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Sprague
Kinds of Sprague Terms modified by Sprague Selected AbstractsDownregulation of oxytocin receptors in right ventricle of rats with monocrotaline-induced pulmonary hypertensionACTA PHYSIOLOGICA, Issue 2 2010T. L. Broderick Abstract Aim:, Pulmonary hypertension (PH) in the rat leads to right ventricular (RV) hypertrophy, inflammation and increased natriuretic peptide (NP) levels in plasma and RV. Because the release of nitric oxide (NO) and atrial natriuretic peptide (ANP) is a function of the oxytocin receptor (OTR), we examined the effect of PH on gene and protein expression of OTR, NP (A, atrial; B, brain) and receptors (NPRs), nitric oxide synthases (NOS), interleukin (IL)-1,, IL-6 and tumour necrosis factor-, in the hypertrophied RV in a model of PH. Methods:, RV hypertrophy was induced in male Sprague,Dawley rats with monocrotaline (MCT; 60 mg kg,1) and was confirmed by the presence of an increased RV weight and RV-to-[left ventricle (LV) and septum] ratio. Results:, In the RV of MCT-treated rats, a ,40% reduction in OTR mRNA and protein was observed compared with the RV of control rats. This reduction was associated with increased transcripts of ANP and BNP in both ventricles and a corresponding increase in NP receptor mRNA expression for receptors A, B and C. Protein expression of inducible NOS was increased in the RV, whereas endothelial NOS transcripts were increased only in the LV of MCT-treated rats. In the RV of MCT-treated rats, downregulation of OTR was also associated with increased mRNA expression of IL-1, and IL-6. Conclusion:, Our results show that downregulation of the OTR in the RV of MCT-treated rats is associated with increased expression of NP and their receptors as well as IL-1, and IL-6. This reduction in OTR in RV myocardium may have an impact on cardiac function in the MCT-induced model of PH. [source] Nitric oxide bioavailability modulates the dynamics of microvascular oxygen exchange during recovery from contractionsACTA PHYSIOLOGICA, Issue 2 2010D. M. Hirai Abstract Aim:, Lowered microvascular PO2 (PO2mv) during the exercise off-transient likely impairs muscle metabolic recovery and limits the capacity to perform repetitive tasks. The current investigation explored the impact of altered nitric oxide (NO) bioavailability on PO2mv during recovery from contractions in healthy skeletal muscle. We hypothesized that increased NO bioavailability (sodium nitroprusside: SNP) would enhance PO2mv and speed its recovery kinetics while decreased NO bioavailability (l -nitro arginine methyl ester: l -NAME) would reduce PO2mv and slow its recovery kinetics. Methods:,PO2mv was measured by phosphorescence quenching during transitions (rest,1 Hz twitch-contractions for 3 min,recovery) in the spinotrapezius muscle of Sprague,Dawley rats under SNP (300 ,m), Krebs-Henseleit (Control) and l -NAME (1.5 mm) superfusion conditions. Results:, Relative to recovery in Control, SNP resulted in greater overall microvascular oxygenation as assessed by the area under the PO2mv curve (PO2 AREA; Control: 3471 ± 292 mmHg s; SNP: 4307 ± 282 mmHg s; P < 0.05) and faster off-kinetics as evidenced by the mean response time (MRToff; Control: 60.2 ± 6.9 s; SNP: 34.8 ± 5.7 s; P < 0.05), whereas l -NAME produced lower PO2 AREA (2339 ± 444 mmHg s; P < 0.05) and slower MRToff (86.6 ± 14.5 s; P < 0.05). Conclusion:, NO bioavailability plays a key role in determining the matching of O2 delivery-to-O2 uptake and thus the upstream O2 pressure driving capillary-myocyte O2 flux (i.e. PO2mv) following cessation of contractions in healthy skeletal muscle. Additionally, these data support a mechanistic link between reduced NO bioavailability and prolonged muscle metabolic recovery commonly observed in ageing and diseased populations. [source] Chronic inhibition of standing behaviour alters baroreceptor reflex function in ratsACTA PHYSIOLOGICA, Issue 3 2009H. Waki Abstract Aim:, To investigate whether daily orthostatic stress during development is an important factor affecting arterial baroreceptor reflex function, we examined the effect of chronic inhibition of upright standing behaviour on the baroreceptor reflex function in rats. Methods:, Upright standing behaviour was chronically inhibited during the developmental period between 3 and 8 weeks of age in Sprague,Dawley rats and heart rate (HR) and aortic nerve activity in response to increased and decreased mean arterial pressure (MAP) was measured after the treatment period. Results:, The baroreceptor cardiac gain in the rats grown without standing behaviour was significantly lower than the control rats grown in a normal commercial cage (1.0 ± 0.1 beats min,1 mmHg,1 vs. 1.6 ± 0.2 beatsmin,1 mmHg,1, P < 0.05). The range of HR change in the MAP,HR functional curve was also lowered by chronic inhibition of orthostatic behaviour (56.2 ± 5.9 beats min,1) compared with that of the control rats (76.8 ± 6.9 beats min,1, P < 0.05). However the aortic afferent function remained normal after the treatment period, indicating that the attenuated baroreceptor reflex function may be due to other mechanisms involving functional alterations in the cardiovascular centres, efferents and/or peripheral organs. Body weight and adrenal weight were not affected by the inhibition of orthostatic behaviour, suggesting that the animals were not exposed to specific stress by this treatment. Conclusion:, These results indicate that active haemodynamic changes induced by orthostatic behaviour are an important factor for setting the basal level of reflex function during development. Moreover, our experimental model may be useful for studying mechanisms of attenuated baroreceptor reflex observed after exposure to a chronic inactive condition. [source] Exercise is the primary factor associated with Hsp70 induction in muscle of treadmill running ratsACTA PHYSIOLOGICA, Issue 4 2006E. G. Noble Abstract Aim:, The cytoprotective, inducible stress protein, Hsp70, increases in muscles of rodents subjected to strenuous treadmill running. Most treadmill running protocols employ negative reinforcement to encourage animals to exercise. As these stimuli may themselves activate stress responses, the present investigation was conducted to determine their contribution to the exercise-induced expression of Hsp70. Methods:, Twenty-one male Sprague,Dawley rats were randomly divided into three equal groups including an exercise group (EX), which ran on a treadmill at 30 m min,1 for 60 min; a stimulation group (STIM), which was not allowed to run, but was stimulated with compressed air and mild electric shock concurrently with their exercising cohort; and a control group (CON), which was housed in the treadmill room during the exercise period. Animals were killed 24 h post-experiment and hearts (H), soleii (SOL) and white gastrocnemii (WG) were harvested and analysed for Hsp70 content (mean% ± SEM of standard). Results:, Significant increases in Hsp70 (as a % of standard) were noted in H and WG (H = 77.4 ± 8.5; WG = 93.9 ± 18.4) of EX but not in STIM (H = 32.5 ± 4.6; WG = 32.0 ± 3.4) or CON (H = 20.5 ± 3.7; WG = 32.4 ± 7.4). In SOL, Hsp70 expression in EX (126.7 ± 6.2) was different from STIM (98.3 ± 10.9) only. This occurred, despite the fact that all groups were exposed to a stressful environment and exhibited elevated (P < 0.001) temperatures (EX ,41.2 ± 0.1 °C > STIM ,40.5 ± 0.2 °C > CON ,39.0 ± 0.1 °C) indicative of a general stress response. Conclusions:, These data suggest that exercise per se, rather than environmental conditions or noxious stimuli, are responsible for the induction of Hsp70 in rat muscle during treadmill running. [source] Effect of ,-trinositol on secretion induced by Escherichia coli ST-toxin in rat jejunumACTA PHYSIOLOGICA, Issue 4 2003A.