Neuroreport

Published by Lippincott, Williams & Wilkins
Online ISSN: 0959-4965
Publications
Article
DC-magnetoencephalography (DC-MEG) technique has been refined and allows to record cortical activity in the infraslow frequency range less than 0.1 Hz noninvasively. Important questions however, remained, especially, how specific these infraslow activations can be recorded and whether different activations, for example, motor versus acoustic, can be separated. To clarify these questions, in the present DC-MEG study, cortical infraslow activity was investigated intraindividually in response to different activation modalities, that is, motor versus acoustic: in 13 individuals, 30-s periods of finger movement or listening to concert music, were interleaved for 60 min. DC-MEG was capable to resolve intermodal differences concerning the relative amplitudes, field patterns, and source localizations. These results clarify that DC-MEG allows to identify and to discriminate modality-specific infraslow cortical neuronal signals.
 
Article
The auditory processing of physical stimulus features can be measured by the mismatch negativity. Past studies have shown that higher-order stimulus features also elicit a mismatch negativity. In some studies, a second component, termed late mismatch negativity, has been observed; yet the functional significance of this component remains unclear. We tested two-tone-pattern stimuli following an abstract rule in healthy adults. As expected, the tone pattern elicited a significant mismatch negativity peaking at 146 ms but a significant late mismatch negativity at around 340 ms was also observed. These findings show that the violation of an abstract rule elicits an early and late mismatch negativity. The late mismatch negativity might be triggered on the basis of auditory rule extraction processes and reflect a transfer of rules to the long-term memory.
 
Article
The large-conductance Ca(2+)-dependent K+ channels or BK channels in cerebellar granule cells were studied by patch-clamp technique, and the effects on channel activity of the molecule NS 004 (1-(2-hydroxy-5-chlorophenyl)-5-trifluoromethyl-2- benzimidazolone) were investigated. The channels had a unit conductance of 187 pS, were blocked by charybdotoxin and activated by internal Ca2+. NS 004 (10-30 microM) significantly increased the single channel opening frequency as well as the mean open time. In whole-cell recordings the compound shifted the BK current-voltage relationship by up to 40 mV towards negative membrane potentials. NS 004 is an efficient BK channel opener, which may represent a novel approach to relaxation of neuronal cells expressing this type of K+ channel.
 
Article
Pain is the most common symptom reported in both the general population and the general medical setting. The aim of this study is to evaluate the effectiveness, tolerance, and safety of venlafaxine extended-release (XR) monotherapy in treating first-episode outpatients fulfilling the Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV) criteria for major depressive disorder with associated painful physical symptoms. Of the 102 outpatients enrolled, 86 (84.3%) completed the study. Venlafaxine XR treatment (75-225 mg/day) was followed by a significant decrease in the total scores for the 17-item Hamilton Depression Rating Scale from baseline to the second weekend (t value=16.12, P<0.0001) and at every subsequent visit (weeks 4, 6, and 8, all P<0.0001). Significant differences were also found in the mean Visual Analog Scales for overall pain and the mean medical outcomes study pain measures from baseline to the second weekend (t value=14.99, P<0.0001; t value=12.59, P<0.0001) and at every visit (all P<0.0001). At the end of the eighth week, venlafaxine XR achieved response and remission rates of 68.6 and 40.2%, respectively. The remission rate for pain responders (improvement in Visual Analog Scale overall pain from baseline to last observation ≥50%) was significantly greater than that for pain nonresponders (56.1 vs. 20.0%, P<0.0001). The most common (≥10%) adverse events were nausea (31.4%), dizziness (26.5%), and somnolence (22.5%). Venlafaxine XR is possibly an effective and safe option in the treatment of depression and associated painful physical symptoms.
 
Article
T-type voltage-dependent calcium channels may play an important role in synaptic plasticity, but lack of specific antagonists has hampered investigation into this possible function. We investigated the role of the T-type channel in a canonical model of in-vivo cortical plasticity triggered by monocular deprivation. We identified a compound (TTA-I1) with subnanomolar potency in standard voltage clamp assays and high selectivity for the T-type channel. When infused intracortically, TTA-I1 reduced cortical plasticity triggered by monocular deprivation while preserving normal visual response properties. These results show that the T-type calcium channel plays a central role in cortical plasticity.
 
Article
Using K+ phosphate buffer with 25 nM spiperone, [3H]YM-09151-2 binding showed a high affinity for sigma receptors but no affinity for D2 dopamine or 5-HT1A receptors in rat brain. The order of pKi values of various sigma compounds at [3H]YM-09151-2 binding sites and stereoisomer selectivity were consistent with previous studies using other sigma ligands such as (+)-[3H]SKF-10047, [3H]DTG and (+)-[3H]3-PPP. Although Scatchard analysis fitted a one-site model, competition between [3H]YM-09151-2 and (+)-pentazocine revealed two sites, sigma 1 and sigma 2 receptors, at which the Ki values of YM-09151-2 were 8.4 nM and 9.6nM, respectively. Autoradiography using [3H]YM-09151-2 also showed a characteristic distribution of sigma receptors in rat brain. [3H]YM-09151-2 is, therefore, a potent and useful radioligand for sigma 1/sigma 2 receptor subtypes.
 
