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PubMed1998

Hypothalamic activation in cluster headache attacks.

BACKGROUND: Cluster headache, one of the most severe pain syndromes in human beings, is usually described as a vascular headache. However, the striking circadian rhythmicity of this strictly half-sided pain syndrome cannot be readily explained by the vascular hypothesis. We aimed to assess changes in regional cerebral blood flow (rCBF) in patients with cluster headache. METHODS: We used positron emission tomography (PET) to assess the changes in rCBF, as an index of synaptic activity, during nitroglycerin-induced cluster headache attacks in nine patients who had chronic cluster headache. Eight patients who had cluster headache but were not in the bout acted as a control group. FINDINGS: In the acute pain state, activation was seen in the ipsilateral inferior hypothalamic grey matter, the contralateral ventroposterior thalamus, the anterior cingulate cortex, and bilaterally in the insulae. Activation in the hypothalamus was seen solely in the pain state and was not seen in patients who have cluster headache but were out of the bout. INTERPRETATION: Our findings establish central nervous system dysfunction in the region of the hypothalamus as the primum movens in the pathophysiology of cluster headache. We suggest that a radical reappraisal of this type of headache is needed and that it should in general terms, be regarded as a neurovascular headache, to give equal weight to the pathological and physiological mechanisms that are at work.

Adult↗

PubMed1986

Behavioral deficits induced by low doses of apomorphine in rats: evidence for a motivational and cognitive dysfunction which discriminates among neuroleptic drugs.

In order to further assess the alterations (motor, motivational or cognitive) that might underlie animal behavioral deficits associated with a reduced dopamine transmission, the effects of apomorphine at doses thought to stimulate dopaminergic autoreceptors were studied on rat operant behavior. Apomorphine (30 micrograms/kg SC) decreased the number of food rewards obtained, when rats trained on a continuous reinforced schedule were shifted to schedules of fixed ratio higher than 2:FR3, FR4, and FR8. In rats shifted to a FR4 schedule, apomorphine (7.5, 15, 30, 60 micrograms/kg SC) dose-relatedly reduced the number of rewards obtained. In rats subjected to previous extinction sessions, apomorphine (30 micrograms/kg) did not affect lever pressing reinstated on presentation of primary reinforcers but inhibited responding renewed on presentation of secondary reinforcers. Under a FR(3 + 1) schedule where the last (rewarded) response was distinct from the initial (non-rewarded) responses, the detrimental effect of apomorphine on response rates was considerably weaker than under a conventional FR4 schedule. The reward deficits caused by apomorphine under the FR4 schedule were dose-dependently and completely reversed by amisulpride (0.125, 0.25, 0.5, 1 and 2 mg/kg), pimozide (0.125 mg/kg), sulpiride (8, 16, 32 and 64 mg/kg), but not by conventional neuroleptics (namely chlorpromazine, fluphenazine, haloperidol, metoclopramide and thioridazine). It is suggested that behavioral deficits associated with a reduced dopamine transmission such as that caused by low doses of apomorphine involve motivational and cognitive dysfunctions rather than motor impairments. In account of its differential sensitivity to neuroleptic drugs, apomorphine-induced deficit might have some relevance for a further delineation of the mechanisms of action of these compounds.

Animals↗

PubMed1992

Effects of aging on signal transmission and transduction systems in the gerbil brain: morphological and autoradiographic study.