-M. Lahti Abstract Aim:,d -myo-inositol-1,2,6-trisphosphate (, -trinositol, PP56), is a synthetic isomer of the intracellular second messenger, d -myo-inositol-1,4,5-trisphospahate. The pharmacological actions of , -trinositol include potent anti-inflammatory properties and inhibition of the secretion induced by cholera toxin and obstructive ileus. In the present study, we investigated whether , -trinositol was able to influence the secretion induced by heat-stable ST-toxin from Escherichia coli in the rat jejunum. Methods:, A midline abdominal incision was performed in anaesthetized male Sprague,Dawley rats and a 6,7 cm long jejunal segment was isolated with intact vascular supply and placed in a chamber suspended from a force displacement transducer connected to a Grass® polygraph. Intestinal net fluid transport was continuously monitored gravimetrically. Crystalline ST-toxin (120 mouse units) was introduced into the intestinal lumen and left there for the rest of the experiment. When a stable secretion was observed, , -trinositol (60 mg kg,1 h,1) or saline were infused during 2 h, followed by a 2-h control period. Results:, , -Trinositol induced a significant (P < 0.001) inhibition of ST-toxin secretion within 30 min, lasting until 2 h after infusion had stopped. The agent also moderately increased (P < 0.05) net fluid absorption in normal jejunum. Mean arterial pressure (P < 0.001) and heart rate (P < 0.001) were reduced by , -trinositol. Conclusion:, The inhibition by , -trinositol of ST-toxin induced intestinal secretion is primarily secondary to inhibition of secretory mechanisms and only to lesser extent due to increased absorption. The detailed mechanisms of action have not been clarified but may involve suppression of inflammation possibly by means of cellular signal transduction. [source] Glutathione deficiency intensifies ischaemia-reperfusion induced cardiac dysfunction and oxidative stressACTA PHYSIOLOGICA, Issue 1 2001S. Leichtweis The efficacy of glutathione (GSH) in protecting ischaemia-reperfusion (I-R) induced cardiac dysfunction and myocardial oxidative stress was studied in open-chest, stunned rat heart model. Female Sprague,Dawley rats were randomly divided into three experimental groups: (1) GSH-depletion, by injection of buthionine sulphoxamine (BSO, 4 mmol kg,1, i.p.) 24 h prior to I-R, (2) BSO injection (4 mmol kg,1, i.p.) in conjunction with acivicin (AT125, 0.05 mmol kg,1, i.v.) infusion 1 h prior to I-R, and (3) control (C), receiving saline treatment. Each group was further divided into I-R, with surgical occlusion of the main left coronary artery (LCA) for 30 min followed by 20 min reperfusion, and sham. Myocardial GSH content and GSH : glutathione disulphide (GSSG) ratio were decreased by ,50% (P < 0.01) in both BSO and BSO + AT125 vs. C. Ischaemia-reperfusion suppressed GSH in both left and right ventricles of C (P < 0.01) and left ventricles of BSO and BSO + AT125 (P < 0.05). Contractility (+dP/dt and ,dP/dt) in C heart decreased 55% (P < 0.01) after I and recovered 90% after I-R, whereas ±dP/dt in BSO decreased 57% (P < 0.01) with ischaemia and recovered 76 and 84% (P < 0.05), respectively, after I-R. For BSO + AT125, ±dP/dt were 64 and 76% (P < 0.01) lower after ischaemia, and recovered only 67 and 61% (P < 0.01) after I-R. Left ventricular systolic pressure in C, BSO and BSO + AT125 reached 95 (P > 0.05) 87 and 82% (P < 0.05) of their respective sham values after I-R. Rate-pressure double product was 11% (P > 0.05) and 25% (P < 0.05) lower in BSO and BSO + AT125, compared with Saline, respectively. BSO and BSO + AT125 rats demonstrated significantly lower liver GSH and heart Mn superoxide dismutase activity than C rats after I-R. These data indicate that GSH depletion by inhibition of its synthesis and transport can exacerbate cardiac dysfunction inflicted by in vivo I-R. Part of the aetiology may involve impaired myocardial antioxidant defenses and whole-body GSH homeostasis. [source] Effect of combined supplementation with vitamin E and alpha-lipoic acid on myocardial performance during in vivo ischaemia-reperfusionACTA PHYSIOLOGICA, Issue 4 2000Coombes Reactive oxygen species (ROS) contribute significantly to myocardial ischaemia-reperfusion (I-R) injury. Recently the combination of the antioxidants vitamin E (VE) and alpha-lipoic acid (, -LA) has been reported to improve cardiac performance and reduce myocardial lipid peroxidation during in vitro I-R. The purpose of these experiments was to investigate the effects of VE and , -LA supplementation on cardiac performance, incidence of dysrhythmias and biochemical alterations during an in vivo myocardial I-R insult. Female Sprague,Dawley rats (4-months old) were assigned to one of the two dietary treatments: (1) control diet (CON) or (2) VE and , -LA supplementation (ANTIOXID). The CON diet was prepared to meet AIN-93M standards, which contains 75 IU VE kg,1 diet. The ANTIOXID diet contained 10 000 IU VE kg,1 diet and 1.65 g , -LA kg,1 diet. After the 14-week feeding period, significant differences (P < 0.05) existed in mean myocardial VE levels between dietary groups. Animals in each experimental group were subjected to an in vivo I-R protocol which included 25 min of left anterior coronary artery occlusion followed by 10 min of reperfusion. No group differences (P > 0.05) existed in cardiac performance (e.g. peak arterial pressure or ventricular work) or the incidence of ventricular dysrhythmias during the I-R protocol. Following I-R, two markers of lipid peroxidation were lower (P < 0.05) in the ANTIOXID animals compared with CON. These data indicate that dietary supplementation of the antioxidants, VE and , -LA do not influence cardiac performance or the incidence of dysrhythmias but do decrease lipid peroxidation during in vivo I-R in young adult rats. [source] Influence of neurohumoral blockade on heart rate and blood pressure responses to haemorrhage in isoflurane anaesthetized ratsACTA PHYSIOLOGICA, Issue 3 2000UllmanArticle first published online: 24 DEC 200 Four groups of Sprague,Dawley rats were anaesthetized with isoflurane (ISO) (1.7% end-tidal concentration) in 40% oxygen, and mechanically ventilated. The animals were bled 15 mL kg,1 b.w. from the femoral vein over 10 min, followed by an observation period of 30 min. Ten minutes before haemorrhage each group of animals was pre-treated with intravenous injection/infusion of either: isotonic saline (Group B; CON; n=7), vasopressin V1 -receptor antagonist [d(CH2)5Tyr(Me)AVP; 10 ,g kg,1] (Group C; AVP-a; n=7), the non-selective angiotensin II receptor antagonist saralasin (10 ,g kg,1 min,1) (Group D; SAR; n=7) or hexamethonium (10 mg kg,1) (Group E; HEX; n=7). A separate group of conscious