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O Lindvall

Publications and source records attributed to O Lindvall.

At least 145 records · Page 8Linked to original sources
PubMed1989

Noradrenergic mechanisms in hippocampal kindling with rapidly recurring seizures.

Rats were subjected to hippocampal kindling with short interstimulus intervals (5 min), so-called rapid kindling. Severe depletion of forebrain noradrenaline (NA) with intraventricular 6-hydroxydopamine or blockade of alpha 2 adrenergic receptors with idazoxan markedly reduced the number of stimulations needed to induce the first severe limbic seizure and increased the total number of such seizures during 40 stimulations. Intracerebral microdialysis demonstrated a 3-fold increase of extracellular NA levels in response to the first kindling stimulations in both the stimulated and the non-stimulated hippocampus. The NA levels then gradually tapered off reaching baseline levels after 14 stimulations. We conclude that central noradrenergic neurons exert a powerful suppressant action, most probably mediated via an alpha 2 adrenergic receptor, on seizure development in rapid hippocampal kindling.

Adrenergic alpha-Antagonists↗
PubMed1989

Human fetal dopamine neurons grafted into the striatum in two patients with severe Parkinson's disease. A detailed account of methodology and a 6-month follow-up.

By using stereotaxic surgical techniques, ventral mesencephalic tissues from aborted human fetuses of 8 to 10 weeks' gestational age were implanted unilaterally into the striata in two patients with advanced Parkinson's disease. The patients were treated with a cyclosporine, azathioprine, and steroid regimen to minimize the risk for graft rejection. They were examined for 6 months preoperatively and 6 months postoperatively and continued to receive the same doses of antiparkinsonian medication. There were no significant postoperative complications. No major therapeutic effect from the operation was observed. However, in the clinical tests, both patients showed small but significant increases of movement speed for repeated pronation-supination, fist clenching, and foot lifting. The rate of walking also increased in the one patient tested. For both patients, there was an initial worsening postoperatively, followed by improvement vs preoperative performance at 1 to 3 months. Both patients also showed significant improvement in the magnitude of response to a single dose of levodopa (L-dopa), but there was no increase in the duration of drug action. The motor readiness potential increased in both patients postoperatively, primarily over the operated hemisphere. Neurophysiological measurements also showed a more rapid performance of simple and complex arm and hand movements on the side contralateral to transplantation in one patient at 5 months postoperatively. Positron emission tomography demonstrated no increased uptake of 6-L-(18F)-fluorodopa in the transplanted striatum at 5 and 6 months. Taken together, these results suggest that the fetal nigral implants may have provided a modest improvement in motor function, consistent with the presence of small surviving grafts. Although our results support further scientific experimentation with transplantation in Parkinson's disease, widespread clinical trials with this procedure are probably not warranted at this time.

Contingent Negative Variation↗
PubMed1989

Electrical stimulation of the lateral habenula increases hippocampal noradrenaline release as monitored by in vivo microdialysis.

Hippocampal extracellular levels of noradrenaline (NA) were monitored with the microdialysis technique during electrical stimulation of the lateral habenula (LHb) in halothane anaesthetized rats. The steady state NA level was 20.8 +/- 4.6 fmole/15 min of perfusion (mean +/- SEM). Electrical stimulation of the LHb for 15 min (15 Hz, 0.5 mA) induced an immediate 228 +/- 48% increase in hippocampal NA release, compared to the pre-stimulation baseline (p less than 0.05). A second stimulation 90 min later induced a similar increase. The effect of LHb stimulation was completely abolished by a knife cut transecting the dorsal NA bundle either immediately rostral to the locus coeruleus or at the level of the parafascicular nucleus. This suggests that the effect was dependent on nerve impulses flow in the coeruleo-hippocampal NA neurons, and was not mediated, e.g., by a local spread of electricity into the hippocampus. Since the LHb has previously been shown to be a powerful activator of the mesencephalic raphe nuclei we tested whether the effect was mediated via the serotonergic system. However, the effect of LHb stimulation on hippocampal NA release persisted after 5,7-dihydroxytryptamine treatment and after complete radiofrequency lesions of the dorsal and central superior raphe nuclei. The present data suggest that electrical stimulation of the LHb can increase hippocampal NA release through an activation of the locus coeruleus, and that this effect is not dependent on the mesencephalic raphe nuclei. The results support the role of the LHb as a link for limbic and striatal forebrain activation of brain stem monoaminergic systems.

