Biomedical subjects

Gavin S Dawe

Publications and source records attributed to Gavin S Dawe.

8 recordsLinked to original sources

PubMed2007

Propranolol blocks chronic risperidone treatment-induced enhancement of spatial working memory performance of rats in a delayed matching-to-place water maze task.

RATIONALE: Atypical antipsychotics improve cognitive function, including working memory, in schizophrenia. Some atypical antipsychotics have been reported to activate the locus coeruleus and induce beta-adrenoceptor antagonist sensitive c-Fos-like immunoreactivity in the prefrontal cortex. MATERIALS AND METHODS: The present study investigated the effects of chronic treatment of rats with risperidone (1 mg kg(-1) day(-1) s.c.), clozapine (10 mg kg(-1) day(-1) s.c.), or acidified saline vehicle control for 2, 4, or 8 weeks on spatial working memory performance in a delayed matching-to-place water maze task with a 60-s inter-trial retention interval with and without acute challenge with propranolol (10 mg/kg i.p.). RESULTS: Treatment with risperidone for 8 weeks, but not 2 or 4 weeks, significantly improved working memory performance. In contrast, treatment with clozapine for up to 8 weeks did not improve working memory. Acute challenge with propranolol blocked the improvement in working memory produced by chronic treatment with risperidone, but had no significant effect on performance in saline- or clozapine-treated animals. CONCLUSIONS: The delayed matching-to-place water maze task may prove valuable in the investigation of the behavioural pharmacology of the cognitive effects of antipsychotic drugs. These data suggest that beta adrenoceptors may contribute to the cognitive effects of chronic treatment with atypical antipsychotics.

Adrenergic beta-Antagonists↗

PubMed2006

Chronic high-dose haloperidol has qualitatively similar effects to risperidone and clozapine on immediate-early gene and tyrosine hydroxylase expression in the rat locus coeruleus but not medial prefrontal cortex.

Acute administration of clozapine has been reported to activate the locus coeruleus (LC) and beta-adrenoceptor-dependent Fos immunoreactivity in the medial prefrontal cortex (mPFC) in rodents. Haloperidol is reported to exhibit a similar acute effect on LC firing and beta-adrenoceptor dependent Fos immunoreactivity in the mPFC but only at high doses. We compared the effects of chronic 4-week treatment with risperidone (1mg/kg/day s.c.), clozapine (10mg/kg/day s.c.) or a high dose of haloperidol (4mg/kg/day s.c.) on immediate-early gene protein (c-Fos, Egr-1 and Egr-2) and tyrosine hydroxylase (TH) expression. In the mPFC, haloperidol decreased, whereas clozapine increased, c-Fos immunoreactivity. Only haloperidol increased Egr-1 immunoreactivity. There was no significant effect on Egr-2 immunoreactivity. In the LC, both Egr-1 and Egr-2 expression was down regulated by all three antipsychotics. Clozapine and risperidone increased TH immunoreactivity in both mPFC and LC. Haloperidol caused a smaller increase in TH expression in the LC, but did not alter expression in the mPFC. In conclusion, despite qualitatively similar effects in the LC, chronic treatment with haloperidol had different effects to clozapine and risperidone in the mPFC. This may relate to the reported advantage of clozapine and risperidone over haloperidol against prefrontal cortical-dependent cognitive and negative symptoms.

Animals↗

PubMed2006

Alterations in spatial learning and memory after forced exercise.

Exercise has been shown to influence learning and memory. Most studies were performed with a voluntary running paradigm (e.g. running wheel) in mice. However, such effects of exercise on learning and memory are less well demonstrated using a forced running paradigm (e.g. treadmill). The present study was designed to examine the effects of 12 weeks of forced treadmill running on learning and memory performance in rats. We have previously shown that forced running resulted in qualitative and quantitative changes in the cholinergic neurons of the horizontal diagonal band of Broca (HDB) in the septum. This study was conducted in order to determine whether or not these changes occur simultaneously with enhanced learning and memory. The one-day version of the Morris water maze (MWM) test [Frick, K.M., Stillner, E.T., Berger-Sweeney, J., 2000. Mice are not little rats: species differences in a one-day water maze task. NeuroReport 11, 3461-3465] was used to test spatial learning and memory after the exercise period. Our data showed that runners displayed better spatial learning and memory when compared to nonrunners. This was evidently shown by a reduction in the time required for spatial acquisition (p<0.05) and superior probe trial performance (p<0.05). A shorter distance swam by the runners also suggested improved learning over the nonrunners (p<0.05). In an attempt to revalidate our earlier quantitative results, we used design-based stereology (DBS) to estimate the number of cholinergic neuronal profile population in the medial septum and diagonal band (MSDB). We confirmed that forced running increased the cholinergic neuronal profile subpopulation in the HDB (Coefficient of Error<0.2). Taken together, these results indicate that forced exercise could influence learning and memory with a concomitant increase in the number of cholinergic neurons in the HDB.