animals were pre-treated with isotonic NaCl and subjected to the same haemorrhage protocol (Group A; AW; n=7). Mean arterial pressure (MAP), heart rate (HR) and blood gases were observed during the experiments. Only pre-treatment with SAR and HEX reduced MAP significantly. The pre-haemorrhage HR was only affected by HEX, which caused a reduction by 17%. The HR was significantly lower at the end of haemorrhage compared with pre-haemorrhage levels in all groups except that group treated with HEX. In that group the HR changed in the opposite direction. The ability to maintain MAP during haemorrhage, and the post-haemorrhage period, was significantly impaired in the groups treated with AVP-a, SAR or HEX compared with the group receiving NaCl. It is concluded that autonomic nervous activity is of major importance for the maintenance of MAP during isoflurane anaesthesia, whereas circulating angiotensin II and vasopressin levels contribute to a much smaller degree in this regard. General anaesthesia in combination with different degrees of neurohumoral blockade impairs the haemodynamic responses to blood loss, seen in conscious individuals. The impairment involves both the early and late phases during haemorrhage, as well as the post-bleeding recovery period. All three neurohumoral systems (autonomic nervous activity, angiotensin II and vasopressin) are of importance for regulating MAP during and after haemorrhage, although the autonomic nervous outflow appears to contribute to a larger extent. [source] Diet-induced obesity in Sprague,Dawley rats causes microvascular and neural dysfunctionDIABETES/METABOLISM: RESEARCH AND REVIEWS, Issue 4 2010Eric P. Davidson Abstract Background The objective of this study was to determine the effect of diet-induced obesity (DIO) on microvascular and neural function. Methods Rats were fed a standard or high fat diet for up to 32 weeks. The following measurements were carried out: vasodilation in epineurial arterioles using videomicroscopy, endoneurial blood flow using hydrogen clearance, nerve conduction velocity using electrical stimulation, size,frequency distribution of myelinated fibres of the sciatic nerve, intraepidermal nerve fibre density using confocal microscopy and thermal nociception using the Hargreaves method. Results Rats fed a high fat diet for 32 weeks developed sensory neuropathy, as indicated by slowing of sensory nerve conduction velocity and thermal hypoalgesia. Motor nerve conduction velocity and endoneurial blood flow were not impaired. Mean axonal diameter of myelinated fibres of the sciatic nerve was unchanged in high fat-fed rats compared with that in control. Intraepidermal nerve fibre density was significantly reduced in high fat-fed rats. Vascular relaxation to acetylcholine and calcitonin gene-related peptide was decreased and expression of neutral endopeptidase (NEP) increased in epineurial arterioles of rats fed a high fat diet. In contrast, insulin-mediated vascular relaxation was increased in epineurial arterioles. NEP activity was significantly increased in the skin of the hindpaw. Markers of oxidative stress were increased in the aorta and serum of high fat-fed rats but not in epineurial arterioles. Conclusion Chronic obesity causes microvascular and neural dysfunction. This is associated with increased expression of NEP but not oxidative stress in epineurial arterioles. NEP degrades vasoactive peptides, which may explain the decrease in microvascular function. Copyright © 2010 John Wiley & Sons, Ltd. [source] Proteomic Identification of the Involvement of the Mitochondrial Rieske Protein in EpilepsyEPILEPSIA, Issue 3 2005Heike Junker Summary:,Purpose: Kindled seizures are widely used to model epileptogenesis, but the molecular mechanisms underlying the attainment of kindling status are largely unknown. Recently we showed that achievement of kindling status in the Sprague,Dawley rat is associated with a critical developmental interval of 25 ± 1 days; the identification of this long, well-defined developmental interval for inducing kindling status makes possible a dissection of the cellular and genetic events underlying this phenomenon and its relation to normal and pathologic brain function. Methods: By using proteomics on cerebral tissue from our new rat kindling model, we undertook a global analysis of protein expression in kindled animals. Some of the identified proteins were further investigated by using immunohistochemistry. Results: We report the identification of a modified variant of the Rieske iron-sulfur protein, a component of the mitochondrial cytochrome bc1 complex, whose isoelectric point is shifted toward more alkaline values in the hippocampus of kindled rats. By immunohistochemistry, the Rieske protein is well expressed in the hippocampus, except in the CA1 subfield, an area of selective vulnerability to seizures in humans and animal models. We also noted an asymmetric, selective expression of the Rieske protein in the subgranular neurons of the dorsal dentate gyrus, a region implicated in neurogenesis. Conclusions: These results indicate that the Rieske protein may play a role in the response of neurons to seizure activity and could give important new insights into the molecular pathogenesis of epilepsy. [source] Use of Chronic Epilepsy Models in Antiepileptic Drug Discovery: The Effect of Topiramate on Spontaneous Motor Seizures in Rats with Kainate-induced EpilepsyEPILEPSIA, Issue 1 2005Heidi L. Grabenstatter Summary:,Purpose: Potential antiepileptic drugs (AEDs) are typically screened on acute seizures in normal animals, such as those induced in the maximal electroshock and pentylenetet-razole models. As a proof-of-principle test, the present experiments used spontaneous epileptic seizures in kainate-treated rats to examine the efficacy of topiramate (TPM) with a repeated-measures, crossover protocol. Methods: Kainic acid was administered in repeated low doses (5 mg/kg) every hour until each Sprague,Dawley rat experienced convulsive status epilepticus for >3 h. Six 1-month trials (n = 6,10 rats) assessed the effects of 0.3,100 mg/kg TPM on spontaneous seizures. Each trial involved six pairs of TPM and saline-control treatments administered as intraperitoneal injections on alternate days with a recovery day between each treatment day. Data analysis included a log transformation to compensate for the asymmetric distribution of values and the heterogeneous variances, which appeared to arise from clustering of seizures. Results: A significant effect of TPM was observed for 12 h (i.e., two 6-h periods) after a 30-mg/kg injection, and full recovery from the drug effect was complete within 43 h. TPM exerted a significant effect at doses of 10, 30, and 100 mg/kg, and the effects of TPM (0.3,100 mg/kg) were dose dependent. Conclusions: These data suggest that animal models with spontaneous seizures, such as kainate- and pilocarpine-treated rats, can be used efficiently for rapid testing of AEDs with a repeated-measures, crossover protocol. Furthermore, the results indicate that this design allows both dose,effect and time-course-of-recovery studies. [source] A Kindling Model of Pharmacoresistant Temporal Lobe Epilepsy in Sprague,Dawley Rats Induced by Coriaria Lactone and Its Possible