Animals↗
PubMed1989

Grafts of fetal locus coeruleus neurons in rat amygdala-piriform cortex suppress seizure development in hippocampal kindling.

Hippocampal kindling was investigated in rats with a 6-hydroxydopamine-induced lesion of the forebrain catecholamine system after implantation of neural tissue from the fetal locus coeruleus region either bilaterally into the amygdala-piriform cortex (i.e., distant to the kindling site) or unilaterally into the hippocampus (close to the kindling site). Lesioned animals with either sham grafts or control grafts consisting of fetal striatal tissue showed a kindling rate much faster than that of normal controls. In contrast, in rats with bilateral locus coeruleus grafts in the amygdala-piriform cortex (implanted at three sites) the development of seizures was similar to that of controls and significantly slower than that in lesioned animals with sham grafts. All these animals had bilateral surviving grafts with a mean of 125 noradrenergic cells per implantation site. In the animals with locus coeruleus grafts in the stimulated hippocampus the kindling rate did not differ from that in the lesioned animals with control grafts. Most of these animals had large surviving grafts and showed a dense noradrenergic reinnervation of the implanted hippocampus. The present findings indicate that grafting of fetal pontine tissue (rich in noradrenergic neurons) to a site distant to the stimulation focus, but important for the generalization and spread of seizures, can retard the development of seizures in hippocampal kindling. Together with the data of our previous report this study also indicates that noradrenergic reinnervation of both hippocampi is important for the seizure-suppressant action in hippocampal kindling of locus coeruleus grafts implanted in the hippocampus.

Amygdala↗
PubMed1989

Noradrenaline and 5-hydroxytryptamine release in the hippocampus during seizures induced by hippocampal kindling stimulation: an in vivo microdialysis study.

The intracerebral microdialysis technique has been used to monitor extracellular levels of noradrenaline, 5-hydroxytryptamine and 5-hydroxyindoleacetic acid in the rat hippocampus in vivo in response to focal and generalized seizures induced by hippocampal kindling stimulation. In fully kindled animals a stimulus-induced generalized seizure gave rise to a three-fold increase of noradrenaline levels in the stimulated hippocampus as compared to baseline levels (15-min samples). The maximal increase of noradrenaline levels occurred within the first minutes after onset of seizure activity, as assessed in 2-min sample fractions with the noradrenaline uptake blocker desipramine added to the perfusion medium. After the peak increase, the noradrenaline levels tapered off, reaching baseline after 8-10 min. In 6-hydroxydopamine-treated animals, baseline noradrenaline levels were markedly reduced and there was no significant increase in noradrenaline release in response to a generalized seizure. These data support the hypothesis that the high extracellular levels of noradrenaline measured in seizures are of neuronal origin. There were no significant changes in extracellular 5-hydroxytryptamine or 5-hydroxyindoleacetic acid levels after a generalized seizure. In non-kindled animals the steady state noradrenaline levels during uptake blockade were two-three times higher than in the kindled rats. However, the peak noradrenaline levels measured in both hippocampi after the first two electrical kindling stimulations giving rise to focal epileptiform activity (afterdischarge) were similar to those observed in the kindled animals in response to generalized seizures. The increase of noradrenaline release in the non-kindled animals was significantly correlated to the duration of afterdischarge. In conclusion, the present study demonstrates the usefulness of the intracerebral dialysis technique for monitoring noradrenaline, 5-hydroxytryptamine and 5-hydroxyindoleacetic acid release during seizures. The results indicate that both focal and generalized hippocampal seizures evoked by electrical kindling stimulation lead to a marked increase of transmitter release from noradrenergic but not from serotonergic neurons in the hippocampus. The ability of the noradrenergic system to respond by increased transmitter release to epileptic seizures is thus retained also in the kindled state.