Article
Defects in complex I and alpha-ketoglutarate dehydrogenase (alpha-KGDH) occur in the substantia nigra in Parkinson's disease (PD). Isoquinoline derivatives structurally related to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or 1-methyl-4-phenylpyridinium (MPP+) are implicated in the cause of PD as endogenous toxins and are inhibitors of complex I. However, their effects on alpha-KGDH and other mitochondrial non-respiratory chain enzymes are unknown. We have examined the effects of six isoquinoline derivatives (isoquinoline, N-methylisoquinolinium, N-n-propylisoquinolinium, 1,2,3,4-tetrahydroisoquinoline, N-methyl-1,2,3,4-tetrahydroisoquinoline and salsolinol) and MPP+ on the activities of alpha-KGDH, citrate synthase (CS) and glutamate dehydrogenase (GDH) in mitochondrial fragments from rat forebrain. None of the compounds examined had any effect on CS or GDH activity. In contrast, all isoquinoline derivatives investigated and MPP+ inhibited alpha-KGDH activity in a concentration-dependent manner with IC50s ranging from 2.0 to 18.9 mM. MPP+ was previously shown to inhibit alpha-KGDH, but this is the first report of inhibition of alpha-KGDH by isoquinoline derivatives. These findings may represent an additional mechanism contributing to mitochondrial dysfunction and cell death in Parkinson's disease.
 
Article
The possible neuroprotective role of a novel and highly selective cyclooxygenase-2 inhibitor GW637185X was studied in a model of acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced injury of nigrostriatal dopaminergic (DA) neurons in the mouse. Stereological and microdensitometrical analysis of nigral tyrosine hydroxylase-immunoreactive cell bodies and striatal tyrosine hydroxylase-immunoreactive terminals, respectively, showed that GW637185X exerted a full protection against MPTP-induced degeneration of the nigro-striatal pathway. In contrast to earlier studies, these findings demonstrate that acute inhibition of cyclooxygenase-2 can result in a full neuroprotective effect not only on nigral DA cell bodies, but also on striatal DA terminals in the mouse MPTP model.
 
Article
Glial cell line-derived neurotrophic factor (GDNF) has significant therapeutic potentials, in particular for neurodegenerative disorders. To determine factors that would enhance GDNF expression, we analysed the effect of 1,25-(OH)2 D3 in C6 glioma cells. Treatment of C6 cells with 10(-7) M, 1,25-(OH)2 D3 for 48 h elicited an 18.5-fold increase in the level of GDNF mRNA. In addition, our results indicate that 1,25-(OH)2 D3 is effective at concentrations as low as 10(-10) M and that retinoic acid has additive effects. These data indicate that 1,25-(OH)2 D3 is a potent inducer of GDNF expression and suggest that 1,25-(OH)2 D3 may contribute to the regulation of GDNF in vivo.
 
Article
The effect of 1,25-dihydroxyvitamin D3 on neurotrophin mRNA expression was studied in primary cultures of astrocytes. In addition to its known effects on NGF expression, 1,25-dihydroxyvitamin D3 was shown to upregulate NT-3 mRNA levels, while NT-4 expression was slightly but significantly downregulated. No effect was observed on BDNF mRNA expression. These data clearly show a differential regulation of the four neurotrophins by 1,25-dihydroxyvitamin D3 in primary cultures of astrocytes and suggest that 1,25-dihydroxyvitamin D3 may participate in the expression of NGF, NT-3 and NT-4 in the central nervous system.
 
Article
In the rat central nervous system (CNS), inositol 1,4,5-trisphosphate receptor (IP3R) type 3 was immunolocalized with a type 3-specific monoclonal antibody (mAb). The protein was expressed principally in prototype astrocytes, ependymal cells around the ventricle, and Bergmann glial cells in the cerebellum. These cells were stained by antibody against glial fibrillary acidic protein (GFAP), indicating the coexistence of GFAP and IP3R type 3. Immunoblot analysis using a brain homogenate detected a 240 kDa protein, verifying that the observed immunoreactivity is from the IP3R type 3 protein. IP3R type 1 and type 2 were not detected immunohistochemically in astrocytes. These results suggest that IP3-induced CA2+ release (IICR) in astroglia is directed by IP3R type 3, whereas IICR in neuronal cells is mediated by IP3R type 1.
 
Article
The mouse fructose-1,6-bisphosphatase (FBPase) cDNA was previously cloned from testicular teratocarcinoma cultured cells (F9 cells). Using this published nucleotide sequence four primer sets were defined and used to amplify FBPase transcript from cerebral cortex, heart, kidney, liver and testis of male C57B1/6 mice. Only one primer set was efficient in all total RNA prepared from the various tissues. The restriction maps of these RNA amplification products suggested the existence of three different FBPase transcripts; this was confirmed by the nucleotide sequences of the FBPase transcripts and by the deduced amino acid sequences. These data are consistent with the existence of three different FBPase genes. This may be relevant in neurological disease in which abnormalities of brain glucose metabolism are involved.
 
Article
Modification of sodium channel availability and behavior is obviously a good candidate for alteration of action potential observed during aging. In the present study, we revealed age-related alterations in the expression of voltage-gated Na+ (Na(v)) channel in rat cerebellum by immunohistochemistry. In the cerebellar cortex of aged rats, Na(v)1.1 immunoreactivity in Purkinje cell bodies was highly increased, whereas granule cells showed lower staining intensity. In the cerebellar nuclei of aged rats, Na(v)1.1 and Na(v)1.2 expression was specifically increased in the cerebellar output neurons, which was confirmed by image analysis. The first demonstration of age-related changes in Na(v) channel expression contributes to our understanding of the mechanisms responsible for alteration in synaptic transmission during aging.
 
