bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effects of hypocretin2‐saporin and antidopamine‐β‐hydroxylase‐saporin neurotoxic lesions of the dorsolateral pons on sleep and muscle tone
Authors: Blanco‐Centurion Carlos , Gerashchenko Dmitry , Salin‐Pascual Rafael J. , Shiromani Priyattam J. 
Published: May 2004

AbstractThe hypocretin neurons have been implicated in regulating sleep‐wake states as they are lost in patients with the sleep disorder narcolepsy. Hypocretin (HCRT) neurons are located only in the perifornical region of the posterior hypothalamus and heavily innervate pontine brainstem neurons, such as the locus coeruleus (LC), which have traditionally been implicated in promoting arousal. It is not known how the hypocretin innervation of the pons regulates sleep‐wake states as pontine lesions have never been shown to increase sleep. It is likely that in previous studies specific neurons were not lesioned. Therefore, in this study, we applied saporin‐based neurotoxins to the dorsolateral pons and monitored sleep in rats. Anti‐dopamine‐β‐hydroxylase‐saporin killed the LC neurons but sleep was affected only during a two hour light‐dark transition period. Application of hypocretin2‐saporin killed fewer LC neurons relative to other adjacent neurons. This occurred because the LC neurons possess the hypocretin receptor 1 but the ligand hypocretin 2 binds to this receptor with less affinity relative to the hypocretin receptor 2. The hypocretin2‐saporin lesioned rats compared to controls had increased sleep during the dark period and displayed increased limb movements during REM sleep. None of the lesioned rats had sleep onset REM sleep periods or cataplexy. We conclude that the hypocretin innervation to the pons functions to awaken the animal when the lights turn off (via its innervation of the LC), sustains arousal and represses sleep during the rest of the night (via a wider innervation of other pontine neurons), and modulates muscle tone.
Suppression of a slow post‐spike afterhyperpolarization by calcineurin inhibitors
Authors: Vogalis F. , Harvey J. R. , Furness J. B. 
Published: May 2004

AbstractA subset of myenteric neurons in the intestine (AH neurons) generate prolonged (>5 s) post‐spike afterhyperpolarizations (slow AHPs) that are insensitive to apamin and tetraethylammonium. Generation of slow AHPs depends critically on Ca2+ entry and intracellular release of Ca2+ from stores, which then leads to the activation of a K+ conductance that underlies the slow AHP (gsAHP). Slow AHPs are inhibited by stimulation of the cAMP/protein kinase A (PKA) pathway, suggesting that phosphorylation of the K+‐channels that mediate the gsAHP (KsAHP‐channels) is responsible for suppression of slow AHPs and possibly for the repolarization phase of slow AHPs. In the present study, we investigated the possibility that the rising phase of the slow AHP is mediated by dephosphorylation of KsAHP‐channels by calcineurin (CaN), a Ca2+‐calmodulin‐dependent protein phosphatase, leading to an increase in gsAHP and activation of the associated current IsAHP. Slow AHPs and IsAHP were recorded using conventional recording techniques, and we tested the actions of two inhibitors of CaN, FK506 and cyclosporin A, and also the effect of the CaN autoinhibitory peptide applied intracellularly, on these events. We report here that all three treatments inhibited the slow AHP and IsAHP (>70%) without significantly affecting the ability of neurons to fire action potentials. In addition, the slow AHP and IsAHP were suppressed by okadaic acid, an inhibitor of protein phosphatases 1 and 2A. Our results indicate that activation of the gsAHP that underlies the post‐depolarization slow AHPs in AH neurons is mediated by the actions CaN and non‐Ca2+‐dependent phosphatases.
Short‐term exposure to constant light promotes strong circadian phase‐resetting responses to nonphotic stimuli in Syrian hamsters
Authors: Knoch Megan E. , Gobes Sharon M. H. , Pavlovska Ivanda , Su Cathy , Mistlberger Ralph E. , Glass J. David 
Published: May 2004