Animals↗
PubMed1989

Noradrenaline metabolism in neocortex and hippocampus following transient forebrain ischemia in rats: relation to development of selective neuronal necrosis.

Noradrenaline (NA) metabolism in the neocortex and hippocampus was examined in rats at 1, 24, and 48 h following 15 min of reversible forebrain ischemia. As assessed by the ratio of accumulated 3,4-dihydroxyphenylalanine (DOPA) to the tissue NA level after inhibition of DOPA decarboxylase, the NA turnover rates were markedly increased (120-148% above the control) at 1 h postischemia in both the neocortex and hippocampal formation (CA1 and CA3 plus dentate gyrus). The DOPA:NA ratio went back to control levels after longer postischemic survival times. The ratio between levels of the deaminated NA metabolite, 3,4-dihydroxyphenylethyleneglycol (DOPEG), and NA, which gives another measure of NA turnover rate, showed similar changes. In the neocortex and the CA3 plus dentate gyrus, the DOPEG:NA ratio was markedly increased (89-118%) 1 h after the ischemia, but this change had disappeared at 24 and 48 h. Thus, both the DOPA accumulation experiments and the NA and DOPEG measurements indicate that following transient forebrain ischemia, there is an increased NA turnover in the hippocampus and cortex only in the early recirculation period and not after longer postischemic survival times. The degree of neuronal necrosis in the CA1 region was examined light microscopically on celestine blue-acid fuchsin-stained sections at 24, 48, and 96 h following the ischemic insult. The neuronal damage in CA1 was sparse after 24 h of recovery, had increased markedly after 48 h, and was very pronounced at 96 h.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Transplantation strategies in the treatment of Parkinson's disease: experimental basis and clinical trials.

Neural grafting has over the last decade emerged as a possible tool for the substitution of damaged neurons in the central nervous system and for the promotion of symptomatic recovery after brain damage. Transplantation studies in the 6-hydroxydopamine lesion rat model of Parkinson's disease were initiated in the late seventies. The first studies were based on the neuronal replacement paradigm, using developing dopamine brain cells obtained from the substantia nigra region of embryonic cadavers. When implanted into the striatum such grafts were found to reinnervate part of the previously denervated striatum and restore dopamine turnover and release to near-normal levels. In both rats and monkeys the nigral grafts have been shown to normalize some, but not all, Parkinson-like symptoms in the dopamine deficient recipients. Grafting of adrenal medullary tissue was introduced in the early eighties as an alternative to the use of embryonic cadaver tissue. The adrenal medullary grafts have, however, so far shown poor long-term survival in both rats and monkeys, and consistent with this no sustained dopamine release have been observed in the brain of long-term grafted animals. Likewise, no long-lasting effects of adrenal medullary grafts on spontaneous motor or sensori-motor behavior have so far been documented in either the rat or the monkey model. The results so far reported from trials using adrenal medullary grafts in patients with Parkinson's disease appear to conform to the available animal experimental data at least in two important respects: significant long-term graft survival has not been possible to document, and any clear-cut functional effects consistent with sustained graft-induced dopamine release have not been demonstrated. Initial results from ongoing trials using grafts of fetal nigral tissue are presented and discussed.

Adrenal Medulla↗
PubMed1989

Repeated cranial computed tomographic and magnetic resonance imaging scans in two cases of eclampsia.

