Glutamate-mediated transmission, alcohol, and alcoholism

Glutamate-mediated neurotransmission may be involved in the range of adaptive changes in brain which occur after ethanol administration in laboratory animals, and in chronic alcoholism in human cases. Excitatory amino acid transmission is modulated by a complex system of receptors and other effecters, the efficacy of which can be profoundly affected by altered gene or protein expression. Local variations in receptor composition may underlie intrinsic regional variations in susceptibility to pathological change. Equally, ethanol use and abuse may bring about alterations in receptor subunit expression as the essence of the adaptive response. Such considerations may underlie the regional localization characteristic of the pathogenesis of alcoholic brain damage, or they may form part of the homeostatic change that constitutes the neural substrate for alcohol dependence. (C) 2000 Elsevier Science Ltd. All rights reserved.

Spatial learning ability of rats following differing levels of exposure to alcohol during early postnatal life

Rats exposed to a relatively high dose (7.5 g/kg body weight) of alcohol on either the fifth or tenth postnatal day of age have been reported to have long-lasting deficits in spatial learning ability as tested on the Morris water maze task. The question arises concerning the level of alcohol required to achieve this effect. Wistar rats were exposed to either 2, 4 or 6 g/kg body weight of ethanol administered as a 10% solution. This ethanol was given over an 8-h period on the fifth postnatal day of age by means of an intragastric cannula. Gastrostomy controls received a 5% sucrose solution substituted isocalorically for the ethanol. Another set of pups raised by their mother were used as suckle controls. All surgical procedures were carried out under halothane vapour anaesthesia. After the artificial feeding regimes all pups were returned to lactating dams and weaned at 21 days of age. The spatial learning ability of these rats was tested in the Morris water maze when they were between 61-64 days of age. This task requires the rats to swim in a pool containing water made opaque and locate and climb onto a submerged platform. The time taken to accomplish this is known as the escape latency. Each rat was subjected to 24 trials over 3 days of the test period. Statistical analysis of the escape latency data revealed that the rats given 6 g/kg body weight of ethanol had significant deficits in their spatial learning ability compared with their control groups. However, there was no significant difference in spatial learning ability for the rats given either 2 or 4 g/kg body weight of ethanol compared with their respective gastrostomy or suckle control animals. We concluded that ethanol exposure greater than 4 g/kg over an 8-h period to 5-day-old rats is required for them to develop long-term deficits in spatial learning behaviour. (C) 1998 Elsevier Science Inc.

Neurology of ciguatera

Ciguatera is a widespread ichthyosarcotoxaemia with dramatic and clinically important neurological features. This severe form of fish poisoning may present with either acute or chronic intoxication syndromes and constitutes a global health problem. Ciguatera poisoning is little known in temperate countries as a potentially global problem associated with human ingestion of large carnivorous fish that harbour the bioaccumulated ciguatoxins of the photosynthetic dinoflagellate Gambierdiscus toxicus. This neurotoxin is stored in the viscera of fish that have eaten the dinoflagellate and concentrated it upwards throughout the food chain towards progressively larger species, including humans. Ciguatoxin accumulates in all fish tissues, especially the liver and viscera, of at risk species. Both Pacific (P-CTX-1) and Caribbean (C-CTX-1) ciguatoxins are heat stable polyether toxins and pose a health risk at concentrations above 0.1 ppb. The presenting signs of ciguatera are primarily neurotoxic in more than 80% of cases. Such include the pathognomonic features of postingestion paraesthesiae, dysaesthesiae, and heightened nociperception. Other sensory abnormalities include the subjective features of metallic taste, pruritis, arthralgia, myalgia, and dental pain. Cerebellar dysfunction, sometimes diphasic, and weakness due to both neuropathy and polymyositis may be encountered. Autonomic dysfunction leads to hypotension, bradycardia, and hypersalivation in severe cases. Ciguatoxins are potent, lipophilic sodium channel activator toxins which bind to the voltage sensitive (site 5) sodium channel on the cell membranes of all excitable tissues. Treatment depends on early diagnosis and the early administration of intravenous mannitol. The early identification of the neurological features in sentinel patients has the potential to reduce the number of secondary cases in cluster outbreaks.