MechanismEPILEPSIA, Issue 4 2003Ying Wang Summary: ,Purpose: The aim of this study was to develop a new animal model of pharmacoresistant temporal lobe epilepsy (TLE) by repeated intramuscular injection of Coriaria lactone (CL) at subthreshold dosages and to explore the mechanisms that might be involved. Methods: Healthy male Sprague,Dawley rats (n = 160) were randomized into four groups during the kindling process: three groups (n = 50 for each group) received CL injection at subthreshold dosages (1.25, 1.5, and 1.75 mg/kg, respectively), and ten received normal saline (NS) injection as a control group. The maximal human adult dosage of carbamazepine (CBZ), valproate (VPA), and phenytoin (PHT) was administered as monotherapy to different groups of kindled rats for 1 month (n = 20 for each group). Changes in EEG recording, seizure number, intensity (expressed as grade 1,5 according to Racine stage), and duration, including spontaneous seizures during different interventions, were compared. The expression of P-170, a multiple drug resistance gene (MDR1) encoding P-glycoprotein, was measured in brain samples from different groups of experimental rats by using an image analysis and measurement system (ImagePro-Plus 4.0). Results: A total of 70 (46.7%) rats were fully kindled with a median of 15 (seven to 20) CL injections. Electrocorticogram (ECoG) including hippocampal (EHG) monitoring revealed the temporal lobe origins of epileptiform potentials, which were consistent with the behavioral changes observed. Spontaneous seizures occurred with frequency and diurnal patterns similar to those of human TLE. The antiepileptic drugs (AEDs) tested lacked a satisfactory seizure control. The maximal P-170 expression was in the kindled rats with AED treatment; the next highest was in the kindled rats without AED intervention. Nonkindled SD rats with CL injection also had increased P-170 expression compared with control SD rats. Conclusions: The study provided a simple and stable animal TLE kindling model with pharmacoresistant properties. The pharmacoresistance observed in the kindled rats to CBZ, VPA, and PHT at maximal human adult dosages together with the increased P-170 expression was a distinct feature of this model. This model might be used in further investigations of the mechanisms involved in pharmacoresistant TLE and for developing new AEDs. [source] Cooling Abolishes Neuronal Network Synchronization in Rat Hippocampal SlicesEPILEPSIA, Issue 6 2002Sam P. Javedan Summary: ,Purpose: We sought to determine whether cooling brain tissue from 34 to 21°C could abolish tetany-induced neuronal network synchronization (gamma oscillations) without blocking normal synaptic transmission. Methods: Intracellular and extracellular electrodes recorded activity in transverse hippocampal slices (450,500 ,m) from Sprague,Dawley male rats, maintained in an air,fluid interface chamber. Gamma oscillations were evoked by afferent stimulation at 100 Hz for 200 ms. Baseline temperature in the recording chamber was 34°C, reduced to 21°C within 20 min. Results: Suprathreshold tetanic stimuli evoked membrane potential oscillations in the 40-Hz frequency range (n = 21). Gamma oscillations induced by tetanic stimulation were blocked by bicuculline, a ,-aminobutyric acid (GABA)A -receptor antagonist. Cooling from 34 to 21°C reversibly abolished gamma oscillations in all slices tested. Short, low-frequency discharges persisted after cooling in six of 14 slices. Single-pulse,evoked potentials, however, were preserved after cooling in all cases. Latency between stimulus and onset of gamma oscillation was increased with cooling. Frequency of oscillation was correlated with chamber cooling temperature (r = 0.77). Tetanic stimulation at high intensity elicited not only gamma oscillation, but also epileptiform bursts. Cooling dramatically attenuated gamma oscillation and abolished epileptiform bursts in a reversible manner. Conclusions: Tetany-induced neuronal network synchronization by GABAA -sensitive gamma oscillations is abolished reversibly by cooling to temperatures that do not block excitatory synaptic transmission. Cooling also suppresses transition from gamma oscillation to ictal bursting at higher stimulus intensities. These findings suggest that cooling may disrupt network synchrony necessary for epileptiform activity. [source] Anticonvulsant Profile and Teratogenicity of N -methyl-tetramethylcyclopropyl Carboxamide: A New Antiepileptic DrugEPILEPSIA, Issue 2 2002Nina Isoherranen Summary: ,Purpose: The studies presented here represent our efforts to investigate the anticonvulsant activity of N -methyl-tetramethylcyclopropyl carboxamide (M-TMCD) and its metabolite tetramethylcyclopropyl carboxamide (TMCD) in various animal (rodent) models of human epilepsy, and to evaluate their ability to induce neural tube defects (NTDs) and neurotoxicity. Methods: The anticonvulsant activity of M-TMCD and TMCD was determined after intraperitoneal (i.p.) administration to CF#1 mice, and either oral or i.p. administration to Sprague,Dawley rats. The ability of M-TMCD and TMCD to block electrical-, chemical-, or sensory-induced seizures was examined in eight animal models of epilepsy. The plasma and brain concentrations of M-TMCD and TMCD were determined in the CF#1 mice after i.p. administration. The induction of NTDs by M-TMCD and TMCD was evaluated after a single i.p. administration at day 8.5 of gestation in a highly inbred mouse strain (SWV) that is susceptible to valproic acid,induced neural tube defects. Results: In mice, M-TMCD afforded protection against maximal electroshock (MES)-induced, pentylenetetrazol (Metrazol)-induced, and bicuculline-induced seizures, as well as against 6-Hz "psychomotor" seizures and sound-induced seizures with ED50 values of 99, 39, 81, 51, and 10 mg/kg, respectively. In rats, M-TMCD effectively prevented MES- and Metrazol-induced seizures and secondarily generalized seizures in hippocampal kindled rats (ED50 values of 82, 45, and 39 mg/kg, respectively). Unlike M-TMCD, TMCD was active only against Metrazol-induced seizures in mice and rats (ED50 values of 57 and 52 mg/kg, respectively). Neither M-TMCD nor TMCD was found to induce NTDs in SWV mice. Conclusions: The results obtained in this study show that M-TMCD is a broad-spectrum anticonvulsant drug that does not induce NTDs and support additional studies to evaluate its full therapeutic potential. [source] Electroencephalographic Characterization of an Adult Rat Model of Radiation-Induced Cortical DysplasiaEPILEPSIA, Issue 10 2001Shinji Kondo Summary: ,Purpose: Cortical dysplasia (CD) is a frequent cause of medically intractable focal epilepsy. The mechanisms of CD-induced epileptogenicity remain unknown. The difficulty in obtaining and testing human tissue warrants the identification and characterization of animal model(s) of CD that share most of the clinical, electroencephalographic (EEG), and histopathologic characteristics of human CD. In this study, we report on the in vivo EEG characterization of the radiation-induced model of CD. Methods: Timed-pregnant Sprague,Dawley rats were irradiated on E17 using a single dose of 145 cGy or left untreated. Their litters were identified and implanted with bifrontal epidural and hippocampal