Acetylcholinesterase↗

PubMed2006

Hydrogen sulphide regulates calcium homeostasis in microglial cells.

Hydrogen sulphide (H2S), which is produced endogenously from L-cysteine in mammalian tissues, has been suggested to function as a neuromodulator in the brain. However, the role of H2S in microglial cells is unclear. In this study, the effect of exogenous and endogenous H2S on intracellular calcium homeostasis was investigated in primary cultured microglial cells. Sodium hydrosulphide (NaHS), a H2S donor, caused a concentration-dependent (0.1-0.5 mM) increase in intracellular calcium concentration ([Ca2+]i). This effect was significantly attenuated in the presence of a calcium-free extracellular solution, Gd3+ (100 microM), a nonselective Ca2+ channel blocker, or thapsigargin (2 microM), an inhibitor of the sarcoplasmic/endoplasmic reticulum Ca2+ -ATPase. These observations suggest that the increase in [Ca2+]i in response to H2S involves both calcium influx across the plasma membrane and calcium release from intracellular stores. The H2S-induced calcium elevation is partly attenuated by H-89, a selective cAMP-dependent protein kinase (PKA) inhibitor, but not by U73122, a phospholipase C (PLC) inhibitor, and chelerythrine, a selective protein kinase C (PKC) inhibitor, suggesting the involvement of cAMP/PKA, but not PLC/PKC/phosphoinositol-3,4,5-inositol (IP3) pathway. Using RT-PCR, only cystathionine gamma-lyase (CSE), a H2S producing enzyme, was detected in primary cultures of microglia. Lowering endogenous H2S level with, D,L-propargylglycine and beta-cyano-L-alanine, two CSE inhibitors, significantly decreased [Ca2+]i, suggesting that endogenous H2S may have a positive tonic influence on [Ca2+]i homeostasis. These findings support the possibility that H2S may serve as a neuromodulator to facilitate signaling between neurons and microglial cells.

Animals↗

PubMed2005

Fetal microchimerism in the maternal mouse brain: a novel population of fetal progenitor or stem cells able to cross the blood-brain barrier?

We investigated whether fetal cells can enter the maternal brain during pregnancy. Female wild-type C57BL/6 mice were crossed with transgenic Green Mice ubiquitously expressing enhanced green fluorescent protein (EGFP). Green Mouse fetal cells were found in the maternal brain. Quantitative real-time polymerase chain reaction (PCR) of genomic DNA for the EGFP gene showed that more fetal cells were present in the maternal brain 4 weeks postpartum than on the day of parturition. After an excitotoxic lesion to the brain, more fetal cells were detected in the injured region. The presence of fetal cells in the maternal brain was also confirmed by quantitative real-time PCR for the sex-determining region of the Y chromosome. Four weeks postpartum, EGFP-positive Green Mouse fetal cells in the maternal brain were found to adopt locations, morphologies, and expression of immunocytochemical markers indicative of perivascular macrophage-, neuron-, astrocyte-, and oligodendrocyte-like cell types. Expression of morphological and immunocytochemical characteristics of neuron- and astrocyte-like cell types was confirmed on identification of fetal cells in maternal brain by Y chromosome fluorescence in situ hybridization. Although further studies are required to determine whether such engraftment of the maternal brain has any physiological or pathophysiological functional significance, fetomaternal microchimerism provides a novel model for the experimental investigation of the properties of fetal progenitor or stem cells in the brain without prior in vitro manipulation. Characterization of the properties of these cells that allow them to cross both the placental and blood-brain barriers and to target injured brain may improve selection procedures for isolation of progenitor or stem cells for brain repair by intravenous infusion.