A. W. Campbells Australian career: 1905-1937

The Australian Alfred Walter Campbell (1868-1937) is remembered as one of the two chief pioneers of the study of the cytoarchitectonics of the primate cerebral cortex. He had worked in Britain carrying out neuroanatomical and neuropathological research for almost two decades before his famous monograph on Histological Studies on the Localisation of Cerebral Function appeared in 1905. In that year he returned to his native Australia and practiced for over 30 years in Sydney as a neurologist rather than a neuropathologist, publishing mainly clinical material though he was involved in the investigation of the epidemic of Australian X disease, a viral encephalitis. His abrupt change in both the nature and the location of his career at a time when he was well established in Britain appears to have been a consequence of his marriage and the need to provide for a family. His simultaneous apparent abandonment of research seems not to have really been the case. As judged from the contents of a paper presented to a local medical congress in Sydney in 1911, it appears that, in Australia, Campbell did carry out a major comparative anatomical and histological investigation of the possibility of localization of function in the cerebellar cortex. He never published this work in detail. His investigation let him to conclude that no such localization of function existed, a view contrary to the then topical interpretation of Bolk (1906), but one in accordance with Gordon Holmes' views a decade later. Campbell's circumstances in Sydney, his extremely reticent nature and the essentially negative outcome of his investigation probably explain his failure to make his study more widely known.

Corticosteroid-induced glaucoma in a child after a scleral reinforcement procedure

Corticoteroid-induced glaucoma can result from either topical or systemic corticosteroid use. Compared with adults, the corticosteroid response in children is less well known. The case is reported of a child who developed glaucoma after receiving topical corticosteroids following a scleral re-inforcement procedure. The raised intraocular pressure was controlled after cessation of the corticosteroids and with the use of antiglaucoma therapy. As many forms of cortico-steroids are widely used, children on corticosteroids should have regular intraocular pressure measurements as part of their management.

A role for the dominant thalamus in language? A linguistic comparison of two cases subsequent to unilateral thalamotomy procedures in the dominant and non-dominant hemispheres

Background: Thalamotomy has been reported to be successful in ameliorating the motor symptoms of tremor and/or rigidity in people with Parkinson's disease (PD), emphasising the bona fide contribution of this subcortical nucleus to the neural circuitry subserving motor function. Despite evidence of parallel yet segregated associative and motor cortico-subcortical-cortical circuits, comparatively few studies have investigated the effects of this procedure on cognitive functions. In particular, research pertaining to the impact of thalamotomy on linguistic processes is fundamentally lacking. Aims: The purpose of this research was to investigate the effects of thalamotomy in the language dominant and non-dominant hemispheres on linguistic functioning, relative to operative theoretical models of subcortical participation in language. This paper compares the linguistic profiles of two males with PD, aged 75 years (10 years of formal education) and 62 years (22 years of formal education), subsequent to unilateral thalamotomy procedures within the language dominant and non-dominant hemispheres, respectively. Methods & Procedures: Comprehensive linguistic profiles comprising general and high-level linguistic abilities in addition to on-line semantic processing skills were compiled up to 1 month prior to surgery and 3 months post-operatively, within perceived on'' periods (i.e., when optimally medicated). Pre- and post-operative language performances were compared within-subjects to a group of 16 non-surgical Parkinson's controls (NSPD) and a group of 16 non-neurologically impaired adults (NC). Outcomes & Results: The findings of this research suggest a laterality effect with regard to the contribution of the thalamus to high-level linguistic abilities and, potentially, the temporal processing of semantic information. This outcome supports the application of high-level linguistic assessments and measures of semantic processing proficiency to the clinical management of individuals with dominant thalamic lesions. Conclusions: The results reported lend support to contemporary theories of dominant thalamic participation in language, serving to further elucidate our current understanding of the role of subcortical structures in mediating linguistic processes, relevant to cortical hemispheric dominance.

Effects of intravenous injection of Clostridium perfringens type D epsilon toxin in calves

In cattle, a neurological lesion similar to that produced in sheep and goats by Clostridium perfringens type D enterotoxaemia has been reported. However, no causal relationship has been established between this disease and the lesion in cattle. The effects of single and multiple intravenous injections of epsilon toxin in three calves aged 6 months were studied. A further calf was inoculated intravenously with saline solution and used as a control. Epsilon toxin invariably produced neurological signs within 2-60 min of the end of the injection process. Clinical signs consisted of loss of consciousness, recumbency, convulsions, paddling, opisthotonus, hyperaesthesia and dyspnoea. Gross changes consisted of severe acute pulmonary oedema, which was particularly marked in the interlobular septa. The histological lesions consisted of intra-alveolar and interstitial oedema of the lung and variable degrees of perivascular proteinaceous oedema in the internal capsule, thalamus and cerebellar white matter. No clinical or post-mortem changes were observed in the control calf. These results show that calves are susceptible to the intravenous injection of epsilon toxin, and that they can show at least some of the histological lesions produced in sheep and goats by this toxin. (C) 2002 Harcourt Publishers Ltd.