In two cases of eclampsia with consumptive thrombocytopenia, the maximum increase in blood pressure and the lowest platelet count coincided with the maximum degree of neurologic and neuroradiologic abnormality. Computed tomograms showed decreased attenuation, and T2-weighted magnetic resonance images showed increased signal intensity focally in the cerebral cortex and the deep gray and white matter. Blood pressure, platelet count, clinical status, and roentgenograms normalized completely in both cases. Severe arterial hypertension and disseminated transitory microvascular occlusions presumably caused multiple small foci of brain edema that resolved without remaining detectable ischemic brain damage.

Adult↗
PubMed1988

Basic characteristics of noradrenaline release in the hippocampus of intact and 6-hydroxydopamine-lesioned rats as studied by in vivo microdialysis.

Extracellular levels of noradrenaline (NA) were measured in the hippocampus of awake and halothane-anaesthetized rats, using intracerebral dialysis coupled to a highly sensitive radioenzymatic assay. In awake animals, steady state NA output after 1 h of perfusion was 69 +/- 21 fmol/30 microliter (15 min). Non-noxious sensory stimulation increased the steady state NA output by 35%, while halothane anaesthesia reduced the levels by 63-72%. During halothane anaesthesia KCl (100 mM) or desipramine (5 microM) added to the perfusion medium increased the NA levels 27-fold and 8-fold, respectively. Tetrodotoxin added in the presence of desipramine reduced the extracellular NA levels by 85%. In 6-OHDA lesioned animals the NA levels were below the limit of detection in virtually all samples (i.e. less than 3 fmol/30 microliter) at 10-16 days after lesion, but there was a partial recovery at longer postoperative time points. These results support the conclusion that the extracellular NA levels recovered in the dialysis perfusates are neuronally derived and can be used as an index of noradrenergic synaptic activity in the brain.

Anesthesia↗
PubMed1988

Facilitation of focal cobalt-induced epilepsy after lesions of the noradrenergic locus coeruleus system.

In this study we analyzed the electrophysiological and clinical effects of selective removal of the forebrain noradrenergic projection from the locus coeruleus, induced by bilateral injections of 6-hydroxydopamine into the dorsal tegmental bundle on focal cobalt-induced epilepsy. Noradrenaline depletion caused a marked potentiation of the epilepsy by increasing the duration and intensity of both the clinical and electrophysiological epileptic parameters: epileptic discharges and myoclonic jerks started earlier; spiking and clinical activity were facilitated; duration of the epileptic syndrome was prolonged. On the basis of the present and previous results it is proposed that the ascending noradrenergic system plays a modulatory role on the spread of paroxysmal activities and on the severity of cobalt-induced epilepsy.

Animals↗
PubMed1988

Human fetal dopamine neurons grafted in a rat model of Parkinson's disease: immunological aspects, spontaneous and drug-induced behaviour, and dopamine release.

We have used a rat model of Parkinson's disease (PD) to address issues of importance for a future clinical application of dopamine (DA) neuron grafting in patients with PD. Human mesencephalic DA neurons, obtained from 6.5-8 week old fetuses, were found to survive intracerebral cell suspension xenografting to the striatum of rats immunosuppressed with Cyclosporin A. The grafts produced an extensive new DA-containing terminal network in the previously denervated caudate-putamen, and they normalized amphetamine-induced, apomorphine-induced and spontaneous motor asymmetry in rats with unilateral lesions of the mesostriatal DA pathway. Grafts from an 11.5-week old donor exhibited a lower survival rate and smaller functional effects. As assessed with the intracerebral dialysis technique the grafted DA neurons were found to restore spontaneous DA release in the reinnervated host striatum to normal levels. The neurons responded with large increases in extracellular striatal DA levels after the intrastriatal administration of the DA-releasing agent d-amphetamine and the DA-reuptake blocker nomifensine, although not to the same extent as seen in striata with an intact mesostriatal DA system. DA fiber outgrowth from the grafts was dependent on the localization of the graft tissue. Thus, grafts located within the striatum gave rise to an extensive axonal network throughout the whole host striatum, whereas grafted DA neurons localized in the neocortex had their outgrowing fibers confined within the grafts themselves. In contrast to the good graft survival and behavioural effects obtained in immunosuppressed rats, there was no survival, or behavioural effects, of human DA neurons implanted in rats that did not receive immunosuppression. In addition, we found that all the graft recipients were immunized, having formed antibodies against antigens present on human T-cells. This supports the notion that the human neurons grafted to the non-immunosuppressed rats underwent immunological rejection. Based on an estimation of the survival rate and extent of fiber outgrowth from the grafted human fetal DA neurons, we suggest that DA neurons that can be obtained from one fetus may be sufficient to restore significant DA neurotransmission unilaterally, in one putamen, in an immunosuppressed PD patient.

