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J W Olney

Publications and source records attributed to J W Olney.

At least 73 records · Page 4Linked to original sources
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↗
PubMed1995

An ex vivo rat retinal preparation for excitotoxicity studies.

Although the isolated chicken embryo retina has been a very useful in vitro preparation for studying mechanisms of excitotoxicity, it is an avian rather than mammalian tissue and its embryonic age makes it unsuitable for a full range of developmental and aging studies. Therefore, we have explored the feasibility of using the rat retina at various ages for in vitro excitotoxicity studies. In this model, retinal segments were isolated in artificial cerebrospinal fluid (CSF) at 5 degrees C then incubated under various conditions at 30 degrees C and assessed histologically for signs of neurodegenerative changes. Retinal segments from 7-, 30-, 120- and 660-day-old rats incubated in CSF for 3 h and from 30-day-old rats incubated for 24 h retained a normal histological appearance. Thus, this preparation is suitable for in vitro studies pertaining to either acute or delayed excitotoxic phenomena in the mammalian CNS at any age from infancy to old age. Excitotoxin agonist experiments in the 30-day-old rat retina revealed the surprising result that the non-NMDA agonists, kainate and AMPA, at a low concentration (100 microM) damaged a much larger number of retinal neurons than NMDA did at a very high concentration (10 mM).

Aging↗
PubMed1995

alpha 2 adrenergic agonists prevent MK-801 neurotoxicity.

Antagonists of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor are of considerable interest for various neurotherapeutic purposes, including preventing neuronal degeneration in stroke and CNS trauma, suppressing neuropathic pain and preventing the development of tolerance to opiate analgesics. Unfortunately, NMDA antagonists can cause potentially serious side effects, including acute neurodegenerative changes in corticolimbic regions of the adult rat brain and psychotic reactions in adult humans. We have been investigating the mechanisms underlying the neuropathological changes in rat brain and exploring methods of suppressing or preventing such changes. Here we report that alpha 2 adrenergic agonists can prevent NMDA antagonist neurotoxicity. Therefore, administering alpha 2 adrenergic agonists together with NMDA antagonists may be a valuable strategy for preventing adverse side effects of NMDA antagonists and making these agents safer for various neurotherapeutic purposes.

Adrenergic alpha-2 Receptor Agonists↗
PubMed1995

NMDA antagonists as neurotherapeutic drugs, psychotogens, neurotoxins, and research tools for studying schizophrenia.

Antagonists of the N-methyl-D-aspartate (NMDA) subtype of glutamate (Glu) receptor have become the focus of considerable attention as potential neurotherapeutic agents in view of mounting evidence implicating NMDA receptors in acute central nervous system (CNS) injury syndromes such as stroke, trauma, and status epilepticus. In addition, NMDA receptor antagonists are of potential interest for the clinical management of neuropathic pain and preventing the development of tolerance to opiate analgesics. A potentially serious obstacle to the development of NMDA antagonists as neurotherapeutic drugs is the paradoxical fact that whereas these agents do have significant neurotherapeutic potential, they also have psychotogenic and neurotoxic properties. We have been intensively investigating the mechanisms underlying these adverse properties and have discovered several methods of suppressing or preventing their expression. In addition, we have been exploring the possibility that a common mechanism may underlie the psychotogenic and neurotoxic actions of these agents and that this mechanism may have relevance to the pathogenesis of idiopathic psychotic processes such as schizophrenia. In this chapter, we will review our findings pertaining to NMDA antagonists in the dual context of their value as tools for exploring mechanisms underlying neuropsychiatric disturbances, particularly schizophrenia, and their potential promise as therapeutic agents. For additional references and a more complete elaboration of our hypothesis pertaining to NMDA receptor dysfunction and schizophrenia, please see a recent review (Olney and Farber 1995).

Age Factors↗
PubMed1995

Delayed excitotoxic neurodegeneration induced by excitatory amino acid agonists in isolated retina.