Granulomatous meningoencephalomyelitis in dogs

Granulomatous meningoencephalomyelitis (GME) is a morphological description of an inflammatory disorder of the canine central nervous system (CNS). It has been reported in many areas of the world. including Australia, and is one of the more common nervous disorders of dogs. Most breeds of dogs of both sexes and all ages can be affected but young to middle-aged small and terrier breeds have been stated as being more susceptible. There are variable anatomical forms and distribution of the lesions in the CNS; the presenting clinical signs can reflect singly or collectively cerebellar, cerebral, and brain stem dysfunction. Meningeal and spinal cord involvement are also common. There is no specific diagnostic test but a combination of clinical signs, history and cerebro-spinal fluid cytology are useful indicators. However differential diagnosis from other inflammatory disorders of the brain is difficult. No infectious agent aetiology has been established for GME and therefore no satisfactory therapeutic approach is available. The role of the immune system in terms of either initiating or potentiating the lesions in the CNS appears to be the most likely direction for further investigation into the nature of this disorder.

Distribution of two splice variants of the glutamate transporter GLT-1 in rat brain and pituitary

We have performed immunocytochemistry on rat brains using a highly specific antiserum directed against the originally described form of the glutamate transporter GLT-1 (referred to hereafter as GLT-1alpha), and another against a C-terminal splice variant of this protein, GLT-1B. Both forms of GLT-1 were abundant in rat brain, especially in regions such as the hippocampus and cerebral cortex, and macroscopic examination of sections suggested that both forms were generally regionally coexistent. However, disparities were evident; GLT-1alpha was present in the intermediate lobe of the pituitary gland, whereas GLT-1B was absent. Similar marked disparities were also noted in the external capsule, where GLT1A labeling was abundant but GLT-1B was only occasionally encountered. Conversely, GLT-1B was more extensively distributed, relative to GLT-1alpha, in areas such as the deep cerebellar nuclei. In most regions, such as the olfactory bulbs, both splice variants were present but differences were evident in their distribution. In cerebral cortex, patches were evident where GLT-1B was absent, whereas no such patches were evident for GLT-1alpha. At high resolution, other discrepancies were evident; double-labeling of areas such as hippocampus indicated that the. two splice variants may either be differentially expressed by closely apposed glial elements or that the two splice variants may be differentially targeted to distinct membrane domains of individual glial cells. (C) 2002 Wiley-Liss, Inc.

Localization of taurine transporters, taurine, and H-3 taurine accumulation in the rat retina, pituitary, and brain

The nervous system contains an abundance of taurine, a neuroactive sulfonic acid. Antibodies were generated against two cloned high-affinity taurine transporters, referred to in this study as TAUT-1 and TAUT-2. The distribution of such was compared with the distribution of taurine in the rat brain, pituitary, and retina. The cellular pattern of [H-3] taurine uptake in brain slices, pituitary slices, and retinas was examined by autoradiography. TAUT-2 was predominantly associated with glial cells, including the Bergmann glial cells of the cerebellum and astrocytes in brain areas such as hippocampus. Low-level labeling for TAUT-2 was also observed in some neurones such as CA1 pyramidal cells. TAUT-1 distribution was more limited; in the posterior pituitary TAUT-1 was associated with the pituicytes but was absent from glial cells in the intermediate and anterior lobes. Conversely, in the brain TAUT-1 was associated with cerebellar Purkinje cells and, in the retina, with photoreceptors and bipolar cells. Our data suggest that intracellular taurine levels in glial cells and neurons may be regulated in part by specific high-affinity taurine transporters. The heterogeneous distribution of taurine and its transporters in the brain does not reconcile well with the possibility that taurine acts solely as a ubiquitous osmolyte in nervous tissues. (C) 2002 Wiley-Liss, Inc.

