrites, degenerating neurons with pyknotic nuclei and markedly swollen cytoplasm, and dark cells with vacuolated cytoplasm. The noncompetitive N-methyl-D-aspartate (NMDA) antagonist, dizocilpine maleate, when administered 30 min before or 1 h after trauma, significantly attenuated the lesion. The competitive NMDA antagonist, 3-((-2)-carboxypiperazine-4-yl)-propyl-1-phosphonate, was also neuroprotective. The alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate/kainate receptor antagonist 2,3-dihydro-6-nitro-7-sulfamoyl-benzo(f)quinoxaline did not significantly suppress the lesion when given as three treatments (30 mg/kg each) 30 min before plus 15 and 75 min after the insult. These findings suggest that traumatic injury in the infant rat brain is mediated by endogenous excitotoxins (Glu and aspartate) acting at NMDA receptors and can be substantially mitigated by timely treatment with NMDA receptor antagonists.

Animals↗

PubMed1996

CSF excitatory amino acids and severity of illness in Alzheimer's disease.

Researchers have proposed that increased release of excitatory amino acids (EAAs) is involved in the pathogenesis of dementia of the Alzheimer type (DAT), and CSF EAA concentrations have been measured to obtain evidence in support of this hypothesis. However, previous comparisons of CSF EAA concentrations in patients with DAT and in controls have yielded inconsistent results, perhaps because patient samples have been heterogeneous as to dementia severity. To determine whether there are changes in CSF concentrations of EAAs related to severity of illness in patients with DAT, we measured CSF concentrations of glutamate, aspartate, and taurine in 32 subjects with DAT, in whom we also assessed the severity of illness using clinical and neuropsychological measures, and 11 age-matched controls. The results suggested that increased CSF aspartate and glutamate concentrations, as well as decreased taurine concentrations, may occur in some persons with more advanced symptoms of DAT.

Aged↗

PubMed1995

Age-specific neurotoxicity in the rat associated with NMDA receptor blockade: potential relevance to schizophrenia?

Agents that block the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor induce a schizophrenialike psychosis in adult humans and injure or kill neurons in several corticolimbic regions of the adult rat brain. Susceptibility to the psychotomimetic effects of the NMDA antagonist, ketamine is minimal or absent in children and becomes maximal in early adulthood. We examined the sensitivity of rats at various ages to the neurotoxic effects of the powerful NMDA antagonist, MK-801. Vulnerability was found to be age dependent, having onset at approximately puberty (45 days of age) and becoming maximal in early adulthood. This age-dependency profile (onset of susceptibility in late adolescence) in the rat is similar to that for ketamine-induced psychosis or schizophrenia in humans. These findings suggest that NMDA receptor hypofunction, the mechanism underlying the neurotoxic and psychotomimetic actions of NMDA antagonists, may also play a role in schizophrenia.

Adolescent↗

PubMed1995

Quantitative analysis of factors influencing neuronal necrosis induced by MK-801 in the rat posterior cingulate/retrosplenial cortex.

A single dose of the non-competitive NMDA receptor antagonist MK-801 (dizocilpine maleate) induces neuronal necrosis in the posterior cingulate/retrosplenial (PC/RS) cortex of adult rats. The present studies further characterized this effect and evaluated several variables that affect its expression. Male and female rats of two strains (Sprague-Dawley and Fischer 344) and two ages (70 and 127 days) were given a single subcutaneous injection of vehicle (water) or MK-801 (0.5, 1.0 or 5.0 mg/kg). A simple behavioral response (recumbency) and number of necrotic neurons in the PC/RS cortex were evaluated. MK-801 induced dose-dependent recumbency which was more severe and of longer duration in females of either strain or age. In addition, female rats (regardless of strain, dose, or age) consistently had significantly more necrotic PC/RS neurons than male rats. In a second study, a high dose of MK-801 was given intraperitoneally (10 mg/kg) to male and female Sprague-Dawley rats (90-120 days of age). Necrotic neuron counts were determined at 5 separate rostrocaudal levels of the PC/RS cortex. At levels where neuronal necrosis occurred, the magnitude of the effect was significantly greater in females than males and the number of necrotic neurons increased along a rostral to caudal gradient. Our findings indicate that (1) MK-801 dose dependently induces recumbency and necrosis of PC/RS cortical neurons in both Sprague-Dawley and Fischer 344 rats, (2) female rats of either strain are more sensitive than their male counterparts, and (3) the extent of necrosis of PC/RS cortical neurons increases along a rostral to caudal gradient.

Aging↗

PubMed1995

Mineralization of the globus pallidus following excitotoxic lesions of the basal forebrain.

The excitotoxin N-methyl aspartic acid was injected into the rat nucleus basalis to destroy basal forebrain cholinergic (BFC) neurons. In long-term survival experiments (up to 11 months post-lesion), conspicuous mineralized deposits were found in the globus pallidus and to a lesser extent in the thalamus. Deposits stained in a manner consistent with a composition of calcium and iron. Typically, deposits were absent from the center of the injection site, where BFC cell loss was most severe, but were present within the ventral and lateral globus pallidus where there was substantial sparing of BFC neurons. The similarity of this pathology to basal ganglia calcification and its relationship to Alzheimer's Disease and Down's syndrome is discussed.

Alzheimer Disease↗

PubMed1995

Halothane prevents MK-801 neurotoxicity in the rat cingulate cortex.