AbstractBehavioral (nonphotic) stimuli can shift circadian rhythms by serotonin (5‐HT) and/or neuropeptide Y (NPY) inputs to the suprachiasmatic nucleus (SCN) circadian clock. Based on the idea that behavioral phase resetting is modulated by endogenous changes in postsynaptic sensitivity to such transmitters, hamsters were exposed to constant light (LL; ∼ 250 lx) for 1–3 days, which suppresses locomotor activity and eliminates the daily rhythm of SCN 5‐HT release measured by microdialysis. Groups subjected to brief LL or maintained under a light/dark cycle (LD) received phase‐resetting treatments with the 5‐HT1A,7 agonist (±)‐2‐dipropyl‐amino‐8‐hydroxyl‐1,2,3,4‐tetrahydronapthalene (8‐OH‐DPAT) or sleep deprivation (SD). Animals were released to constant darkness at the start of the treatments. Phase advances to 8‐OH‐DPAT and SD during the day were 11 and 3 h for LL vs. 2 and 1 h for LD, respectively. Phase delays during the night were −12 and −5 h for LL vs. no responses for LD, respectively. Phase‐transition curves for both LL treatments had slopes approximating 0, indicative of Type 0 phase resetting. For all treatments, the degree of locomotor suppression by LL was not correlated with the phase shift magnitude. Re‐establishing locomotor activity by overnight food deprivation did not prevent potentiated shifting to SD. However, re‐establishing peak extracellular 5‐HT levels by intra‐SCN 5‐HT reverse microdialysis perfusion in LL did significantly reduce potentiated 8‐OH‐DPAT phase advances. Constant light also enhanced intra‐SCN NPY‐induced phase advances during the day (6 vs. 2 h for LD). These results suggest that LL promotes Type 0 phase resetting by supersensitizing 5‐HT and/or NPY postsynaptic responses and possibly by attenuating the amplitude of the circadian pacemaker, thus enhancing circadian clock resetting nonspecifically.
The cytosolic II–III loop of Cav2.3 provides an essential determinant for the phorbol ester‐mediated stimulation of E–type Ca2+ channel activity
Authors: Klöckner Udo , Pereverzev Alexey , Leroy Jérôme , Krieger Andreas , Vajna Rolf , Pfitzer Gabriele , Hescheler Jürgen , Malécot Claire O. , Schneider Toni 
Published: May 2004

AbstractThere is growing evidence that E‐type voltage dependent Ca2+ channels (Cav2.3) are involved in triggering and controlling pivotal cellular processes like neurosecretion and long‐term potentiation. The mechanism underlying a novel Ca2+ dependent stimulation of E‐type Ca2+ channels was investigated in the context of the recent finding that influx of Ca2+ through other voltage dependent Ca2+ channels is necessary and sufficient to directly activate protein kinase C (PKC). With Ba2+ as charge carrier through Cav2.3 channel α1 subunits expressed in HEK‐293 cells, activation of PKC by low concentrations of phorbol ester augmented peak IBa by approximately 60%. In addition, the non‐inactivating fraction of IBa was increased by more than three‐fold and recovery from short‐term inactivation was accelerated. The effect of phorbol ester on IBa was inhibited by application of the specific PKC inhibitor bisindolylmaleimide I. With Ca2+ as charge carrier, application of phorbol ester did not change the activity of Cav2.3 currents but they were modified by the PKC inhibitor bisindolylmaleimide I. These results suggest that with Ca2+ as charge carrier the incoming Ca2+ can activate PKC, thereby augmenting Ca2+ influx into the cytosol. No modulation of Cav2.3 channels by PKC was observed when an arginine rich region in the II–III loop of Cav2.3 was eliminated. Receptor independent stimulation of PKC and its interaction with Cav2.3 channels therefore represents an important positive feedback mechanism to decode electrical signals into a variety of cellular functions.
Tetrodotoxin administration in the suprachiasmatic nucleus prevents NMDA‐induced reductions in pineal melatonin without influencing Per1 and Per2 mRNA levels
Authors: Paul Ketema N. , Gamble Karen L. , Fukuhara Chiaki , Novak Colleen M. , Tosini Gianluca , Albers H. Elliott 
Published: May 2004

AbstractThe suprachiasmatic nucleus (SCN) of the anterior hypothalamus contains a light‐entrainable circadian pacemaker. Neurons in the SCN are part of a circuit that conveys light information from retinal efferents to the pineal gland. Light presented during the night acutely increases mRNA levels of the circadian clock genes Per1 and Per2 in the SCN, and acutely suppresses melatonin levels in the pineal gland. The present study investigated whether the ability of light to increase Per1 and Per2 mRNA levels and suppress pineal melatonin levels requires sodium‐dependent action potentials in the SCN. Per1 and Per2 mRNA levels in the SCN and pineal melatonin levels were measured in Syrian hamsters injected with tetrodotoxin (TTX) prior to light exposure or injection of N‐methyl‐d‐aspartate (NMDA). TTX inhibited the ability of light to increase Per1 and Per2 mRNA levels and suppress pineal melatonin levels. TTX did not, however, influence the ability of NMDA to increase Per1 and Per2 mRNA levels, though it did inhibit the ability of NMDA to suppress pineal melatonin levels. These results demonstrate that action potentials in the SCN are not necessary for NMDA receptor activation to increase Per1 and Per2 mRNA levels, but are necessary for NMDA receptor activation to decrease pineal melatonin levels. Taken together, these data support the hypothesis that the mechanism through which light information is conveyed to the pacemaker in the SCN is separate from and independent of the mechanism through which light information is conveyed to the SCN cells whose efferents suppress pineal melatonin levels.
Frequency‐dependent requirement for calcium store‐operated mechanisms in induction of homosynaptic long‐term depression at hippocampus CA1 synapses
Authors: Nakano Makoto , Yamada Shin‐ichiro , Udagawa Rie , Kato Nobuo 
Published: May 2004