Article
Focal cortical dysplasia (FCD) is one of the causes of intractable epilepsy in humans. Cytomegalic neurons, not balloon cells, are considered to be the putative generators of epileptic activity in FCD type IIb (FCDIIb). Voltage-gated sodium channel III α-isoforms (Nav1.3) play crucial roles in the initiation and propagation of action potentials and are important regulators of neuronal excitability. Here, we examined 12 FCDIIb surgical specimens from patients undergoing surgery for epilepsy and used age-matched normal control cortical tissue (CTX) from 10 autopsy samples as controls. Using reverse transcription-PCR and western blot techniques, we found that the mRNA and protein levels of Nav1.3 were clearly upregulated in FCDIIb surgical specimens compared with the controls (CTX). Results of immunohistochemistry analyses demonstrated that Nav1.3 immunoreactivity was widely present in FCDIIb lesion tissue; specifically, high levels of Nav1.3 immunoreactive proteins were located mainly in cytomegalic neurons of different sizes and shapes, not in balloon cells. Double-labeling studies showed most cytomegalic neurons expressing Nav1.3 colabeled with neuronal markers and glutamate receptors-1. Taken together, our results show an upregulation of Nav1.3 protein and a specific cellular distribution of Nav1.3 proteins in FCDIIb lesion tissue samples, suggesting that Nav1.3 may be involved in the generation of epileptic activity in FCDIIb.
 
Article
The tetrodotoxin-resistant voltage-gated sodium channel Nav 1.8 is expressed only in nociceptive sensory neurons. This channel has been proposed to contribute significantly to the sensitization of primary sensory neurons after injury. We have studied the nociceptive behaviours of mice carrying a null mutation in the Nav 1.8 gene (Nav 1.8 -/-) in models of peripheral inflammation as well as a model of neuropathic pain. The results from the present studies reveal that Nav 1.8 is a necessary mediator of NGF-induced thermal hyperalgesia but is not essential for PGE2-evoked hypersensitivity. Neuropathic pain behaviours were unchanged in Nav 1.8 -/- mice indicating that this channel is not involved in the alteration of sensory thresholds following peripheral nerve injury.
 
Article
The NMDA antagonist CGX-1007 (Conantokin-G) has previously been shown to possess potent neuroprotective properties when administered intracranially following experimental ischemic brain injury. Using the same model of middle cerebral artery occlusion (MCAo) in rats we now report the neuroprotective effects of CGX-1007 when delivered intrathecally (i.t.). When given 4 h post-occlusion, a reduction in brain infarction was measured along with significant neurological recovery. Furthermore, we describe an i.t. neuroprotective therapeutic window lasting > or = 8 h from the start of the injury. Critically, this is the first comprehensive report of a neuroprotective agent that can be administered i.t. to ameliorate experimental brain injury and potentially provide an excellent therapeutic window as a neuroprotection treatment.
 
Article
S-100 beta, which is capable of exerting neurotrophic effects on cultured neurones and promoting the survival of motor neurones in vivo, has recently been found in distinct neurones of the rat hindbrain. Here we report that S-100 beta, as well as being present in satellite and Schwann cells, is also present in neurones of sensory ganglia (dorsal root ganglion, trigeminal, petrosal, jugular and nodose ganglia) but absent from neurones of the superior cervical ganglion. In the sensory ganglia, many neurones were immunoreactive, while the staining intensity varied among the neurones. Neuronal S-100 beta appeared in developing rats as early as postnatal day 1. No immunoreactive neurones were observed in the superior cervical ganglion during development. The results are suggestive of selective neurotrophic effects of S-100 beta.
 
Article
The brain peptide cholecystokinin (CCK) has been shown to counteract the analgesic effects of morphine suggesting a physiological antagonism between opioid and CCK neural systems. This has been definitely demonstrated in this study by co-administration of the CCK-B selective antagonist L-365,260 with RB 101, a systemically active inhibitor of peptidases, which fully protects the endogenous opioids, the enkephalins, from their inactivation. The naloxone reversible analgesic effects induced by RB 101 in the mouse hot-plate and rat tail-flick tests were strongly increased by low doses of L-365,260. These results could have important clinical applications by reducing the efficient dose of RB 101, which has recently been shown to be practically devoid of morphine-like side-effects.
 
Article
The effects of huperzine A on memory impairments induced by scopolamine were evaluated using a radial maze task and inhibition of cholinesterase in vitro compared with the effects of E2020 and tacrine. Scopolamine (0.2 mg kg-1) significantly impaired spatial memory in rats. Huperzine A (0.1-0.4 mg kg-1, p.o.), E2020 (0.5-1.0 mg kg-1, p.o.) and tacrine (1.0-2.0 mg kg-1, p.o.) could reverse these scopolamine-induced memory deficits. The ratios of huperzine A, E2020 and tacrine for butyrylcholinesterase:acetylcholinesterase determined by a colourimetric method were 884.57, 489.05, and 0.80, respectively. The results demonstrated that huperzine A was the most selective acetylcholinterase inhibitor, and improved the working memory deficit induced by scopolamine significantly better than did E2020 or tacrine, suggesting it may be a promising agent for clinical therapy of cognitive impairment in patients with Alzheimer's Disease.
 