Amphetamine↗
PubMed1988

Projections from the ventral tegmental area and mesencephalic raphe to the dorsal raphe nucleus in the rat. Evidence for a minor dopaminergic component.

The origins of the dopaminergic innervation of the rat dorsal raphe nucleus (NRD) have been investigated using a combination of fluorescent retrograde tracing and fluorescence histochemistry. Stereotaxic microinjections of True Blue were placed in the central, caudal and lateral portions of the NRD, and after 6-12 days survival the brains were processed for fluorescence histochemical detection of catecholamines. Retrogradely labeled neurons were searched for in the diencephalic A11 and A13 dopaminergic cell groups, substantia nigra, ventral tegmental area (VTA) and the linear, central superior and dorsal raphe nuclei. The various NRD injections consistently resulted in retrograde labeling of a small number of catecholamine-containing, presumed dopaminergic cell bodies, confined mainly to three regions: the VTA, the linear and central superior raphe nuclei and the NRD itself. The present findings indicate that not only dopaminergic neurons in the VTA but also the system of catecholamine-containing cells, extending dorsally and caudally from the VTA within the midline raphe area, project to the NRD. Although often similar in size, shape and distribution to the catecholaminergic neurons the majority of retrogradely labeled cells in these regions were, however, found to be non-catecholaminergic.

Animals↗
PubMed1988

Human fetal dopamine neurons grafted in a rat model of Parkinson's disease: ultrastructural evidence for synapse formation using tyrosine hydroxylase immunocytochemistry.

Human fetal mesencephalic dopamine (DA) neurons, obtained from 6.5-9 week old aborted fetuses, were grafted to the striatum of immunosuppressed rats with 6-hydroxydopamine lesions of the ascending mesostriatal DA pathway. The effects on amphetamine-induced motor asymmetry were studied at various timepoints after grafting. At eight weeks, functional graft effects were not evident but after 11 weeks small effects on motor asymmetry could be monitored and rats tested 19-21 weeks after grafting exhibited full reversal of the lesion-induced rotational behaviour. Four rats were sacrificed at different timepoints between 8 and 20 weeks and the grafted DA neurons were studied in tyrosine hydroxylase (TH) immunocytochemically stained sections at the light and electronmicroscopic level. The grafts contained a total of 500-700 TH-positive neurons in each rat. In one rat sacrificed 8 weeks after grafting the grafted neurons were TH-positive but exhibited virtually no fiber outgrowth. In another rat, sacrificed after 11 weeks, a sparse TH-positive fiber plexus was seen to extend into the adjacent host neostriatum. Two rats sacrificed after 20 weeks both contained TH-positive neurons that gave rise to a rich fiber network throughout the entire host neostriatum, and this fiber network was also seen to extend into the globus pallidus and nucleus accumbens. Very coarse TH-positive processes, identified as dendrites in the electron microscope, projected up to 1.5-2.0 mm from the graft into the host striatum. Ultrastructural analysis revealed that the grafted neurons had formed no TH-positive synaptic contacts with host striatal neurons after 8 weeks, and at 11 weeks some few TH-positive synapses were identified. Twenty weeks after transplantation, abundant TH-positive synaptic contacts with host neurons were seen throughout the neostriatum, and such contacts were identified in the globus pallidus as well. Thus, the present study provides tentative evidence for a time-link between the development of synaptic contacts and the appearance of functional graft effects. Similar to the normal mesostriatal DA pathway, ingrowing TH-positive axons formed symmetric synapses and were mainly seen to contact dendritic shafts and spines. However, in comparison to the normal rat striatum there was a higher incidence of TH-immunoreactive boutons forming synapses onto neuronal perikarya. The TH-positive dendrites that extended into the host striatum were seen to receive non-TH-immunoreactive synaptic contacts, presumably arising from the host neurons.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1988