depth electrodes for prolonged continuous EEG recordings. After prolonged EEG monitoring, animals were killed and their brains sectioned and stained for histologic studies. Results: In utero,irradiated rats showed frequent spontaneous interictal epileptiform spikes and spontaneous seizures arising independently from the hippocampal or the frontal neocortical structures. No epileptiform or seizure activities were recorded from age-matched control rats. Histologic studies showed the presence of multiple cortical areas of neuronal clustering and disorganization. Moreover, pyramidal cell dispersion was seen in the CA1>CA3 areas of the hippocampal formations. Conclusions: Our results further characterize the in vivo EEG characteristics of the in utero radiation model of CD using long-term EEG monitoring. This model may be used to study the molecular and cellular changes in epileptogenic CD and to test the efficacy of newer antiepileptic medications. [source] Regulation of GADD153 induced by mechanical stress in cardiomyocytesEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 11 2009W. P. Cheng Abstract Background, Growth arrest and DNA damage-inducible gene 153 (GADD153), an apoptosis regulated gene, increased during endoplasmic reticulum stress. However, the expression of GADD153 in cardiomyocytes under mechanical stress is little known. We aimed to investigate the regulation mechanism of GADD153 expression and apoptosis induced by mechanical stress in cardiomyocytes. Materials and methods, Aorta-caval shunt was performed in adult Sprague,Dawley rats to induce volume overload. Rat neonatal cardiomyocytes grown on a flexible membrane base were stretched by vacuum to 20% of maximum elongation, at 60 cycles min,1. Results, The increased ventricular dimension measured using echocardiography in the shunt group (n = 8) was reversed to normal by treatment with chaperon 4-phenylbutyric acid (PBA) (n = 8) at 500 mg kg,1 day,1 orally for 3 days. GADD153 protein and mRNA were up-regulated in the shunt group when compared with sham group (n = 8). Treatment with PBA reversed the protein of GADD153 to the baseline values. The TUNEL assay showed that PBA reduced the apoptosis induced by volume overload. Cyclic stretch significantly increased GADD153 protein and mRNA expression after 14 h of stretch. Addition of c-jun N-terminal kinase (JNK) inhibitor SP600125, JNK small interfering RNA and tumour necrosis factor-, (TNF-,) antibody 30 min before stretch, reduced the induction of GADD153 protein. Stretch increased, while GADD153-Mut plasmid, SP600125 and TNF-, antibody abolished the GADD153 promoter activity induced by stretch. GADD153 mediated apoptosis induced by stretch was reversed by GADD153 siRNA, GADD153-Mut plasmid and PBA. Conclusions, Mechanical stress enhanced apoptosis and GADD153 expression in cardiomyocytes. Treatment with PBA reversed both GADD153 expression and apoptosis induced by mechanical stress in cardiomyocytes. [source] PRECLINICAL STUDY: Morphine withdrawal decreases responding reinforced by sucrose self-administration in progressive ratioADDICTION BIOLOGY, Issue 2 2007Dengke Zhang ABSTRACT Previous studies have shown that withdrawal from psychostimulant drugs such as d -amphetamine or methamphetamine decreases motivation to work for a natural reinforcement, which is thought to be associated with the withdrawal-induced depressive state and hypofunction of the mesolimbic dopamine system. However, to our knowledge, studies exploring the effect of morphine withdrawal on motivation for a natural reinforcement are lacking. The purpose of the present study was to examine whether motivation to work for a natural reinforcement changes during morphine withdrawal. Three groups of male Sprague,Dawley rats were trained to respond on a nose poke for a 4% sucrose solution under a progressive ratio schedule and were subsequently administered a 10-day regimen of injection of high or low dose of morphine or saline. Their duration of break point and withdrawal symptoms were assessed. The finding showed that break points were significantly reduced on day 1 and persisted to at least day 10 of withdrawal without change in locomotor activity. There were hardly any differences bear mentioning when comparing the magnitude of the decrease between the high- and the low-dose group, whereas the withdrawal scales were significant greater in the high-dose group than in the low-dose group. The results suggest that the morphine withdrawal resulted in decreased motivation to obtain the natural reinforcement. The progressive ratio procedure may be a useful technique for evaluation of changes in motivation for natural reinforcing stimuli following withdrawal from opiates. [source] Cannabinoid modulation of limbic forebrain noradrenergic circuitryEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 2 2010Ana F. Carvalho Abstract Both the endocannabinoid and noradrenergic systems have been implicated in neuropsychiatric disorders. Importantly, low levels of norepinephrine are seen in patients with depression, and antagonism of the cannabinoid receptor type 1 (CB1R) is able to induce depressive symptoms in rodents and humans. Whether the interaction between the two systems is important for the regulation of these behaviors is not known. In the present study, adult male Sprague,Dawley rats were acutely or chronically administered the CB1R synthetic agonist WIN 55,212-2, and ,2A and ,1 adrenergic receptors (AR) were quantified by Western blot. These AR have been shown to be altered in a number of psychiatric disorders and following antidepressant treatment. CB1R agonist treatment induced a differential decrease in ,2A- and ,1-ARs in the nucleus accumbens (Acb). Moreover, to assess long-lasting changes induced by CB1R activation, some of the chronically treated rats were killed 7 days following the last injection. This revealed a persistent effect on ,2A-AR levels. Furthermore, the localization of CB1R with respect to noradrenergic profiles was assessed in the Acb and in the nucleus of the solitary tract (NTS). Our results show a significant topographic distribution of CB1R and dopamine beta hydroxylase immunoreactivities (ir) in the Acb, with higher co-localization observed in the NTS. In the Acb, CB1R-ir was found in terminals forming either symmetric or asymmetric synapses. These results suggest that cannabinoids may modulate noradrenergic signaling in the Acb, directly by acting on noradrenergic neurons in the NTS or indirectly by modulating inhibitory and excitatory input in the Acb. [source] Diabetes downregulates presynaptic proteins and reduces basal synapsin I phosphorylation in rat retinaEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 1 2008Heather D. VanGuilder Abstract Diabetic retinopathy can result in vision loss and involves progressive neurovascular degeneration of the retina. This study tested the hypothesis that diabetes decreases the retinal expression of presynaptic proteins involved in synaptic function. The protein and mRNA contents for synapsin I, synaptophysin, vesicle-associated membrane protein 2, synaptosomal-associated protein of 25 kDa and postsynaptic density protein of 95 kDa were measured by immunohistochemistry, immunoblotting and real-time quantitative