The Mongolian gerbil was used as a model of aging because of its relatively short lifespan, genetic homogeneity and the fact that data had been collected previously. Furthermore, gerbils have been widely used in biomedical investigations of stroke and epilepsy. Age-related differences in signal transmission and transduction systems were investigated in brains of three-, 11- and 21-month-old gerbils by morphological and in vitro receptor autoradiographic studies. Morphometric analysis revealed a decreased number of neurons in layer III of the occipital cortex and also a decrease in cerebellar Purkinje cells in 21-month-old animals. However, no statistical differences were observed in the hippocampal formation, the dorsolateral striatum and layer III of the frontal cortex. Autoradiography was used to map muscarinic cholinergic (labeled with [3H]quinuclidinyl benzilate), serotonin2 ([3H]spiperone), dopamine D2 ([3H]spiperone), adenosine A1 ([3H]cyclohexyladenosine), GABAA ([3H]muscimol), naloxone ([3H]naloxone), protein kinase C ([3H]phorbol 12,13-dibutyrate), adenylate cyclase ([3H]forskolin), cyclic AMP ([3H]cyclic AMP) and L-type Ca2+ channels ([3H]PN200-110). Muscarinic cholinergic receptor and protein kinase C, cyclic AMP and L-type Ca2+ channels were significantly decreased in the cerebral cortex and/or in the CA1 subfield of the hippocampus in the 21-month-old group. Muscarinic cholinergic receptor and L-type Ca2+ channel binding sites were significantly reduced in the dentate gyrus. In contrast, protein kinase C was increased in this area in the 21-month-old group. Also, naloxone binding sites were increased in the CA3 subfield, hilus, dentate gyrus and molecular layer of the cerebellum in the 11- and 21-month-old groups. Muscarinic cholinergic, serotonin2 and dopamine D2 receptors and adenylate cyclase were significantly decreased in the striatum. On the other hand, adenosine A1 and GABAA receptors remained unchanged in the 21-month-old group. Although age-related histopathological abnormalities were only observed in the occipital cortex and in the cerebellum, alterations of signal transmission and transduction systems were noticed in all areas examined (e.g. cerebral cortex, CA1 subfield, dentate gyrus and striatum). These data indicate that changes in these receptors and binding sites may be related to dysfunction of learning and memory and to the loss of motor function. The aged gerbil model is a good system for studying aging and is of value for simulating aging after epilepsy and stroke.

Aging↗

PubMed2001

Phosphodiesterase 5 inhibitors and nitrergic transmission-from zaprinast to sildenafil.

Phosphodiesterase 5 terminates the cellular actions of the second messenger molecule cyclic GMP; inhibitors of phosphodiesterase 5 will therefore increase and prolong the actions of endogenous substances that signal via the cyclic GMP pathway, including nitric oxide released as a neurotransmitter from nitrergic nerves. To date, the most widely used phosphodiesterase 5 inhibitors, zaprinast and sildenafil, have proved vital in the elucidation of the widespread role of cyclic GMP in nitrergic transmission and, specifically in the case of sildenafil, have provided a major breakthrough in the treatment of erectile dysfunction in men. Although still a matter of debate, early evidence indicates that sildenafil may also be of benefit in some forms of sexual dysfunction in women. The remarkable clinical success of sildenafil has prompted the search for further novel phosphodiesterase 5 inhibitors which might be used to enhance nitrergic function in other disease states.

3',5'-Cyclic-AMP Phosphodiesterases↗

PubMed1998

Effects of NMDA antagonism on striatal dopamine release in healthy subjects: application of a novel PET approach.

Agents that antagonize the glutamatergic N-methyl-d-aspartate (NMDA) receptor, such as phenylcyclidine (PCP) and ketamine, produce a behavioral state in healthy volunteers that resembles some aspects of schizophrenia. A dysfunction in NMDA-dopaminergic interactions has been proposed as a mechanism for these behavioral effects. In this study, we examined the effects of ketamine on striatal dopamine release in healthy human subjects with a novel 11C-raclopride/PET displacement paradigm and compared these effects to administration of saline and the direct-acting dopamine agonist amphetamine. We found that the percent decreases (mean +/- SD) in specific 11C-raclopride binding from baseline for ketamine (11.2 +/- 8.9) was greater than for saline (1.9 +/- 3.7) (t = 2.4, df = 13, P = 0.003) indicating that ketamine caused increases in striatal synaptic dopamine concentrations. Ketamine-related binding changes were not significantly different than the decreases in percent change (mean +/- SD) in specific 11C-raclopride binding caused by amphetamine (15.5 +/- 6.2) (t = 1.3, df = 19, P = 0.21). Ketamine-induced changes in 11C-raclopride-specific binding were significantly correlated with induction of schizophrenia-like symptoms. The implications of this brain imaging method for studies of schizophrenia and the mechanism of action of antipsychotic drugs are discussed.

Adult↗

PubMed1986

GABA-agonist therapy for Alzheimer's disease.