Evidence from in vitro studies suggests that excitotoxic neuronal degeneration can occur by either an acute or delayed mechanism. Studies of the acute mechanism in isolated chick embryo retina using histological methods indicate that this process is rapidly triggered by activation of glutamate receptors of either the N-methyl-D-aspartate (NMDA) or non-NMDA subtypes. The delayed mechanism, studied primarily in cortical and hippocampal cell cultures prepared from embryonic rodent brain, requires activation of NMDA receptors. In these cell culture systems, stimulation of non-NMDA receptors does not rapidly trigger delayed neuronal degeneration, or does so only indirectly, via activation of NMDA receptors secondary to glutamate release. To provide a more valid basis for comparison of these two mechanisms, we have modified the isolated chick embryo retina model to permit studies of delayed as well as acute excitotoxic neurodegeneration. Retinas maintained for 24 h exhibited no morphological or biochemical signs of damage. Retinal damage was assessed by measuring lactate dehydrogenase (LDH) present in the medium at various times after exposure to agonists and normalized to total LDH in each retina. Glutamate exposure (1 mM, 30 min) did not result in LDH release by the end of the exposure period, but LDH was released over the following 24 h. Briefer periods also led to substantial LDH release. Incubation in the presence of NMDA, or the non-NMDA agonists kainate (KA) or alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), led rapidly to delayed LDH release.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Excitotoxic cytopathology, progression, and reversibility of thiamine deficiency-induced diencephalic lesions.

The present study examined the cytopathological changes within diencephalon of a rat model of Wernicke's encephalopathy and determined whether administration of thiamine at various intervals after onset of neurological signs can arrest or reverse the cytopathological process. Electron microscopic examination of the brains from animals sacrificed at four progressively severe stages of pyrithiamine-induced thiamine deficiency (PTD) revealed neurocytopathological changes identical to those that have been described in glutamate-induced excitotoxic lesions. These degenerative changes occurred in gelatinosus (Ge) and anteroventral ventrolateral (AVVL) nuclei at an early symptomatic stage and in the ventroposterolateral (VPL), ventroposteromedial (VPM), and ventrolateral (VL) nuclei at slightly later stages of PTD. Light microscopic evaluation of separate groups of PTD rats administered thiamine at each of the same four neurologic stages and allowed to recover for 1 week demonstrated that thiamine treatment is more effective when administered at earlier stages. However, Ge, AVVL, and VPL nuclei sustain severe damage even when thiamine is administered prior to acute neurologic signs. Furthermore, pathologic changes in the mammillary and several midline intralaminar nuclei begin after thiamine administration and reinstitution of thiamine-replete diet to animals in more severe stages of thiamine deficiency. These and other recent findings suggest that excitotoxic and possibly apoptotic mechanisms may mediate neuronal degeneration in the PTD rat model of Wernicke's encephalopathy, and that multiple factors conducive to excitotoxicity may act in concert to produce this syndrome.

Acute Disease↗
PubMed1994

Effects of lactate and pyruvate on glucose deprivation in rat hippocampal slices.

Rat hippocampal slices were used to evaluate the effects of glucose deprivation and the ability of lactate or pyruvate to preserve histological integrity and synaptic function. Dark cell changes were observed during 180 min incubations in glucose-free solutions. These changes were blocked by substituting 10 mM lactate or pyruvate for glucose during the incubation. Excitatory postsynaptic potentials disappeared during 60 min of glucose deprivation but were restored by subsequent introduction of glucose, lactate or pyruvate. Incubation of slices with iodoacetate revealed a distinct pattern of damage that was blocked completely by pyruvate and partially by lactate. These results indicate that exogenous pyruvate and lactate can serve as energy substrates in the hippocampus when glucose is unavailable or glycolytic metabolism is impaired.

Animals↗
PubMed1994

Quisqualate injection into the nucleus basalis magnocellularis produces seizure-related brain damage that is prevented by MK-801.