Mechanisms of hypoglycemic brain damage. Evidence against a significant role of the noradrenergic locus coeruleus system.

Selective lesions of the noradrenergic locus coeruleus (LC) system have recently been shown to aggravate both ischemic and epileptic brain damage. This study explores the possibility that the LC system also influences hypoglycemic brain injury. Bilateral 6-hydroxydopamine lesions of the LC projection to the forebrain were found to cause no change in the degree of neuronal necrosis in the neocortex, hippocampal formation and caudate-putamen following 30 min of reversible insulin-induced hypoglycemic coma. We propose that selective neuronal necrosis in ischemia and status epilepticus is due to the action of excitatory amino acids at synaptic sites, which can be partly counteracted by noradrenaline release from inhibitory LC terminals. In hypoglycemia, excitatory amino acids probably cause brain damage via a local and more diffuse toxic effect which is not significantly influenced by the activation of the LC system.

Animals↗
PubMed1988

Studies on dopamine-, tyrosine hydroxylase- and aromatic L-amino acid decarboxylase-containing cells in the rat diencephalon: comparison between formaldehyde-induced histofluorescence and immunofluorescence.

The morphology, number and distribution of catecholaminergic neurons, as visualized either with the aluminum-catalysed formaldehyde method for catecholamines or with the immunohistochemical method for the catecholamine-synthesizing enzymes tyrosine hydroxylase and aromatic L-amino acid decarboxylase, respectively, were analysed within the rat dorsal hypothalamus, ventral thalamus and adjoining regions (A11 and A13 cell groups). Both polyclonal rabbit and monoclonal mouse tyrosine hydroxylase antibodies were used in elution-restaining and double-staining experiments, respectively. Some of the animals also received spinal injections of the fluorescent tracer True Blue in order to retrogradely label cells projecting to the spinal cord. With respect to the number and distribution of catecholaminergic neurons in the A11 and medial A13 cell groups, including the spinal-projecting subpopulation, the results obtained with the two methods were very similar, indicating that within these regions of the CNS the two methods in principle visualize identical cell populations. However, the catecholaminergic cells were distinctly larger and their processes appeared more extensive with the immunohistochemical method. Animals processed for immunohistochemistry exhibited a lower total number of retrogradely labelled cells in the A11 area than those analysed with aldehyde-induced fluorescence despite the fact that both methods revealed similar numbers of retrogradely labelled tyrosine hydroxylase-positive and catecholamine-containing cells, respectively. The reason for these discrepancies, which are probably of methodological nature, are discussed. While this study shows that the results obtained with the two methods within the A11 and medial A13 cell group are very similar and thus strengthens the earlier proposed concept of the organization of the diencephalospinal dopaminergic system, it also documents that in intermingling and nearby CNS regions there are cell bodies which cannot be demonstrated with the aldehyde fluorescence method, but which still contain tyrosine hydroxylase and/or aromatic L-amino acid decarboxylase-like immunoreactivity. One explanation is low levels of enzyme and/or dopamine combined with a comparatively low sensitivity of the histochemical method. Thus, neurons containing both enzymes are probably dopaminergic, even if catecholamine fluorescence cannot be demonstrated. Neurons containing tyrosine hydroxylase, but lacking both aldehyde induced fluorescence and aromatic L-amino acid decarboxylase, may also still be dopaminergic.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