Article
The effect of topical application of interleukin 2 (IL-2) on afferent sensory transmission to the neurones in the primary somatosensory (SI) cortex was determined quantitatively in anaesthetized rats. IL-2 (0.1, 1.0, 5.0 units) significantly suppressed afferent sensory transmission in SI cortical neurones (n = 19) in a dose-dependent manner. IL-2-induced suppression fully recovered by 60 min after drug. In control experiments, saline solution containing 0.2% bovine serum albumin, used as a vehicle, did not affect afferent sensory transmission. Our results suggest that IL-2 and its receptor present in the SI cortex may be involved in the processing of afferent sensory information.
 
Article
The contribution of vasodilator cyclooxygenase (COX) metabolites to the maintenance of the cerebrocortical blood flow (CBF) has been studied under physiological conditions and in nitric oxide (NO) deficiency. Inhibition of COX decreased resting CBF without changing arterial blood pressure. NO synthase blockade resulted in hypertension and CBF reduction as well as in enhanced cerebral prostacyclin and prostaglandin E2 production. Despite the increased vasodilator prostanoid release in the absence of NO, the CBF-decreasing effect of COX blockade failed to increase. Therefore, the COX pathway seems to play a similar role under physiological and NO-deficient conditions in the maintenance of the resting CBF.
 
Article
Nitroglycerin, which may be regarded as a prodrug for nitric oxide, induces a mild to moderate headache in healthy subjects. In order to study whether migraine patients are more sensitive to nitric oxide than non-migrainous subjects, four different doses of intravenous nitroglycerin were given in a double blind design to 17 migraine patients, 17 age and sex matched healthy controls and 9 subjects with tension-type headache. The nitroglycerin-induced headache was significantly more severe in migraine sufferers, lasted longer and fulfilled diagnostic criteria for migraine more often. We have previously shown a similar supersensitivity to histamine which in human cerebral arteries activates endothelial H1 receptors and causes endothelial production of nitric oxide. Migraine patients are thus supersensitive to exogenous nitric oxide from nitroglycerin as well as to endothelially produced nitric oxide. It is suggested that nitric oxide may be partially or completely responsible for migraine pain.
 
Article
The serotonin hypothesis in schizophrenia had regained interest with the superior efficacy of clozapine in the refractory schizophrenic patients. Among the serotonin receptors, the serotonin 2A (5HT2A) receptor subtype is the most widely studied. Previous studies on the association between a silent mutation polymorphism of the 5HT2A gene (102T/C) and schizophrenia or clozapine response have yielded conflicting findings. Therefore, we investigated whether these genetic variants of the 5HT2A receptor are associated with schizophrenia or with response to clozapine treatment in a Chinese population. Ninety-seven schizophrenic patients and 101 control subjects were included in the study. The receptor variants were found at similar frequencies in schizophrenic patients and healthy control subjects. Also, we did not find the variants to influence the response to clozapine in schizophrenic patients. We suggest that the assessment method of clozapine response and the ethnicity may influence the result.
 
Article
Hyperactivity of the dopaminergic system and a hypoglutamatergic state have been hypothesized to underlie schizophrenia. It has also been proposed that neuroleptics may interact not only with the dopaminergic system but also with the glutamatergic system. We found that daily intraperitoneal injections of haloperidol (1 mg kg-1) for 21 days resulted in increased binding (10-20%) to the NMDA type of glutamate receptors in the outer layers of rat parietal cortex. Quantitative receptor autoradiography indicates that the action of haloperidol is regionally specific since no changes in NMDA receptors were found in the hippocampus and thalamus. Our data suggest that haloperidol may exert its antipsychotic effects by enhancement of glutamatergic functions as well as by the blockade of dopamine receptors.
 
Article
A hydrophobic, fibrillogenic peptide fragment of human prion protein (PrP106-126) had in vitro toxicity to neurons expressing cellular prion protein (PrP(C)). In this study, we proved that primary cultures of mouse cerebral endothelial cells (MCEC) express PrP(C). Incubation of MCEC with PrP106-126 (25-200 microM) caused a dose-dependent toxicity assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, lactate dehydrogenase release, bis-benzimide staining for nuclear morphology, and trypan blue exclusion test. Pentosan polysulphate (50-100 microg/ml), a drug effective in scrapie prophylaxis, dose-dependently attenuated the injury. MCEC cultures from mice homogenous for the disrupted PrP gene were resistant to the toxicity of PrP106-126. In conclusion, cerebral endothelium expressing PrP(C) may be directly damaged during spongiform encephalopathies.
 
Article
We reviewed 107 blood flow activation studies carried out with positron emission tomography and published between January 1993 and November 1996. These studies had reported their findings as peaks of significant difference in cerebral blood-flow (CBF) between two scans/tasks and had located the peaks in standardized stereotaxic space. We coded each task along several dimensions, including the type and rate of input and output, the types of cognitive processes, and the relative difficulty of tasks within a study. Based on this coding, a difference score (A-B) was calculated for each subtraction. Subsequently, the frequency distributions of the difference scores for subtractions yielding a peak in the anterior cingulate region (cingulate peak) were compared with those distributions obtained from subtractions without a cingulate peak (no cingulate-peak). The cingulate peak subtractions (n = 158) differed from the no cingulate peak subtractions (n = 229) in terms of difficulty level (p = 0.001) and the presence of a remote memory component (p = 0.01). Regional differences in the frequency distribution of certain task parameters, such as difficulty level, recent memory and the use of the hand for responding, were also observed when peaks found in the anterior cingulate cortex (ACC) were further classified as located in the rostral vs caudal ACC, supracallosal vs subcallosal ACC, and limbic vs paralimbic parts of the supracallosal ACC. We conclude that task difficulty plays a major role in modulating blood-flow response in the ACC, possibly interacting with other parameters such as the nature of the response and memory demands.
 