AbstractFor induction of long‐term depression (LTD), mechanisms dependent on N‐methyl‐d‐aspartate receptors (NMDARs) and on intracellular calcium stores have been separately known. How these two mechanisms coexist at the same synapses is not clear. Here, induction of LTD at hippocampal Schaffer collateral‐to‐CA1 pyramidal cell synapses was shown to depend on NMDARs throughout the theoretically predicted activation range for LTD induction. With stimulation at 1 Hz, the largest LTD was induced in a store‐independent manner. With stimulation at 0.5 and 2.0 Hz the induced LTD was much smaller, and dependence on calcium stores appeared. Under caffeine application, an enlarged LTD was induced with 0.5 Hz stimulation. Postsynaptic blockade of ryanodine receptors prevented this caffeine‐induced enhancement of LTD. It is therefore suggested that calcium release from calcium stores facilitated by caffeine contributed to the LTD enhancement, and that the caffeine effect was exerted on the postsynaptic side. Induction of this enhanced LTD was resistant to NMDAR blockade. We thus propose that the store‐dependent mechanism for LTD induction is dormant at the centre of the theoretically predicted activation range for LTD induction, but operates at the fringes of this activation range, with its contribution more emphasized when ample calcium release occurs.
Differential regulation of the mitochondrial and death receptor pathways in neural stem cells
Authors: Tamm Christoffer , Robertson John D. , Sleeper Eric , Enoksson Mari , Emgård Mia , Orrenius Sten , Ceccatelli Sandra 
Published: May 2004

AbstractDespite an increasing interest in neural stem cell (NSC) research, relatively little is known about the biochemical regulation of cell death pathways in these cells. We demonstrate here, using murine‐derived multipotent C17.2 NSCs, that cells undergo mitochondria‐mediated cell death in response to apoptotic stimuli such as oxidative stress induced by 2,3‐dimethoxy‐1,4‐naphthoquinone (DMNQ). In particular, treated cells exhibited apoptotic features, including Bax translocation, cytochrome c release, activation of caspase‐9 and ‐3, chromatin condensation and DNA fragmentation. Although C17.2 cells possess the Fas receptor and express procaspase‐8, agonistic Fas mAb treatment failed to induce apoptosis. Fas treatment activated the extracellular signal‐regulated protein kinase (ERK) pathway, which may have an antiapoptotic as well as a growth stimulating role. Combined, our findings indicate that while NSCs are sensitive to cytotoxic stimuli that involve an engagement of mitochondria, Fas treatment does not induce death and may have an alternative role.
Targeted introduction of V642I mutation in amyloid precursor protein gene causes functional abnormality resembling early stage of Alzheimer's disease in aged mice
Authors: Kawasumi Masaoki , Chiba Tomohiro , Yamada Marina , Miyamae‐Kaneko Makiko , Matsuoka Masaaki , Nakahara Jin , Tomita Taisuke , Iwatsubo Takeshi , Kato Shigeaki , Aiso Sadakazu , Nishimoto Ikuo , Kouyama Keisuke 
Published: May 2004