polymerase chain reaction in whole retinas and retinal synaptosomes from streptozotocin-diabetic and control Sprague,Dawley rats. There was less presynaptic protein immunoreactivity after 1 and 3 months of diabetes than in controls. Discrete synaptophysin-immunoreactive puncta were significantly smaller and fewer in sections from 1- and 3-month diabetic rat retinas than in those from controls. The content of presynaptic proteins was significantly less in whole retinas of 1- and 3-month diabetic rats, and in synaptosomes from 1-month diabetic rats, than in controls. Whole retinas had significantly less mRNA for these genes after 3 months but not 1 month of diabetes, as compared to controls (with the exception of postsynaptic density protein of 95 kDa). In contrast, there was significantly less mRNA for synaptic proteins in synaptosomes of 1-month diabetic rats than in controls, suggesting a localized depletion at synapses. Protein and mRNA for ,-actin and neuron-specific enolase were unchanged by diabetes. The ratio of phosphorylated to total synapsin I was also reduced in whole retina and isolated synaptosomes from 1-month diabetic rats, as compared to controls. These data suggest that diabetes has a profound impact on presynaptic protein expression in the retina, and may provide a mechanism for the well-established defects in vision and the electrophysiological response of the retina in diabetes. [source] Oxytocin injected into the ventral tegmental area induces penile erection and increases extracellular dopamine in the nucleus accumbens and paraventricular nucleus of the hypothalamus of male ratsEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 4 2007Maria Rosaria Melis Abstract The neuropeptide oxytocin (20,100 ng), induces penile erection when injected unilaterally into the caudal but not rostral mesencephalic ventral tegmental area (VTA) of male Sprague,Dawley rats. Such pro-erectile effect started 30 min after treatment and was abolished by the prior injection of d(CH2)5Tyr(Me)2 -Orn8 -vasotocin (1 µg), an oxytocin receptor antagonist injected into the same caudal ventral tegmental area or of haloperidol (1 µg), a dopamine receptor antagonist, injected either into the nucleus accumbens shell (NAs) or into the paraventricular nucleus of the hypothalamus (PVN) ipsilateral to the injected ventral tegmental area. Penile erection was seen 15 min after the occurrence of, or concomitantly to, an increase in extracellular dopamine and its metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) in the dialysate obtained from the nucleus accumbens or the paraventricular nucleus, which was also abolished by d(CH2)5Tyr(Me)2 -Orn8 -vasotocin (1 µg), injected into the ventral tegmental area before oxytocin. In the caudal ventral tegmental area oxytocin-containing axons/fibres (originating from the paraventricular nucleus) appeared to closely contact cell bodies of mesolimbic dopaminergic neurons retrogradely labelled with Fluorogold injected into the nucleus accumbens shell, suggesting that oxytocin effects are mediated by the activation of mesolimbic dopaminergic neurons, followed in turn by that of incerto-hypothalamic dopaminergic neurons impinging on oxytocinergic neurons mediating penile erection. As the stimulation of paraventricular dopamine receptors not only induces penile erection, but also increases mesolimbic dopamine neurotransmission by activating oxytocinergic neurons, these results provide further support for the existence of a neural circuit in which dopamine and oxytocin influence both the consummatory and motivational/rewarding aspects of sexual behaviour. [source] Glial cell loss, proliferation and replacement in the contused murine spinal cordEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 6 2007Judith M. Lytle Abstract Studies in the rat have shown that contusive spinal cord injury (SCI) results in devastating pathology, including significant loss of mature oligodendrocytes and astrocytes even in spared white matter. Subsequently, there is increased proliferation of endogenous NG2+ cells, postulated to contribute to replacement of mature glia chronically, which is important for functional recovery. Studies of mechanisms that stimulate endogenous progenitor cells would be facilitated by using mouse models with naturally occurring and genetically engineered mutations. To determine whether the murine response is similar to that in the rat, we performed contusive SCI on adult female C57Bl/6 mice at the T8,9 level. Animals received bromodeoxyuridine injections in the first week following injury and were killed at 1, 3, 4, 7 or 28 days postinjury (DPI). The overall loss of macroglia and the temporal,spatial response of NG2+ cells after SCI in the (C57Bl/6) mouse was very similar to that in the (Sprague,Dawley) rat. By 24 h after SCI nearly half of the macroglia in spared ventral white matter had been lost. Cell proliferation was increased at 1,7 DPI, peaking at 3,4 DPI. Dividing cells included NG2+ cells and Cd11b+ macrophages and microglia. Furthermore, cells dividing in the first week expressed markers of mature glia at 28 DPI. The similarities in endogenous progenitor cell response to SCI in the mouse and rat suggest that this is a fundamental injury response, and that transgenic mouse models may be used to further probe how this cellular response to SCI might be enhanced to improve recovery after SCI. [source] Topographical organization of pathways from somatosensory cortex through the pontine nuclei to tactile regions of the rat cerebellar hemispheresEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 10 2006Trygve B. Leergaard Abstract The granule cell layer of the cerebellar hemispheres contains a patchy and noncontinuous map of the body surface, consisting of a complex mosaic of multiple perioral tactile representations. Previous physiological studies have shown that cerebrocerebellar mossy fibre projections, conveyed through the pontine nuclei, are mapped in registration with peripheral tactile projections to the cerebellum. In contrast to the fractured cerebellar map, the primary somatosensory cortex (SI) is somatotopically organized. To understand better the map transformation occurring in cerebrocerebellar pathways, we injected axonal tracers in electrophysiologically defined locations in Sprague,Dawley rat folium crus IIa, and mapped the distribution of retrogradely labelled neurons within the pontine nuclei using three-dimensional (3-D) reconstructions. Tracer injections within the large central upper lip patch in crus IIa-labelled neurons located centrally in the pontine nuclei, primarily contralateral to the injected side. Larger injections (covering multiple crus IIa perioral representations) resulted in labelling extending only slightly beyond this region, with a higher density and more ipsilaterally labelled neurons. Combined axonal tracer injections in upper lip representations in SI and crus IIa, revealed a close spatial correspondence between the cerebropontine terminal fields and the crus IIa projecting neurons. Finally, comparisons with previously published three-dimensional distributions of pontine neurons labelled following tracer injections in face receiving regions in the paramedian lobule (downloaded from