Article
To determine the cell groups which are activated by novelty stress, we examined the induction of c-fos mRNA in brain tissues following introduction of male rats to a novel open field. Male Fischer 344 rats were placed in a brightly lit open field and allowed to roam free for 20 min. Control animals were sacrificed upon removal from their home cage. Northern blot analysis revealed a 2.2 kb hybridization signal which increased in density following novelty. In situ hybridization analysis showed that c-fos mRNA was induced in a specific pattern consistent with the behavior. The regions of induction included the medial prefrontal and orbital cortex, cingulate and parietal cortex, hippocampal CA1 and CA3 pyramidal cell regions, dorsal and ventral anterior thalamic n. and paraventricular n. of the hypothalamus. C-fos mRNA also increased in the anterior pituitary gland and this increase correlated with the secretion of ACTH. These data demonstrate the brain areas undergoing genomic activation following complex behavior paradigms such as introduction to a novel environment.
 
Article
alpha 1-tubulin is an isotype of alpha-tubulin, and its mRNA is expressed in the rodent nervous system. A high level of alpha 1-tubulin mRNA in neurones is associated with axonal outgrowth during development as well as with axonal regeneration after axotomy in adult animals. We quantitated alpha 1-tubulin mRNA levels in motor neurone-like NG 108-15 cells using Northern blots in order to determine whether the expression of this neurite outgrowth-associated gene is regulated in NG 108-15 cells during neurite extension and during inhibition of this process by CNS myelin. Here we report that during the acute phase of neurite outgrowth, alpha 1-tubulin mRNA level increases in NG 108-15, a maximal induction of 1.7-fold over the initial level occurring 24 h after neurite outgrowth onset. By contrast, when these cells are plated on CNS myelin alpha 1-tubulin mRNA levels show no such increase. These findings indicate that an increase of the alpha 1-tubulin mRNA level is associated with neurite outgrowth of NG 108-15 cells. More interestingly, this study also demonstrates that the inhibition of neurite outgrowth by CNS myelin may affect the expression of a gene encoding a protein involved in neurite extension.
 
Article
The effects of post-training administration of GF 109203X (5 and 50 ng i.c.v.), a selective inhibitor of protein kinase C, on retention performance were investigated in a positively reinforced lever press task, in male Swiss mice. Both doses of GF 109203X suppressed the spontaneous improvement of performance observed in control animals between the last 5 min of the acquisition session and the first 5 min of the retention session 24 h later. GF 109203X had no effect on food intake and locomotor activity. These data suggest that GF 109203X selectively interferes with mechanisms underlying post-training organization of information and that protein kinase C is involved in this memory process.
 
Article
Expression of interleukin-6 (IL-6), a neurotrophic cytokine, is up-regulated after cerebral ischemia, but the underlying mechanism of the up-regulation remains unclear. NS-7 is a novel blocker of voltage-sensitive Ca2+ and Na+ channels and is known to reduce cerebral damage by ischemia. The present study was undertaken to examine the association between increases in intracellular Ca2+ concentration induced by membrane depolarization and IL-6 induction. IL-6 expression in rat brain was investigated by immunohistochemistry and Western blot analysis following 3.5-48 h of reperfusion after 1.5 h of occlusion of the middle cerebral artery. NS-7 (1 mg/kg; NS-7 group) or saline (saline group) was injected i.v. 5 min after the start of reperfusion. The saline group showed clear IL-6 expression in various cortical regions, which peaked at 24 h of reperfusion. By contrast, IL-6 expression was significantly suppressed in the NS-7 group throughout the reperfusion period. Microglia activation was also reduced in the NS-7 group. These findings suggest that IL-6 expression may be up-regulated by the increased intracellular Ca2+ concentration triggered by membrane depolarization after cerebral ischemia.
 
Article
Expression patterns of mRNAs for the NMDARI subunit (NRI) carboxy-terminus isoforms were investigated in postmortem brain tissue using isotopic in situ hybridization. Three brain regions (superior temporal, middle frontal and visual cortices) were examined in patients with schizophrenia (n = 6) and control subjects (n = 6). A 22% higher level of expression of the NRI isoform that contains neither spliced exon was observed in the superior temporal gyrus of patients with schizophrenia compared with controls (p = 0.01). No differences were observed in the expression of the other isoforms in the three regions studied. These data suggest that NRI alternative splicing might be abnormal in schizophrenia and reinforce previous findings implicating the superior temporal gyrus as a site of neural dysfunction in schizophrenia.
 
Article
Prosaposin (the precursor of saposins A-D) has been identified as a neurotrophic factor in vitro and in vivo. In this study, a novel 11-mer retro-inverso peptidomimetic, Prosaptide D5, was injected i.m. to assess its effectiveness in a rat ischemic model produced by reversible total occlusion of the left middle cerebral artery (MCA). Prosaptide (300 microg/kg, i.m.) injected 3 h after reversible occlusion reduced brain infarct area by 56% compared with a saline group (p < 0.01) at 21 h of reperfusion. A similar injection of D5 6h after occlusion produced a 32% decrease.
 