Quisqualate (Quis) and other excitotoxins such as ibotenate and N-methyl aspartate, have been used to destroy neurons in the area of the nucleus basalis magnocellularis (NBM) in order to study the relationship between loss of cholinergic neurons in the basal forebrain and various behavioral deficits, including learning and memory impairments. The results of several studies suggest that although Quis NBM lesions may produce greater depletions in cortical choline acetyltransferase levels than ibotenate lesions, the learning/memory deficits tend to be milder following Quis lesions. In these studies, it was often assumed that the lesions induced by Quis were restricted to the local vicinity of the injection. However, in the present study, we found that an injection of Quis into the NBM/substantia inominata (SI) region often induces limbic seizures and disseminated brain damage. Specifically, we found that an injection of Quis into the NBM/SI area of female rats at a dose (120 nmol) used by others in previous behavioral studies produced massive damage in areas distant from the lesion site, particularly in the amygdala and piriform cortex. This disseminated damage occurred in 50% of the rats treated with Quis, was typically more severe than damage at the injection site, and was often accompanied by equally severe "mirror" lesions in the contralateral amygdala and piriform cortex. Injecting rats with MK-801 (1 mg/kg) 30 min before the Quis injection protected against the disseminated damage. These data underscore the need for careful histological evaluation of excitotoxic lesions and for caution in interpreting the relationship between altered transmitter markers and learning/memory impairment seen following these lesions.

Amygdala↗
PubMed1994

Neurotoxicity of NMDA receptor antagonists: an overview.

The glutamate transmitter system provides several benevolent/malevolent paradoxes. Glutamate itself serves vitally important functions in the CNS but has enormous neurodestructive potential. NMDA glutamate receptor antagonists protect many neurons against glutamate neurotoxicity, while injuring or destroying certain other neurons and inducing psychotic symptoms and memory impairment. Therefore, the challenge in developing protective therapies against glutamate's neurodestructive potential is to find benevolent agents that are not malevolent as well. There are two possible approaches. One is to develop neuroprotective agents that are free from neuropsychopathological side effects; the other is to use NMDA antagonists even though they have neuropsychopathological side effects, but to use them in combination with other agents that block the side effects without producing side effects of their own.

Animals↗
PubMed1994

Excitotoxins in foods.

Evidence is reviewed pertaining to excitatory neurotoxins (excitotoxins) encountered in human food supply. The most frequently encountered food excitotoxin is glutamate (Glu) which is commercially added to many foods despite evidence that it can freely penetrate certain brain regions and rapidly destroy neurons by hyperactivating the NMDA subtype of Glu receptor. Hypersensitivity of NMDA receptors during development makes the immature nervous system especially sensitive to Glu excitotoxicity. On the other hand, elderly consumers are particularly sensitive to domoic acid, a powerful excitotoxic Glu analog that activates both NMDA and non-NMDA receptors. A high content of domoic acid in shell fish caused a recent food poisoning incident that killed some elderly victims and caused brain damage and memory impairment in others. Neurolathyrism is a crippling neurodegenerative condition associated with ingestion of a legume that naturally contains BOAA, an excitotoxic Glu analog that hyperactivates non-NMDA receptors. Thus, the human food supply is a source of excitotoxins that can damage the brain by one type of mechanism to which immature consumers are hypervulnerable, or by other mechanisms to which adult and elderly consumers are peculiarly sensitive.

Amino Acids, Diamino↗
PubMed1994

New mechanisms of excitatory transmitter neurotoxicity.

Accumulating evidence suggests that either excessive activation or suppression of either ionotropic or metabotropic EAA receptors can have neurotoxic consequences, and a variety of different mechanisms may be involved. The major excitatory neurotransmitters in the mammalian CNS-glutamate (Glu) and acetylcholine (ACh)--have vitally important beneficial functions, but also harbor treacherous neurotoxic potential which, as will be described in this review, can be expressed as classical excitotoxicity or in several other ways that have yet to be studied in detail.

Acetylcholine↗
PubMed1994

Efficacy of clozapine compared with other antipsychotics in preventing NMDA-antagonist neurotoxicity.

The focus of this article will be on toxic symptoms associated with blockade of the N-methyl-D-aspartate (NMDA) subtype of the glutamate receptor. We have been studying two parallel phenomena: NMDA-antagonist neurotoxicity (NAN) in rats and NMDA-antagonist psychotogenicity (NAP) in humans. These phenomena have a common denominator--NMDA receptor hypofunction, which is putatively a mechanism operative in schizophrenia. We have found that the NAN reaction in rats can be prevented by specific drugs that prevent NAP in humans and by certain antipsychotic agents, including clozapine, that ameliorate symptoms in schizophrenia. By studying mechanisms by which clozapine prevents the NAN reaction in rats, we hope to gain insight into mechanisms by which clozapine or other atypical antipsychotics ameliorate symptoms in schizophrenia.

Adolescent↗