Oxidative stress is responsible for deficient survival and dendritogenesis in Purkinje neurons from ataxia-telangiectasia mutated mutant mice

Atm gene-disrupted mice recapitulate the majority of characteristics observed in patients with the genetic disorder ataxia-telangiectasia (A-T). However, although they exhibit defects in neuromotor function and a distinct neurological phenotype, they do not show the progressive neurodegeneration seen in human patients, but there is evidence that ataxia-telangiectasia mutated ( Atm)-deficient animals have elevated levels of oxidized macromolecules and some neuropathology. We report here that in vitro survival of cerebellar Purkinje cells from both Atm knock-out and Atm knock-in mice was significantly reduced compared with their wild-type littermates. Although most of the Purkinje neurons from wild-type mice exhibited extensive dendritic elongation and branching under these conditions, most neurons from Atm-deficient mice had dramatically reduced dendritic branching. An antioxidant ( isoindoline nitroxide) prevented Purkinje cell death in Atm-deficient mice and enhanced dendritogenesis to wild-type levels. Furthermore, administration of the antioxidant throughout pregnancy had a small enhancing effect on Purkinje neuron survival in Atm gene-disrupted animals and protected against oxidative stress in older animals. These data provide strong evidence for a defect in the cerebellum of Atm-deficient mice and suggest that oxidative stress contributes to this phenotype.

Nutritional effects on neuron numbers

Undemutrition during early life is known to cause deficits and distortions of brain structure although it has remained uncertain whether or not this includes a diminution of the total numbers of neurons. Estimates of numerical density (e.g. number of cells per microscopic field, or number of cells per unit area of section, or number of cells per unit volume of tissue) are extremely difficult to interpret and do not provide estimates of total numbers of cells. However, advances in stereological techniques have made it possible to obtain unbiased estimates of total numbers of cells in well defined biological structures. These methods have been utilised in studies to determine the effects of varying periods of undernutrition during early life on the numbers of neurons in various regions of the rat brain. The regions examined so far have included the cerebellum, the dentate gyrus, the olfactory bulbs and the cerebral cortex. The only region to show, unequivocally, that a period of undernutrition during early life causes a deficit in the number of neurons was the dentate gyrus. These findings are discussed in the context of other morphological and functional deficits present in undernourished animals.

The role of group I metabotropic glutamate receptor's in neuronal excitotoxicity in Alzheimer's disease

Neurodegenerative diseases such as Huntington's disease, ischemia, and Alzheimer's disease (AD) are major causes of death. Recently, metabotropic glutamate receptors (mGluRs), a group of seven-transmembrane-domain proteins that couple to G-proteins, have become of interest for studies of pathogenesis. Group I mGluRs control the levels of second messengers such as inositol 1,4,5-triphosphate (IP3) Cal(2+) ions and cAMP. They elicit the release of arachidonic acid via intracellular Ca2+ mobilization from intracellular stores such as mitochondria and endoplasmic reticulum. This facilitates the release of glutamate and could trigger the formation of neurofibrillary tangles, a pathological hallmark of AD. mGluRs regulate neuronal injury and survival, possibly through a series of downstream protein kinase and cysteine protease signaling pathways that affect mitochondrially mediated programmed cell death. They may also play a role in glutamate-induced neuronal death by facilitating Cal(2+) mobilization. Hence, mGluRs have become a target for neuroprotective drug development. They represent a pharmacological path to a relatively subtle amelioration of neurotoxicity because they serve a modulatory rather than a direct role in excitatory glutamatergic transmission.

Dose determination of haloperidol, risperidone and olanzapine using an in vivo dopamine D-2-receptor occupancy method in the rat

The purpose of the present study was to determine antipsychotic doses that achieve 80% striatal doparnine D-2-receptor occupancy for haloperidol, risperidone and olanzapine in rats. Wistar rats were treated with normal saline vehicle (controls), haloperidol (0.25 and 0.5 mg/kg/ day), risperidone (3, 5 and 6 mg/kg/day) and olanzapine (5 and 10 mg/kg/day) for 7 days via osmotic minipumps. Striatal and cerebellar tissue were collected and in vivo dopamine D2-receptor occupancies were determined using H-3-raclopride. The doses required to achieve dopamine D-2-receptor occupancy of 80% in 11- and 24-week old rats were: haloperidol 0.25 mg/kg/day, risperidone 5 mg/kg/day and olanzapine 10 mg/kg/day. (c) 2006 Elsevier B.V All rights reserved.