AbstractWhile the exact aetiology of Alzheimer's disease (AD) is unknown, distinct genetic mutations have been identified for the rare cases of familial AD (FAD). V642I mutation in amyloid precursor protein (APP) co‐segregates with FAD with perfect penetration, and the clinicopathological characteristics of patients with this mutation resemble that of sporadic AD. To examine the pathogenic process of this FAD‐linked trait in vivo, we produced a mouse with the corresponding point mutation in the APP gene using homologous recombination and Cre‐loxP site‐specific recombination (‘knock‐in’ technique). Mice with the heterozygous V642I‐APP allele most precisely reflected the genotype of humans bearing this mutation. For the observation period of 2.5 years the mutants stayed apparently indistinguishable from the wild‐type littermates. However, behavioural analysis revealed significantly deteriorated long‐term memory in mutants when examined for the retention of spatial attention. Interestingly, acquisition of spatial memory was slightly affected but short‐term working memory was not deteriorated at all. Histological examination was negative for formation of neuritic plaques or neurofibrillary tangles, whereas the relative amount of longer form of β‐amyloid species Aβ42(43) was significantly increased against that of the shorter form (Aβ40) in the mutant brain homogenates. We conclude that a V642I‐APP mutant allele in aged mice confers functional components, but not organic components, of the AD‐related phenotype that are observed in the early stage of AD. This V642I‐APP knock‐in mutant line may serve as a model to study the early pathogenic processes of AD in vivo and to develop therapeutics for this stage.
A parvalbumin‐containing, axosomatic synaptic network in the rat medial septum: relevance to rhythmogenesis*
Authors: Henderson Z. , Fiddler G. , Saha S. , Boros A. , Halasy K. 
Published: May 2004

AbstractThe medial septal diagonal band complex (MS/DB), made up of cholinergic and GABAergic neurons, plays an important role in the generation of the hippocampal theta rhythm. A GABAergic neuron type in the MS/DB that has fast spiking properties was shown previously to contain parvalbumin immunoreactivity and to form axosomatic connections with unidentified somata. The aim in the current study was to determine the neurochemical identities of these target neurons. In slices and in perfused‐fixed brain, staining for parvalbumin immunoreactivity first of all revealed the presence of two types of parvalbumin‐positive somata in the MS/DB: medially located neurons with parvalbumin‐positive basket‐like terminals on them, and more laterally located neurons with fewer parvalbumin‐positive contacts on them. In MS/DB slices, the terminals of fast spiking neurons filled with biocytin correspondingly made either numerous contacts that surrounded the parvalbumin‐positive cell body in basket‐like formation, or 1–5 contacts on a localized patch of the soma. These contacts were shown by electron microscopy to form synaptic junctions. No terminals of biocytin‐filled fast spiking neurons were observed on cholinergic neurons, and dual staining in perfused‐fixed brain did not reveal the presence of parvalbumin‐containing terminals on cholinergic somata. Our results suggest therefore that there are two subtypes of parvalbumin‐containing neuron in the MS/DB, and that these are interconnected via axosomatic synapses. The contrasting topographical organization of the two types of parvalbumin‐containing neuron suggests that they may receive different types of afferent input, but this will require substantiation in future studies. We propose that generation of rhythmic activity in the MS/DB is controlled by contrasting contributions from two types of parvalbumin‐positive neuron, and that the role of the cholinergic neuron is modulatory.
Plexin‐B family members demonstrate non‐redundant expression patterns in the developing mouse nervous system: an anatomical basis for morphogenetic effects of Sema4D during development
Authors: Worzfeld Thomas , Püschel Andreas W. , Offermanns Stefan , Kuner Rohini 
Published: May 2004

AbstractSemaphorins and their receptors play important roles in patterning the connectivity of the developing nervous system and recent data suggest that members of the plexin‐B family of semaphorin receptors may be involved in axonal guidance. Here we show that the mRNAs of the three plexin‐B genes, plxnb1, plxnb2 and plxnb3 (plexin‐B1, plexin‐B2 and plexin‐B3), respectively, are expressed in highly specific and non‐redundant patterns in peripheral and central components of the nervous system over defined periods during murine development. Whereas plexin‐B1 and plexin‐B2 are strongly expressed in the neuroepithelium and developing neurons, plexin‐B3 mRNA is selectively localized to the white matter. Moreover, plexin‐B1 and its ligand Sema4D are expressed in complementary patterns in several regions such as the developing neopallial cortex, the dorsal root ganglia and the spinal cord over embryonic stages. The Sema4d gene demonstrates a dramatic switch from prenatal expression in neuronal populations to a postnatal expression in oligodendrocytes. In contrast to its collapsing activity on growth cones of embryonic retinal ganglion cells and hippocampal neurons, soluble Sema4D enhances axonal outgrowth in embryonic cortical explants cultured in collagen matrices. Thus, plexin‐B family members and Sema4D are likely to play complex and non‐redundant roles during the development of the nervous system.
Effects of single or combined histamine H1‐receptor and leukotriene CysLT1‐receptor antagonism on nasal adenosine monophosphate challenge in persistent allergic rhinitis
Authors: Lee Daniel K. C. , Jackson Catherine M. , Soutar Patricia C. , Fardon Thomas C. , Lipworth Brian J. 
Published: May 2004