Evidence suggesting a reduction of cerebral gamma-aminobutyric acid (GABA) neurons in Alzheimer's disease has been reported. To evaluate the possible contribution of GABA system dysfunction to the intellectual decline associated with this disorder, a controlled therapeutic trial of a potent and specific GABA agonist, THIP [4,5,6,7-tetrahydroisoxazolo(5,4,-c)pyridin-3-ol], was undertaken. Six Alzheimer patients with mild to moderately severe dementia and low spinal-fluid GABA levels received THIP at maximum individually tolerated dosage. No significant change in cognitive function could be discerned, despite attainment of dose levels that produced centrally mediated adverse effects similar to those of other GABA agonists. The results support the views that pharmacologic attempts to stimulate central GABA-mediated synaptic function may not confer therapeutic benefit to patients with Alzheimer's disease and that a GABA system deficit may not serve as a critical determinant of the dementia that characterizes this disorder.

Alzheimer Disease↗

PubMed1992

Long-term neuromuscular dysfunction produced by passive transfer of amyotrophic lateral sclerosis immunoglobulins.

We investigated the role of the immune system in the pathogenesis of amyotrophic lateral sclerosis (ALS) by studying the long-term consequences of ALS immunoglobulin (Ig) application on the levator auris muscle of the mouse. We applied Ig from seven ALS patients, four disease controls, and a pool of normal Ig (6 mg of Ig in 2 weeks) by subcutaneous injection; removed the muscles 4 to 12 weeks after the beginning of treatment; and recorded both spontaneous and evoked release of transmitter. None of the control Ig induced changes in transmitter, whereas five of seven ALS Ig induced a significant increase in the rate of spontaneous release, and all ALS Ig produced significant changes in the quantal content of evoked release. In muscles treated with one of the ALS Igs, synaptic activity was completely absent. Cholinesterase and silver staining demonstrated intact neuromuscular junctions in the control Ig-treated muscles and also in many areas of ALS Ig-treated muscles. Axonal degeneration and denervation were present in most muscles treated with ALS Ig. There was complete denervation when no synaptic activity could be recorded. Thus, ALS Ig appears to lead to long-lasting effects at the neuromuscular junction, and such effects may be an early stage in the immune-mediated pathogenesis of ALS.

Adult↗

PubMed2005

Alterations in N-methyl-D-aspartate receptor sensitivity and magnesium blockade occur early in development in the R6/2 mouse model of Huntington's disease.

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder that affects primarily the striatum and cerebral cortex. A search for the factors that increase the vulnerability of striatal neurons will lead to a better understanding of the pathological cascades of this disease. A current hypothesis for neurodegeneration of striatal medium-sized spiny neurons in HD is an alteration in N-methyl-D-aspartate (NMDA) receptor function. In the present study we examined electrophysiological properties of NMDA receptors in the R6/2 transgenic mouse model. These animals express exon 1 of the human HD gene and present an overt behavioral phenotype at about 5 weeks of age. Whole-cell voltage clamp recordings from acutely dissociated striatal neurons were obtained from three different age groups of transgenic mice (15, 21, and 40 days old) and their littermate controls (WT). In transgenic animals, two groups of neurons were found with respect to NMDA and Mg2+ sensitivity. One group of R6/2 cells displayed responses similar to those of WT, whereas the other showed increased responses to NMDA and decreased Mg2+ sensitivity. These cells were encountered in all age groups. The abnormal sensitivity to NMDA and Mg2+ indicates that NMDA receptor alterations occur very early in development and suggest the presence of constitutively abnormal NMDA receptors. These alterations may contribute to an enhancement of NMDA responses at hyperpolarized membrane potentials that may be a key factor in striatal neuronal dysfunction.

Animals↗

PubMed1988

Loss of neurons in the rat basal forebrain cholinergic projection system after prolonged intake of ethanol.