Article
Endothelin-11-31 (ET-11-31) is a 31-amino-acid vasoactive peptide that plays an important role in the regulation of cardiovascular function. However, the cardiovascular effects of central ET-11-31 are still not fully understood. In this study, we assess the effects of ET-11-31 within the nucleus tractus solitarius (NTS) of anesthetized rats and explore the underlying mechanisms of these effects. Bilateral microinjections of ET-11-31 into the NTS produced dose-dependent hypotension and bradycardia, very similar to the effects of a unilateral microinjection of ET-11-31 into the NTS. Bilateral microinjections of ET-11-31 into the NTS significantly decreased baroreflex function in a time-dependent manner. The hypotensive and bradycardic effects induced by the microinjection of ET-11-31 into the NTS were significantly decreased by the ETA receptor antagonist BQ123 and by kynurenic acid, but not by the ETB receptor antagonist BQ788. These results show that ET-11-31 injected into the NTS produces hypotension and bradycardia, mediated by ETA receptors and, at least partly, by the glutamate receptor.
 
Article
To construct a model for the relapse of drug use, we investigated the reinstatement of morphine-induced conditioned place preference (CPP) in rats. After the morphine CPP paradigm was established, rats were left extinguishing for 9 days, then exposed to 15 min of random foot shock or s.c. drug priming with different doses of morphine or amphetamine, respectively. Foot shock or a higher dose (0.25 mg/kg) of both drugs could reinstate the CPP induced by 4 mg/kg of morphine after a 9-day extinction, while a lower dose (0.125 mg/kg) of both drugs had no effect. It is concluded that the CPP extinction-reinstatement paradigm might be used as a model to investigate the mechanism of relapse in addicts.
 
Article
The capacity of human infants to discriminate contrasting speech sounds specializes to the native language by the end of the first year of life, when the first signs of word recognition have also been found, using behavioural measures. The extent of voluntary attentional involvement in such word recognition has not been explored, however, nor do we know what its neural time-course may be. Here we demonstrate that 11-month-old children shift their attention automatically to familiar words within 250 ms of presentation onset by measuring event-related potentials elicited by familiar and unfamiliar words. A significant modulation of the first negative peak (N200), known to index implicit change detection in adults, was induced by word familiarity in the infants.
 
Article
Unilateral 6-hydroxydopamine lesion to rat substantia nigra pars compacta resulted in a modest, but significant, decrease in the specific binding of N-alpha-[methyl-3H]histamine (19 +/- 5% reduction) to synaptosomal membranes from ipsilateral striata. Dopamine synthesis was assessed in striatal slices by determining [3H]DOPA accumulation after inhibition of DOPA decarboxylase. [3H]DOPA synthesis induced by 50 mM K+ (151 +/- 4% of basal) was prevented by either Ca2+ removal or by Ni2+. Depolarization-stimulated [3H]DOPA accumulation was reduced by the selective H3-agonist immepip (100 nM; 68 +/- 7% inhibition). The effect of immepip was reversed by thioperamide (100 nM), a selective H3-antagonist. Taken together, our results indicate that histamine modulates striatal dopamine synthesis by acting at H3-receptors located on dopaminergic nerve terminals.
 
Article
To investigate CNS habituation (i.e. response decrement due to stimulus repetition) the present study used positron emission tomography (PET) to measure regional cerebral blood flow (rCBF) in eight healthy women during two repetitions of complex visual stimuli. Repeated visual stimulation resulted in neural habituation bilaterally in the secondary visual cortex and in the right medial temporal cortex including the amygdala and the hippocampus. Regional CBF in the left thalamus was elevated as a function of repeated stimuli presentations. Thus, repeated presentation of complex visual stimuli result in rCBF habituation in later stages of the visual processing chain. The elevated neural activity in the thalamus might be associated with interruption of further neural transmission related to suppression of non-meaningful behavior.
 
Article
Quantitative PCR was used to analyse the expression of GluR1, GluR2, GluR2 flip, GluR2 flop and GluR3 mRNA in animals after ischemia and tolerance-inducing ischemia. The ischemic animals showed a decrease in the GluRs to approximately 30%, except for GluR2-flip, which decreased to 75%. The tolerance animals displayed regulation of GluR1 to 75%, GluR2 and GluR2-flop to 283% and 265% respectively. We did not find a correlation between GluR2 regulation and cell loss in the ischemic group. The selective upregulation of GluR2/GluR2 flop in tolerant animals indicates a possible mechanism for enhanced AMPA receptor desensitisation leading to tolerance to ischemia.
 
Article
Mechanisms by which perinatal viral infections can disrupt hippocampal development and cause selective neuronal death may have implications for temporal lobe epilepsy and schizophrenia. Despite abnormalities of inhibitory interneurons in these diseases, the causal relationships between such neurotransmitter changes and viral infections remain unclear. This relationship was examined in a model in which rats, infected with lymphocytic choriomeningitis virus (LCMV) as neonates, manifest a gradual loss of hippocampal dentate granule cells and neuronal hyperexcitability. The current data demonstrate that GABAergic interneurons are dual immunostained for LCMV antigens prior to the loss of dentate granule cells, supporting the hypothesis that LCMV may disrupt developing inhibitory circuits causing unbalanced excitatory neurotransmission and the eventual death of dentate granule cells due to excitotoxicity.
 