BackgroundThe effects of single or combined histamine H1‐receptor and leukotriene CysLT1‐receptor antagonism on nasal adenosine monophosphate (AMP) challenge in allergic rhinitis are unknown.ObjectiveWe elected to study the effects of usual clinically recommended doses of fexofenadine (FEX), montelukast (ML) and FEX + ML combination, compared with placebo (PL), on nasal AMP challenge in patients with persistent allergic rhinitis.MethodsTwelve patients with persistent allergic rhinitis (all skin prick positive to house dust mite) were randomized in a double‐blind cross‐over fashion to receive for 1 week either FEX 180 mg, ML 10 mg, FEX 180 mg + ML 10 mg combination, or PL, with nasal AMP challenge performed 12 h after dosing. There was a 1‐week washout period between each randomized treatment. The primary outcome measure was the maximum percentage peak nasal inspiratory flow (PNIF) fall from baseline over a 60‐min period after nasal challenge with a single 400 mg ml−1 dose of AMP. The area under the 60‐min time–response curve (AUC) and nasal symptoms were measured as secondary outcomes.ResultsThere was significant attenuation (P < 0.05) of the mean maximum percentage PNIF fall from baseline after nasal AMP challenge vs. PL, 48; with FEX, 37; 95% confidence interval for difference 2, 20; ML, 35 (4, 22); and FEX + ML, 32 (7, 24). The AUC (%.min) was also significantly attenuated (P < 0.05) vs. PL, 1893; with FEX, 1306 (30, 1143); ML, 1246 (214, 1078); and FEX + ML, 1153 (251, 1227). There were no significant differences for FEX vs. ML vs. FEX + ML comparing either the maximum or AUC response. The total nasal symptom score (out of 12) was also significantly improved (P < 0.05) vs. PL, 3.3; with FEX, 2.1 (0.3, 2.0); ML, 2.0 (0.5, 1.9); and FEX + ML, 2.5 (0.1, 1.4).ConclusionFEX and ML as monotherapy significantly attenuated the response to nasal AMP challenge and improved nasal symptoms compared with PL, while combination therapy conferred no additional benefit.
Population pharmacokinetics of (R)‐, (S)‐ and rac‐methadone in methadone maintenance patients
Authors: Foster David J. R. , Somogyi Andrew A. , White Jason M. , Bochner Felix 
Published: May 2004

AimTo construct a population pharmacokinetic model for methadone enantiomers in the setting of methadone maintenance treatment for opioid dependence.MethodsA population pharmacokinetic model was developed using P‐Pharm software for rac‐, (R)‐ and (S)‐methadone using data (8–13 plasma samples per subject) obtained from 59 methadone maintenance patients during one interdosing interval at steady state. The patients were randomly assigned to either a development (n = 38) or a validation dataset (n = 21). The model was refined by inclusion of all subjects to construct a final basic model, which was used to construct a covariate model.ResultsA population‐based two‐compartment open model with first‐order absorption and lag time was developed and validated for all analytes. The population geometric mean (coefficient of variation) of maximum a posteriori probability Bayesian estimated values for clearance, terminal half‐life and volume of distribution at steady‐state of the active (R)‐enantiomer were 8.7 (42%) l h−1, 51 (45%) h and 597 (45%) l, respectively. For all analytes, the volume of the central compartment was decreased with increasing plasma α1‐acid glycoprotein concentration and was lower in females, while the delay in absorption was longer at higher doses. No covariates were identified for apparent oral clearance. The apparent oral clearance of (R)‐methadone (geometric mean ratio; 95% confidence interval) was 105% (99, 110), that of (S)‐methadone (P = 0.19), while (R)‐methadone Vc/F (154%; 151, 157), Vdss /F  (173%; 164, 183), t1/2β (162%; 153, 172) and mean residence time (166%; 156, 176) were significantly greater (P < 0.0001) than for (S)‐methadone. The population pharmacokinetic models were able to predict accurately oral clearance values from limited (one or two samples) blood sampling protocols.ConclusionsThe substantial stereoselectivity in methadone disposition reinforces the potential for misinterpretation of racemic methadone disposition data. The marked interindividual variability in (R)‐methadone clearance, with no covariates identified, highlights the need for alternative methods to determine an individual's metabolic clearance. The ability to predict (R)‐methadone clearance from one to two blood samples at steady state may prove clinically useful if a drug–drug interaction or poor adherence are suspected and guide the prescriber in deciding if a client's request for a dose increase is warranted or whether an alternative opioid would be more appropriate.