A reduction in the number of acetylcholinesterase (AChE)-positive neurons in the basal nucleus of Meynert complex (NbM, Ch 1 to Ch4) to 83% of control values was observed in rat after ethanol intake (20% v/v) for 12 weeks. Activity of choline acetyltransferase (ChAT) and AChE in the basal forebrain was simultaneously reduced to 74% and 81% and content of acetylcholine (ACh) to 56% of control values respectively. Neuronal loss showed a gradient over the rostro-caudal extension of the cholinergic projection system being most pronounced in the septal-diagonal band area and reaching 27% in the medial septum (Ch1). Number of AChE-positive neurons was insignificantly reduced in the pedunculopontine nucleus (Ch5) and unchanged in the laterodorsal tegmental gray of the periventricular area (Ch6). ACh content and activity of AChE was significantly reduced in target areas of the NbM such as cortex, hippocampus and amygdala, but changes were less pronounced than in the basal nucleus. The results indicate a neurotoxic effect of prolonged intake of ethanol on cholinergic neurons in the NbM leading to a partial cholinergic denervation of cortex, hippocampus and amygdala. Chronic intake of ethanol in rat is suggested to represent an animal model suitable to test the cholinergic hypothesis of geriatric memory dysfunction and to develop strategies for an amelioration of the impairment in memory and cognitive function in dementing disorders associated with a degeneration in the NbM such as postalcoholic dementia and Alzheimer's disease.

Acetylcholinesterase↗

PubMed2002

Flash visual evoked potentials in the hypomyelinated mutant mouse shiverer.

Myelin basic protein (MBP) is an essential component of central nervous system (CNS) myelin, as demonstrated by shiverer mutant mice that have deletions of most of the Mbp structural gene. These mutants do not produce detectable MBP protein, and their CNS is hypomyelinated. Although the function of the visual pathway is presumed to be adversely affected by hypomyelination of the optic nerve, it has never been studied. We compared flash visual evoked potentials (FVEPs) of shiverer homozygotes with those of their wild-type littermates in order to characterize any dysfunction. There was a statistically significant delay in the implicit times of a negative component peaking at 85 ms and a large positive component peaking at 170 ms in the FVEPs of the shiverer mice. The amplitudes of the two components did not differ significantly in the shiverers and wild-type controls. Barring a retinal pathology, which cannot be excluded by these data, the delayed FVEP of the shiverer can likely be attributed to effects of hypomyelination of the optic nerve, optic tract and visual radiations on conduction time in the visual pathway and subsequent further post-synaptic delays.

Animals↗

PubMed2005

Early impairment in dopaminergic neurotransmission in brains of SIV-infected rhesus monkeys due to microglia activation.

Movement disorders are a common neurological complication of immunodeficiency virus infection and are thought to result from dopaminergic dysfunction in the basal ganglia. We measured levels of dopamine, and its metabolites homovanillic acid and 3,4-dihydroxyphenylacetic acid, in the putamen of healthy and simian immunodeficiency virus (SIV)-infected rhesus monkeys from infection until the development of AIDS. Changes in expression levels of cAMP response element binding protein (CREB), a transcription factor involved in the signalling pathway of dopamine, were also examined. Furthermore, we isolated microglia from the same animals and investigated their activation status in order to explore whether neurochemical findings are associated with immune activation. Plasma and CSF viral RNA load, T-cell analysis and basal ganglia histopathology provided information about disease progression in the animals. Putamen dopamine content was significantly reduced within 3 months of SIV infection, due to decreased dopamine synthesis initially, followed by loss of tyrosine hydroxylase-positive cells in substantia nigra, and accompanied by a decrease in total CREB expression. Pharmacological manipulation of dopaminergic tone with L-DOPA and selegiline showed that the reduction in CREB expression was due to reduced levels of dopamine. These neurochemical changes were significantly correlated with microglia activation in the absence of gross histopathological lesions. Our data demonstrate that putamen dopaminergic function is impaired during SIV infection and indicate that microglia may trigger endogenous mechanisms involved in the dysfunction of dopaminergic systems.

Animals↗

PubMed1996

Etiology and pathogenesis of attention-deficit hyperactivity disorder (ADHD): significance of prematurity and perinatal hypoxic-haemodynamic encephalopathy.