Representative stimuli utilized in block paradigm. (a) `Match'. Subjects were instructed to select the face (bottom) whose affect matched that of the target face (top). (b) `Label'. Subjects were instructed to select the label (bottom) which best described the affect of the target face (top). (c) Control. Subjects were instructed to select the form (bottom) which matched the target (top).
Activations associated with matching and labeling affect. ( a ) Statistical parametric map (SPM) for contrast of `match' with control illustrating activation in the FFA and bilateral activation of the amygdalae. ( b ) SPM for contrast of `label' with control illustrating activation in the FFA and absence of amygdalae activation. Coordinates of these activations are presented in Table 1. 
Article
Humans share with animals a primitive neural system for processing emotions such as fear and anger. Unlike other animals, humans have the unique ability to control and modulate instinctive emotional reactions through intellectual processes such as reasoning, rationalizing, and labeling our experiences. This study used functional MRI to identify the neural networks underlying this ability. Subjects either matched the affect of one of two faces to that of a simultaneously presented target face (a perceptual task) or identified the affect of a target face by choosing one of two simultaneously presented linguistic labels (an intellectual task). Matching angry or frightened expressions was associated with increased regional cerebral blood flow (rCBF) in the left and right amygdala, the brain's primary fear centers. Labeling these same expressions was associated with a diminished rCBF response in the amygdalae. This decrease correlated with a simultaneous increase in rCBF in the right prefrontal cortex, a neocortical region implicated in regulating emotional responses. These results provide evidence for a network in which higher regions attenuate emotional responses at the most fundamental levels in the brain and suggest a neural basis for modulating emotional experience through interpretation and labeling.
 
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AlphaB-crystallin is a small heat shock protein (hsp) and molecular chaperone that can interact with a wide spectrum of cellular components including intermediate filaments (IF). The significance of these interactions is not currently known. We have tested whether increased alphaB-crystallin expression effects changes in the IF systems in situ. Adenoviral-mediated gene transfer was used to overexpress alphaB-crystallin in primary astrocytes. A positive correlation was observed between overexpression of alphaB-crystallin and diffuse, filigree IF. AlphaB-crystallin did not appear to alter the polymerization state of IF proteins. These data show that an increase in alphaB-crystallin expression in the absence of stress can modify the organizational state of IF and that alphaB-crystallin can function as an IF debundling protein.
 
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Acute exposure of the nicotinic acetylcholine receptor (AchR) to hydrocortisone (HC) induced a dose-dependent reduction in the channel open time and burst duration and an increase in the closed time, with no changes in channel amplitude. Similar effects were observed with 11-desoxycortisone, thus suggesting that the oxygen atom at position 11 is not required for channel modification. The changes were observed when HC was added to either face of the membrane, but the concentration dependence of the effect differed, indicating a certain sidedness of the corticoid action. The results are consistent with the corticoids acting either at a site on the AChR which can be reached via a membrane pathway or at the lipid annulus immediately surrounding the AChR, i.e. at the lipid-protein interface.
 
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In the present study, we examined the actions of the NMDA antagonist dizocilpine (MK801) on electrically evoked release and uptake of noradrenaline (NA) in the locus coeruleus (LC), serotonin (5-HT) in the dorsal raphe nucleus (DRN) and dopamine (DA) in the nucleus accumbens (NAc), measured by fast cyclic voltammetry (FCV) in rat brain slices. Dizocilpine (10 microM) significantly increased NA (to 248 +/- 15%) and 5-HT release (to 184 +/- 29%) and slowed monoamine uptake in the LC (t1/2 = 853 +/- 129%) and the DRN (t1/2 = 387 +/- 70%), respectively. However, dizocilpine had no effect on DA release or uptake in NAc. Actions on monoamines are thus likely and should be considered in the interpretation of data regarding dizocilpine.
 
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In an earlier study in rodents, we showed that the aromatase that converts androgens to estrogens in the preoptic area and bed nucleus of stria terminalis was significantly increased in concentration after exposure to anabolic-androgenic steroids. To confirm whether this occurs in primates, we conducted a positron emission tomographic study using macaque monkeys. Male rhesus monkeys were treated with nandrolone decanoate for 3 weeks. To measure aromatase concentrations, we performed positron emission tomographic imaging using a 11C-labeled specific aromatase inhibitor, [11C]vorozole. After treatment with nandrolone, significant increase in [11C]vorozole binding was observed in the hypothalamus but not other areas including the amygdala, which is also aromatase enriched. These findings in monkeys are consistent with those we obtained earlier in rats. These findings strongly suggest that aromatase in the hypothalamus may play a crucial role in the emotional instability of anabolic-androgenic steroids abusers.
 
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The slow auditory evoked (wave N1m) and mismatch field (MMF) elicited by sequences of pure tones of 1000 Hz and deviant tones of 1050, 1010 and 1005 Hz were measured before, during and 3 weeks after subjects were trained at frequency discrimination for 15 sessions (over 3 weeks) using an odd-ball procedure. The task of the subject was to detect deviants differing by progressively smaller frequency shifts from the standard stimulus. Frequency discrimination improved rapidly in the first week and was followed by small but constant improvements thereafter. N1m and MMF responses to the deviant stimuli increased in amplitude during training. This enhancement persisted until training was finished, but decreased 3 weeks later. The results suggest a plastic reorganization of the cortical representation for the trained frequencies.
 