Subcutaneous administration of the N-methyl-D-aspartic acid (NMDA) antagonist, MK-801, to adult rats causes a toxic vacuole reaction in neurons of the posterior cingulate cortex which is readily detected in histological sections 4 h following MK-801 administration. Certain drugs that facilitate neurotransmission at gamma-aminobutyric acidA (GABAA) receptors block this neurotoxic action of MK-801. The anesthetic actions of halothane (fluothane) are thought to be due, at least in part, to an interaction with GABAA receptors. In the present study, we investigated the effect of halothane on MK-801 neurotoxicity. When halothane was administered for either 1 or 2 h, then terminated immediately prior to MK-801 treatment, the vacuole reaction detected 4 h later was almost as severe as in controls not exposed to halothane. Administration of halothane for 1 h after MK-801 injection postponed but did not prevent a relatively full vacuole reaction. However, when rats were kept under halothane anesthesia continuously throughout the 4 h period following MK-801 administration, the vacuole reaction was completely prevented. We postulate that halothane blocks MK-801 neurotoxicity by a facilitative action at GABAA receptors. Because halothane's duration of action is fleeting compared to the very long duration of action of MK-801, the efficacy of halothane in blocking MK-801 neurotoxicity varies in direct proportion to the length of time following MK-801 treatment that the rat brain is exposed to halothane.

Animals↗

PubMed1995

Distribution of metabotropic glutamate receptor mGluR5 immunoreactivity in rat brain.

The receptor mGluR5 is a metabotropic glutamate receptor with messenger RNA abundantly present throughout cortex, hippocampus, and caudate/putamen that is also coupled to phosphatidyl inositide hydrolysis and calcium mobilization. In this study, the distribution of mGluR5 was examined in rat brain by immunocytochemistry. The antibody utilized is highly specific and does not cross react with the most closely related other metabotropic glutamate receptor, as determined by Western blot analysis of nonneuronal cells transfected with metabotropic receptor coding sequences. The receptor mGluR5 is widely expressed with the highest density in olfactory bulb, caudate/putamen, lateral septum, cortex, and hippocampus, as confirmed with both immunocytochemistry and Western blot analysis. Electron microscopic studies in hippocampus and cortex indicate that the labeling is mostly on membranes of dendritic spines and shafts. Light and electron microscopic evidence indicates that some mGluR5 immunoreactivity is located in presynaptic axon terminals, suggesting that mGluR5 may function as a presynaptic receptor.

Amino Acid Sequence↗

PubMed1995

Glutamate receptor dysfunction and schizophrenia.

In this article, we advance a unified hypothesis pertaining to combined dysfunction of dopamine and N-methyl-D-aspartate glutamate receptors that highlights N-methyl-D-aspartate receptor hypofunction as a key mechanism that can help explain major clinical and pathophysiological aspects of schizophrenia. The following fundamental features of schizophrenia are accommodated by this hypothesis: (1) the occurrence of structural brain changes during early development that have the potential for producing subsequent clinical manifestations of schizophrenia, (2) a quiescent period in infancy and adolescence before clinical manifestations are expressed, (3) onset in early adulthood of psychotic symptoms, (4) involvement of dopamine (D2) receptors in some cases but not others that would explain why some but not all patients are responsive to typical neuroleptic therapy, and (5) ongoing neurodegenerative changes and cognitive deterioration in some patients. We propose that since N-methyl-D-aspartate receptor hypofunction can cause psychosis in humans and corticolimbic neurodegenerative changes in the rat brain, and since these changes are prevented by certain antipsychotic drugs, including atypical neuroleptic agents (clozapine, olanzapine, fluperlapine), a better understanding of the N-methyl-D-aspartate receptor hypofunction mechanism and ways of preventing its neurodegenerative consequences in the rat brain may lead to improved pharmacotherapy in schizophrenia.

Animals↗

PubMed1995

Age dependent sensitivity of the rat retina to the excitotoxic action of N-methyl-D-aspartate.

We have found that the rat retina can be isolated atraumatically and incubated ex vivo for up to 24 h without showing signs of histological deterioration, and that retinas from adult or aged rats can be isolated as successfully as those from immature rats. In the present study we used this preparation to show that rat retinal neurones at postnatal day zero (PND 0) are relatively insensitive to the excitotoxic action of the glutamate agonist, N-methyl-D-aspartate (NMDA), then gradually show increasing sensitivity that peaks at about PND 9 and declines from PND 15-30 after which it remains at a low level up to the last time point studied (10 months of age). This is consistent with other developmental NMDA receptor data and underscores the need for caution in using immature in vitro central; nervous system (CNS) tissue preparations as a basis for interpreting the role of NMDA receptors in adult neurological diseases.

Age Factors↗

PubMed1995

Blockade of the second messenger functions of the glutamate metabotropic receptor is associated with degenerative changes in the retina and brain of immature rodents.

Activation of metabotropic glutamate receptors (mGluR) by Glu or related mGluR agonists triggers phosphoinositide (PI) hydrolysis, intracellular Ca2+ mobilization and protein kinase C activation. These mGluR agonist-stimulated events are inhibited strongly by 2-amino-3-phosphono-L-propionic acid (L-AP3) and L-aspartate-beta-hydroxamate (L-A beta H), and much more weakly by D-AP3 and L-serine-O-phosphate (L-SOP). Daily s.c. administration of DL-AP3 subchronically to infant rodents causes the developing retina and optic nerves to degenerate. In the present study, we describe the evolution of the cytopathological reaction in the developing rodent retina following DL-AP3 treatment and show that DL-AP3 can induce similar cytopathological changes in several regions of the immature rodent brain. In addition, we show that the retinotoxic action of DL-AP3 is mimicked by L-A beta H but not by L-SOP, and that L-AP3 is a much stronger retinotoxin that D-AP3. These observations suggest a possible mechanistic link between the PI-hydrolysis blocking action and retinotoxic action. Our findings are consistent with the hypothesis that under normal physiological circumstances, the Glu metabotropic receptor through its PI-hydrolysis-linked second messenger functions provides vitally important support for developing neurons, and that disruption of this support can cause widespread neuronal degeneration.

Alanine↗