http://www.rbwb.org) revealed similar correspondence. The present data support the coherent topographical organization of cerebro-ponto-cerebellar networks previously suggested from physiological studies. We discuss the present findings in the context of transformations from cerebral somatotopic to cerebellar fractured tactile representations. [source] Minocycline attenuates hypoxia,ischemia-induced neurological dysfunction and brain injury in the juvenile ratEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 2 2006Lir-Wan Fan Abstract To investigate whether minocycline provides long-lasting protection against neonatal hypoxia,ischemia-induced brain injury and neurobehavioral deficits, minocycline was administered intraperitoneally in postnatal day 4 Sprague,Dawley rats subjected to bilateral carotid artery occlusion followed by exposure to hypoxia (8% oxygen for 15 min). Brain injury and myelination were examined on postnatal day 21 (P21) and tests for neurobehavioral toxicity were performed from P3 to P21. Hypoxic,ischemic insults resulted in severe white matter injury, enlarged ventricles, deficits in the hippocampus, reduction in numbers of mature oligodendrocytes and tyrosine hydroxylase-positive neurons, damage to axons and dendrites, and impaired myelination, as indicated by the decrease in myelin basic protein immunostaining in the P21 rat brain. Hypoxic,ischemic insult also significantly affected physical development (body weight gain and eye opening) and neurobehavioral performance, including sensorimotor and locomotor function, anxiety and cognitive ability in the P21 rat. Treatments with minocycline significantly attenuated the hypoxia,ischemia-induced brain injury and improved neurobehavioral performance. The protection of minocycline was associated with its ability to reduce microglial activation. The present results show that minocycline has long-lasting protective effects in the neonatal rat brain in terms of both hypoxia,ischemia-induced brain injury and the associated neurological dysfunction. [source] Aquaporin 4 changes in rat brain with severe hydrocephalusEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 11 2006Xiaoyan Mao Abstract Hydrocephalus is characterized by impaired cerebrospinal fluid (CSF) flow with enlargement of the ventricular cavities of the brain and progressive damage to surrounding tissue. Bulk water movement is altered in these brains. We hypothesized that increased expression of aquaporins, which are water-permeable channel proteins, would occur in these brains to facilitate water shifts. We used quantitative (real-time) RT-PCR, Western blotting and immunohistochemistry to evaluate the brain expression of aquaporins (AQP) 1, 4, and 9 mRNA and protein in Sprague,Dawley rats rendered hydrocephalic by injection of kaolin into cistern magna. AQP4 mRNA was significantly up-regulated in parietal cerebrum and hippocampus 4 weeks and 9 months after induction of hydrocephalus (P < 0.05). Although Western blot analysis showed no significant change, there was more intense perivascular AQP4 immunoreactivity in cerebrum of hydrocephalic brains at 3,4 weeks after induction. We did not detect mRNA or protein changes in AQP1 (located in choroid plexus) or AQP9 (located in select neuron populations). Kir4.1, a potassium channel protein linked to water flux, exhibited enhanced immunoreactivity in the cerebral cortex of hydrocephalic rats; the perineuronal distribution was entirely different from that of AQP4. These results suggest that brain AQP4 up-regulation might be a compensatory response to maintain water homeostasis in hydrocephalus. [source] REM sleep: a sensitive index of fear conditioning in ratsEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 4 2005Sushil K. Jha Abstract To examine the influence of conditioned fear stimuli on sleep-wake states, we recorded sleep in Sprague,Dawley rats after exposure to tones previously paired with footshock. After habituation to a recording chamber and the recording procedure, a baseline sleep recording was obtained the next day. One day later, experimental animals were exposed to shock training designed to induce conditioned fear (FC), consisting of five tone-footshock pairings. The 5-s tones (conditioned stimuli; CS) co-terminated with 1-s footshocks (unconditioned stimuli; US). The next day sleep was recorded for 4 h in the recording chamber after presentation of five CSs alone. Sleep efficiency (total sleep time/recording period) and REM sleep (REM) and non-REM (NREM) measures were determined. While sleep efficiency was not significantly changed after CS presentation, the percentage of total sleep time spent in REM (REM percentage) was reduced in the FC animals. The reduction in REM percentage in the FC animals was due to a decrease in the number of REM bouts. In a separate experiment, we repeated the procedures, except the tones and shocks were presented in an explicitly unpaired (UP) fashion. The next day, presentation of the tones increased REM percentage in the UP group. Results are discussed in terms of the decreases in REM as a response to conditioned fear, and the relevance of these findings to the sleep changes seen in post-traumatic stress disorder (PTSD). [source] Descending respiratory polysynaptic inputs to cervical and thoracic motoneurons diminish during early postnatal maturation in rat spinal cordEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 3 2005Laurent Juvin Abstract Isolated brainstem-spinal cord preparations were used to explore the coexistence of a direct and an indirect descending drive from the brainstem respiratory centre to cervical and thoracic respiratory motoneurons in the neonatal Sprague,Dawley rat. Polysynaptic spinal relay pathways from the respiratory centre were suppressed by selectively perfusing the cord with mephenesin (1 mm) or a solution enriched with Ca2+ and Mg2+. At birth, both direct and spinally relayed pathways are functional and contribute equally to the global descending respiratory drive. However, during the first postnatal week, significant maturational changes appear in the way the respiratory centre controls its target respiratory motoneurons in the cervical and thoracic spinal cord, with the direct respiratory drive becoming progressively predominant with maturation (from 50% to around 75% of the global descending command). The relative contributions of the monosynaptic and the polysynaptic spinal pathways may therefore have important implications for effective respiratory control during early postnatal development. [source] Cocaine increases medial prefrontal cortical glutamate overflow in cocaine-sensitized rats: a time course studyEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 6 2004Jason M. Williams Abstract Excitatory amino acid transmission within mesocorticolimbic brain pathways is thought to play an important role in behavioural sensitization to psychomotor stimulants. The current studies evaluated a time course of the effects of cocaine on extracellular glutamate levels within the medial prefrontal cortex (mPFC) following increasing periods of withdrawal from repeated cocaine exposure. Male Sprague,Dawley rats underwent stereotaxic surgeries and were pretreated daily with saline (1 mL/kg/day × 4 days, i.p.) or cocaine (15 mg/kg/day × 4 days, i.p.) and withdrawn for 1, 7 or 30 days. After withdrawal rats were challenged with the same dose of saline or cocaine and in vivo microdialysis of the mPFC was conducted with concurrent analysis of locomotor activity. Animals that were withdrawn from repeated daily cocaine for 1 day and 7 days displayed an augmentation in cocaine-induced mPFC glutamate levels compared to saline and acute control subjects, which were similarly unaffected by cocaine challenge. At the 7 day time point, a subset of animals that received repeated cocaine did not express behavioural sensitization, nor did these animals exhibit the enhancement in mPFC glutamate in response to cocaine challenge. In contrast to these early effects, 30 days of withdrawal resulted in no significant changes in cocaine-induced mPFC glutamate levels regardless of the pretreatment or behavioural response. These data suggest that repeated cocaine administration transiently increases cocaine-induced glutamate levels in the mPFC during the first week of withdrawal, which may play an important role in the development of behavioural sensitization to cocaine. [source] Pre- and postsynaptic contributions of voltage-dependent Ca2+ channels to nociceptive transmission in rat spinal lamina I neuronsEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 1 2004B. Heinke Abstract Activation of voltage-dependent Ca2+ channels (VDCCs) is critical for neurotransmitter release, neuronal excitability and postsynaptic Ca2+ signalling. Antagonists of VDCCs can be antinociceptive in different animal pain models. Neurons in lamina I of the spinal dorsal horn play a pivotal role in the processing of pain-related information, but the role of VDCCs to the activity-dependent Ca2+ increase in lamina I neurons and to the synaptic transmission between nociceptive afferents and second order neurons in lamina I is not known. This has now been investigated in a lumbar spinal cord slice preparation from young Sprague,Dawley rats. Microfluorometric Ca2+ measurements with fura-2 have been used to analyse the Ca2+ increase in lamina I neurons after depolarization of the cells, resulting in a distinct and transient increase of the cytosolic Ca2+ concentration. This Ca2+ peak was reduced by the T-type channel blocker, Ni2+, by the L-type channel blockers, nifedipine and verapamil, and by the N-type channel blocker, ,-conotoxin GVIA. The P/Q-type channel antagonist, ,-agatoxin TK, had no effect on postsynaptic [Ca2+]i. The NMDA receptor channel blocker D-AP5 reduced the Ca2+ peak, whereas the AMPA receptor channel blocker CNQX had no effect. Postsynaptic currents, monosynaptically evoked by electrical stimulation of the attached dorsal roots with C-fibre and A,-fibre intensity, respectively, were reduced by N-type channel blocker ,-conotoxin GVIA and to a much lesser extent, by P/Q-type channel antagonist ,-agatoxin TK, and the L-type channel blockers verapamil, respectively. No difference was found between unidentified neurons and neurons projecting to the periaqueductal grey matter. This is the first quantitative description of the relative contribution of voltage-dependent Ca2+ channels to the synaptic transmission in lamina I of the spinal dorsal horn, which is essential in the processing of pain-related information in the central nervous system. [source] NMDA receptor-mediated metaplasticity during the induction of long-term depression by low-frequency stimulationEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 11 2002Bruce Mockett Abstract Metaplasticity refers to the activity-dependent modification of the ability of synapses to undergo subsequent synaptic plasticity. Here, we have addressed the question of whether metaplasticity contributes to the induction of long-term depression (LTD) by low-frequency stimulation (LFS). The experiments were conducted using standard extracellular recording techniques in stratum radiatum of area CA1 in hippocampal slices made from adult Sprague,Dawley rats. The degree of LTD induction was found to be a nonlinear function of the number of pulses during a 1-Hz LFS. Little LTD was observed following 600 or 900 pulses, but a significant LTD occurred following 1200 pulses of LFS, whether delivered in one episode, or in two bouts of 600 pulses given 10 min apart. A similar pattern was observed for 3 Hz LFS. The data support the suggestion that pulses occurring early in the LFS train prime synapses for LTD induction, as triggered by later occurring stimuli. The priming effect lasted at least 120 min, when tested by giving two bouts of 1 Hz LFS (600 pulses each) at different intervals. Neither heterosynaptic nor homosynaptic stimulation by itself was sufficient to prime LTD. However, a combination of the stimuli, induced by increased stimulus strength during the LFS, appeared necessary for inducing the effect. An N -methyl- d -aspartate (NMDA) receptor antagonist markedly reduced total LTD induction, regardless of whether it was administered during the first or second LFS in a protocol employing two bouts of 600 pulse LFS, 30 min apart. These findings strongly support the hypothesis that NMDA receptor-dependent metaplasticity processes contribute to the induction of LTD during standard LFS protocols. [source] Detraining losses of skeletal muscle capillarization are associated with vascular endothelial growth factor protein expression in ratsEXPERIMENTAL PHYSIOLOGY, Issue 2 2010Moh H. Malek The purposes of this study were as follows: (1) to examine basal vascular endothelial growth factor (VEGF) protein concentrations following 10 weeks of endurance training and after 7 days of detraining; and (2) to examine the acute VEGF protein response to a single 1 h exercise work bout in trained and detrained animals in relationship to changes in capillary indices following training and detraining. Thirty-three Sprague,Dawley rats were randomized into the following six groups: (1) control,basal; (2) control,acute exercise; (3) trained,basal; (4) trained,acute exercise; (5) detrained,basal; and (6) detrained,acute exercise. Groups 3,6 performed endurance training on a rodent treadmill three times per week for 10 weeks. Following the training intervention, rats in groups 5 and 6 remained cage confined (i.e. detrained) for 7 days. As expected, training increased soleus and plantaris muscle capillarity and attenuated the VEGF response to acute exercise. Seven days of detraining, however, resulted in a regression of capillary contacts and individual capillary-to-fibre ratio in the plantaris and soleus muscles compared with the trained group (P < 0.05). Restoration of the VEGF protein response to acute exercise was evident in both muscles, but only statistically significant in the plantaris muscle (P < 0.05). This is the first study to demonstrate the temporal relationship between VEGF protein expression and skeletal muscle capillarity within the first week of detraining. The findings of the present investigation are consistent with the hypothesis that reduced capillarity impairs oxygen availability to the working muscles. The results indicated that training-induced angiogenic remodelling was reversible following 1 week of detraining and may be modulated by VEGF. [source] | ||||||||||||||||||||||||||||||||||