Attention-deficit Hyperactivity Disorder (ADHD), defined as a disorder of awareness with impulsivity, has lately been characterized as a dysfunction of the striatum (neostriatum = globus pallidus + putamen). This structure is in a unique position of contextual analysis and samples information samples information from almost the entire cortex through its spiny neurons. The etiology is heterogeneous, with genetic as well as lesional factors. Among the latter, pre- and perinatal events are prominent. Advances in the understanding of the role of fetal circulatory insufficiency with loss of autoregulation and systemic hypotension have drawn attention to the vulnerability of watershed regions, including the striatum. Not only circulatory facts are important for this selectivity, however. The anatomical characteristics, with convergent glutaminergic afferent synaptic transmission from almost the entire cortex contribute to the vulnerability in ischemia-induced liberation of glutamate: The striatum becomes the victim of its virtue. Repeated hypoxic-ischemic events are particularly common in prematurity, a fact which seems to explain the high incidence of ADHD in this patient group. The magnitude, of the problem is increasing with the increased survival rate among premature infants.

Animals↗

PubMed2000

Influence of acute cerebellar lesions on somatosensory evoked potentials (SEPs) in cats.

We studied the effect of acute unilateral cerebellar lesions on the cerebello-thalamo-cortical projection in cats. The lesions were classified into two groups according to their extent. In group I the lesion only covered the cerebellar cortex, while in group II both the cerebellar cortex and deep cerebellar nuclei were removed. Early (short-latency) and late (long-latency) waves, evoked by an electrical stimulation of a forelimb, were collected contralateral to the stimulated leg hemisphere. Pre- and postsurgery recordings from primary and non-primary (motor and parietal) cortices were compared. Cerebellar impairment had a strong influence on discharges of all the considered cortical areas. Early non-primary and primary responses increased in group I and remained unchanged in group II. Late somatosensory evoked potentials components were suppressed in both groups. An inhibitory influence of the cerebellar cortex on the thalamo-cortical projection was confirmed. Changes within the primary sensory cortex may suggest an engagement of that area in the compensation process of cerebellar dysfunction shortly after cerebellar lesion. An alteration in the unaffected hemisphere activation indicate that the spino-cerebellar and cerebello-cortical inputs, responsible for somatosensory evoked potentials generation, are regulated through contralateral and ipsilateral pathways. These pathways are unmasked by cerebellar lesion.

Acute Disease↗

PubMed2004

Glutamate-mediated excitotoxicity and neurodegeneration in Alzheimer's disease.

Alzheimer's disease (AD) is the most common form of dementia, accounting for 60-70% of cases in subjects over 65 years of age. Several postulates have been put forward that relate AD neuropathology to intellectual and functional impairment. These range from free-radical-induced damage, through cholinergic dysfunction, to beta-amyloid-induced toxicity. However, therapeutic strategies aimed at improving the cognitive symptoms of patients via choline supplementation, cholinergic stimulation or beta-amyloid vaccination, have largely failed. A growing body of evidence suggests that perturbations in systems using the excitatory amino acid L-glutamate (L-Glu) may underlie the pathogenic mechanisms of (e.g.) hypoxia-ischemia, epilepsy, and chronic neurodegenerative disorders such as Huntington's disease and AD. Almost all neurons in the CNS carry the N-methyl-D-aspartate (NMDA) subtype of ionotropic L-glutamate receptors, which can mediate post-synaptic Ca2+ influx. Excitotoxicity resulting from excessive activation of NMDA receptors may enhance the localized vulnerability of neurons in a manner consistent with AD neuropathology, as a consequence of an altered regional distribution of NMDA receptor subtypes. This review discusses mechanisms for the involvement of the NMDA receptor complex and its interaction with polyamines in the pathogenesis of AD. NMDA receptor antagonists have potential for the therapeutic amelioration of AD.

Alzheimer Disease↗

PubMed2002

The role of mitochondria in epileptogenesis.

Mitochondrial dysfunction has gained considerable interest as a potential cause of epileptic seizures and therapy-resistant forms of severe epilepsy. Impairment of mitochondrial function has recently been observed in the seizure focus of human and experimental epilepsy. Additionally, a broad variety of mutation of mitochondrial DNA leading to the inhibition of mitochondrial respiratory chain or directly of mitochondrial adenosine triphosphate synthesis in epileptogenic areas of the human brain has been associated with epileptic phenotypes. Since mitochondrial oxidative phosphorylation provides the major source of adenosine triphosphate in neurons, and mitochondria participate in cellular Ca2+ homeostasis they can modulate neuronal excitability and synaptic transmission. Furthermore, mitochondria are intimately involved in pathways leading to the neuronal cell death characteristic for the areas of epileptogenesis.