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The haem precursors delta-aminolaevulinic acid (ALA) and porphobilinogen (PBG), over-produced in acute intermittent porphyria (AIP), may mediate porphyric neuropathy. Porphyrins bind to peripheral benzodiazepine receptors, putative mitochondrial porphyrin translocation sites. In AIP, ALA and PBG may interfere with porphyrin transport causing a deficit in essential haemoproteins. The effects of ALA, PBG and protoporphyrin 1X on the binding of [3H]-PK 11195 to platelets were examined. Ligand binding was also examined in platelets from porphyric patients. The haem precursor protoporphyrin 1X (10 microM) caused an increase in Kd values (p < 0.05) whereas Bmax values remained unaltered. Neither ALA (10 microM) nor PBG (10 microM) altered ligand binding. Patient platelets showed no change in ligand binding values. ALA and PBG are unlikely to compete with porphyrins for peripheral benzodiazepine sites.
 
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Stimulation of the Schaffer collateral projection to the CA1 region in rat hippocampal slices at 1 Hz for 15 min produced a N-methyl-D-aspartate (NMDA) receptor-dependent long-term depression (LTD) of synaptic responses and, when given after tetanic stimulation, reversed long-term potentiation (LTP). Both LTD and the reversal of LTP were blocked by the nitric oxide (NO) inhibitor L-NG-monomethylargine (L-NMMA). L-NG-nitroarginine (L-NOArg) and hemoglobin also blocked LTD. The inhibition of LTD by L-NMMA was overcome by L- but not D-arginine. Sodium nitroprusside and S-nitrosocysteine, agents that spontaneously release NO, mimicked the effect of 1 Hz stimulation. These results indicate that NO mediates LTD produced by sustained 1 Hz activation of CA1 synapses and support the hypothesis that NO mediates the inhibition of LTP produced by untimely activation of NMDA receptors.
 
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Recent data have suggested that adipocytes synthesize and secrete a 16 kDa peptide which acts centrally to regulate weight gain by suppressing appetite and activating the sympathetic nervous system. To exert such effects, it may function as an endogenous ligand in the CNS, since specific receptors (OB-R) have been recently reported to be widely distributed in the brain. We have speculated that this peptide, now known as leptin, may act centrally by stimulating the release of corticotrophin-releasing hormone (CRH), a recognized potent inhibitory modulator of appetite. We tested in vitro the effect of murine leptin on CRH secretion in the dose range of 0.1 pM-100 nM. The static rat hypothalamic incubation system used involved fresh hypothalamic explants maintained in EBSS with consecutive 20 min incubations, and estimation of CRH concentrations in the medium by a specific and sensitive radioimmunoassay. The effect of heat-denatured leptin at a dose of 1 nM and 10 nM, was also investigated. Any possible modulation of leptin effects by adrenergic pathways was then explored by coincubating hypothalami with leptin 10 nM and equimolar concentrations of the alpha 1-adrenergic antagonist prazosin or the beta-adrenergic antagonist propranolol. The active leptin, but not the heat-inactivated peptide, caused a dose-dependent stimulation of CRH release in vitro (p < 0.05- < 0.0001 vs control), with a plateau effect at a dose of 10 nM. The addition of either prazosin or propranolol was without effect on leptin-dependent CRH stimulation. These findings are consistent with the reported presence of leptin receptors in the rat brain, and suggest that leptin may act to regulate appetite at least in part by directly modulating the secretion of CRH from the hypothalamus. It would also appear that such effect occurs via a non-adrenergic mechanism.
 
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J-113397 (1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one) is a recently developed antagonist of the opioid receptor-like 1 (ORL1) receptor. We compared the in vitro functional profile J-113397 on [35S]guanosine 5'-O-(gamma-thio)triphosphate (GTPgammaS) binding to mouse brain with that of [Phe1psi(CH2-NH)Gly2]nociceptin(1-13)NH2 and naloxone benzoylhydrazone (NalBzoH). J-113397 antagonized nociceptin/orphanin FQ-stimulated [35S]GTPgammaS binding to mouse brain with an IC50 value of 7.6 nM, but had no effect on basal [35S]GTPgammaS binding by itself. [Phe1psi(CH2-NH)Gly2]nociceptin(1-13)NH2 partially antagonized nociceptin/orphanin FQ-stimulated [35S]GTPgammaS binding but showed agonistic activity on ORL1 by itself. NalBzoH showed antagonistic activity on ORL1 receptor but had significant agonistic activity on other opioid receptors at lower doses. Schild plot analysis demonstrated competitive antagonism of J-113397 on ORL1 receptor in mouse brain. A [35S]GTPgammaS binding study using ORL1 receptor-deficient mice confirmed the selective antagonism of J-113397 on ORL1 receptor. These data indicate that J-113397 is the most potent and selective antagonist of ORL1 receptor in mouse brain that has yet been reported, and therefore will be a useful tool for characterization of ORL1 receptors in the brain.
 
Top-cited authors
Chris D Frith
  • University College London
John D E Gabrieli
  • Massachusetts Institute of Technology
Sara W Lazar
  • Massachusetts General Hospital
Robert Zatorre
  • McGill University
Tomas Hokfelt
  • Karolinska Institutet