Animals↗

PubMed2004

NB-3/Notch1 pathway via Deltex1 promotes neural progenitor cell differentiation into oligodendrocytes.

Neurons and glia in the vertebrate central nervous system arise in temporally distinct, albeit overlapping, phases. Neurons are generated first followed by astrocytes and oligodendrocytes from common progenitor cells. Increasing evidence indicates that axon-derived signals spatiotemporally modulate oligodendrocyte maturation and myelin formation. Our previous observations demonstrate that F3/contactin is a functional ligand of Notch during oligodendrocyte maturation, revealing the existence of another group of Notch ligands. Here, we establish that NB-3, a member of the F3/contactin family, acts as a novel Notch ligand to participate in oligodendrocyte generation. NB-3 triggers nuclear translocation of the Notch intracellular domain and promotes oligodendrogliogenesis from progenitor cells and differentiation of oligodendrocyte precursor cells via Deltex1. In primary oligodendrocytes, NB-3 increases myelin-associated glycoprotein transcripts. Thus, the NB-3/Notch signaling pathway may prove to be a molecular handle to treat demyelinating diseases.

Active Transport, Cell Nucleus↗

PubMed2002

Inhibitors of the tyrosine kinase signaling cascade attenuated thrombin-induced guinea pig airway smooth muscle cell proliferation.

Airway remodeling is one of the major hallmarks of asthma. The present study examined the effects of tyrosine kinase inhibitors on thrombin-induced guinea pig ASM cell proliferation, in comparison with inhibitors of mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K). The ASM cells expressed smooth muscle alpha-actin and myosin, and responded to thrombin by increasing cytosolic Ca(+2). Thrombin (1-10 U/ml) induced [(3)H]thymidine incorporation into ASM cells. Tyrphostin 47, a broad-spectrum tyrosine kinase inhibitor, PP2, a Src-specific inhibitor, and piceatannol, a Syk-selective inhibitor, significantly attenuated thrombin-induced [(3)H]thymidine incorporation. In addition, the tyrosine kinase inhibitors significantly reduced thrombin-induced cyclin D(1) expression in ASM cells. PD098059 and U0126, two MAPK kinase inhibitors, and LY294002, a PI3K inhibitor, significantly blocked thrombin-induced [(3)H]thymidine incorporation and cyclin D(1) expression in ASM cells. Our data show that inhibitors of Src and, probably Syk, can modulate thrombin-induced ASM cell proliferation, which may have therapeutic potential for asthma.

Animals↗

PubMed2002

Central noradrenergic blockade prevents autotomy in rat: implication for pharmacological prevention of postdenervation pain syndrome.

Following transection of peripheral nerve, rats exhibit autotomy, which is considered to be the animal model of postdenervation pain syndrome. It has been suggested that phantom limb pain is a result of peripheral denervation leading to reorganization of somatosensory pathways, particularly in the cerebral cortex, which is shown to depend upon central noradrenergic activity. In this study, sciatic and saphenous nerves were sectioned in the left hindpaw of 30 adult rats resulting in complete loss of pain sensation in the hindpaw. A group of rats received normal saline, compared to another group which received N-(2-) Chloroethyl-N-ethyl-2-bromobenzylamine (DSP4) injection 24 h prior to transection. The latter group was also compared to a third group whose central noradrenergic system were also blocked by bilateral injection of 6-OHDA into the ascending noradrenergic bundle 1 week prior to transection. A fourth group received contralateral cortical ablation in addition to peripheral nerve transection and was compared to the first group whose cortex remained intact. The animals were observed daily for 60 days and autotomy was scored in accordance to the system of Wall et al. After 1 week, control animals began to exhibit autotomy. In contrast, autotomy was absent in rats treated with DSP4, similar to rats which received 6-OHDA. Rats which had contralateral cortical ablation showed a considerably delayed onset of autotomy and a reduction in final autotomy scores. We conclude that autotomy, as a model of postdenervation pain syndrome, can be prevented by blockade of noradrenergically mediated cortical reorganization. The clinical implications of this finding are discussed.

Afferent Pathways↗