Brain↗

PubMed1995

Ischaemia-induced long-term hyperexcitability in rat neocortex.

The long-term structural and functional consequences of transient forebrain ischaemia were studied with morphological, immunohistochemical and in vitro electrophysiological techniques in the primary somatosensory cortex of Wistar rats. After survival times of 10-17 months postischaemia, neocortical slices obtained from ischaemic animals were characterized by a pronounced neuronal hyperexcitability in comparison with untreated age-matched controls. Extra- and intracellular recordings in supragranular layers revealed all-or-none long-latency recurrent responses to orthodromic synaptic stimulation of the afferent pathway. These responses were characterized by durations up to 1.7 s, by multiple components and by repetitive synaptic burst discharges. The reversible blockade of this late activity by DL-amino-phosphonovaleric acid (APV) suggested that this activity was mediated by N-methyl-D-aspartate (NMDA) receptors. The peak conductance of inhibitory postsynaptic potentials was significantly smaller in neurons recorded in neocortical slices obtained from ischaemic animals than those from the controls. However, the average number of parvalbumin (PV)-labelled neurons per mm3, indicative of a subpopulation of GABAergic interneurons, and the average number and length of dendritic processes arising from PV-containing cells was not significantly different between ischaemic and control cortex. The prominent dysfunction of the inhibitory system in ischaemic animals occurred without obvious structural alterations in PV-labelled cells, indicating that this subpopulation of GABAergic interneurons is not principally affected by ischaemia. Our data suggest a long-term down-regulation of inhibitory function and a concurrent NMDA receptor-mediated hyperexcitability in ischaemic neocortex. These alterations may result from structural and/or functional properties of inhibitory non-PV-positive neurons or permanent functional modifications on the subcellular molecular level, i.e. alterations in the phosphorylation status of GABA and/or NMDA receptors. The net result of these long-term changes is an imbalance between the excitatory and inhibitory systems in the ischaemic cortex with the subsequent expression and manifestation of intracortical hyperexcitability.

Animals↗

PubMed2001

Gap junction-mediated bidirectional signaling between human fetal hippocampal neurons and astrocytes.

Gap junctions are clusters of intercellular channels that connect the interiors of coupled cells. In the brain, gap junctions function as electrotonic synapses between neurons and as pathways for the exchange of metabolites and second-messenger molecules between glial cells. Astrocytes, the most abundant glial cell type coupled by gap junctions, are intimately involved in the active control of neuronal activity including synaptic transmission and plasticity. Previous studies have suggested that astrocytic-neuronal signaling may involve gap junction-mediated intercellular connections; this issue remains unresolved. In this study, we demonstrate that second-trimester human fetal hippocampal neurons and astrocytes in culture are coupled by gap junctions bidirectionally; we show that human fetal neurons and astrocytes express both the same and different connexin subtypes. The formation of functional homotypic and heterotypic gap junction channels between neurons and astrocytes may add versatility to the signaling between these cell types during human hippocampal ontogeny; disruption of such signaling may contribute to CNS dysfunction during pregnancy.

Astrocytes↗

PubMed2002

Calcium regulation in photoreceptors.

In this review we describe some of the remarkable and intricate mechanisms through which the calcium ion (Ca2+) contributes to detection, transduction and synaptic transfer of light stimuli in rod and cone photoreceptors. The function of Ca2+ is highly compartmentalized. In the outer segment, Ca2+ controls photoreceptor light adaptation by independently adjusting the gain of phototransduction at several stages in the transduction chain. In the inner segment and synaptic terminal, Ca2+ regulates cells' metabolism, glutamate release, cytoskeletal dynamics, gene expression and cell death. We discuss the mechanisms of Ca2+ entry, buffering, sequestration, release from internal stores and Ca2+ extrusion from both outer and inner segments, showing that these two compartments have little in common with respect to Ca2+ homeostasis. We also investigate the various roles played by Ca2+ as an integrator of intracellular signaling pathways, and emphasize the central role played by Ca2+ as a second messenger in neuromodulation of photoreceptor signaling by extracellular ligands such as dopamine, adenosine and somatostatin. Finally, we review the intimate link between dysfunction in photoreceptor Ca2+ homeostasis and pathologies leading to retinal dysfunction and blindness.

Adaptation, Physiological↗