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R E Brown

Publications and source records attributed to R E Brown.

At least 19 recordsLinked to original sources
PubMed2006

Electrophysiological characterization of neurons in the dorsolateral pontine rapid-eye-movement sleep induction zone of the rat: Intrinsic membrane properties and responses to carbachol and orexins.

Pharmacological, lesion and single-unit recording techniques in several animal species have identified a region of the pontine reticular formation (subcoeruleus, SubC) just ventral to the locus coeruleus as critically involved in the generation of rapid-eye-movement (REM) sleep. However, the intrinsic membrane properties and responses of SubC neurons to neurotransmitters important in REM sleep control, such as acetylcholine and orexins/hypocretins, have not previously been examined in any animal species and thus were targeted in this study. We obtained whole-cell patch-clamp recordings from visually identified SubC neurons in rat brain slices in vitro. Two groups of large neurons (mean diameter 30 and 27 mum) were tentatively identified as cholinergic (rostral SubC) and noradrenergic (caudal SubC) neurons. SubC reticular neurons (non-cholinergic, non-noradrenergic) showed a medium-sized depolarizing sag during hyperpolarizing current pulses and often had a rebound depolarization (low-threshold spike, LTS). During depolarizing current pulses they exhibited little adaptation and fired maximally at 30-90 Hz. Those SubC reticular neurons excited by carbachol (n=27) fired spontaneously at 6 Hz, often exhibited a moderately sized LTS, and varied widely in size (17-42 mum). Carbachol-inhibited SubC reticular neurons were medium-sized (15-25 mum) and constituted two groups. The larger group (n=22) was silent at rest and possessed a prominent LTS and associated one to four action potentials. The second, smaller group (n=8) had a delayed return to baseline at the offset of hyperpolarizing pulses. Orexins excited both carbachol excited and carbachol inhibited SubC reticular neurons. SubC reticular neurons had intrinsic membrane properties and responses to carbachol similar to those described for other reticular neurons but a larger number of carbachol inhibited neurons were found (>50%), the majority of which demonstrated a prominent LTS and may correspond to pontine-geniculate-occipital burst neurons. Some or all carbachol-excited neurons are presumably REM-on neurons.

Anesthetics, Local↗
PubMed2006

Effects of arousal- and feeding-related neuropeptides on dopaminergic and GABAergic neurons in the ventral tegmental area of the rat.

Many neuropeptides regulate feeding and arousal; the ventral tegmental area (VTA) is likely to be one site where they act. We used whole-cell patch-clamp and single-unit extracellular recordings to examine the effects of such neuropeptides on the activity of VTA neurons. Substance P (SP; 300 nM) increased the firing rate of the majority of VTA dopaminergic and gamma-aminobutyric acid (GABA)ergic neurons, and induced oscillations in two dopaminergic cells. Corticotropin-releasing factor (CRF; 200 nM) excited the majority of VTA cells directly, whereas neuropeptide Y (NPY; 300 nM) directly inhibited a subset of dopaminergic and GABAergic cells. Consecutive application of several neuropeptides revealed that all the neurons were excited by at least one of the excitatory neuropeptides SP, CRF or/and orexins. Alpha-melanocyte-stimulating hormone had no effect on dopaminergic cells (at concentrations of 500 nM and 1 microM) and affected only a small proportion of GABAergic neurons. Ghrelin (500 nM), agouti-related peptide (1 microM); cocaine and amphetamine-related transcript (500 nM) and leptin (500 nM and 1 microM) did not modulate the firing rate and membrane potential of VTA neurons. Single-cell reverse transcription polymerase chain reaction analysis showed that all NPY receptors were present in VTA neurons, and all but one cell expressed NPY and/or at least one NPY receptor. CRF was expressed in 70% of dopaminergic VTA cells; the expression of CRF receptor 2 was more abundant than that of receptor 1. These findings suggest a link between the ability of neuropeptides to promote arousal and their action on VTA neurons.

Animals↗
PubMed2006

Visual detection, pattern discrimination and visual acuity in 14 strains of mice.

Based on the procedure of Prusky et al. (2000, Vision Research, 40, 2201-2209), we used a computer-based, two-alternative swim task to evaluate visual detection, pattern discrimination and visual acuity in 14 strains of mice from priority groups A and B of the JAX phenome project (129S1/SvImJ, A/J, AKR/J, BALB/cByJ, BALB/cJ, C3H/HeJ, C57BL/6J, CAST/Ei, DBA/2J, FVB/NJ, MOLF/Ei, SJL/J, SM/J and SPRET/Ei). Each mouse was tested for eight trials/day for 8 days on each of the three tests. There was a significant strain difference in visual ability in all three tests. Mice with reported normal vision (129S1/SvImJ, C57BL/6J and DBA/2J) and one albino strain (AKR/J) performed very well in these tasks. The other albino strains (A/J, BALB/cByJ and BALB/cJ) took longer to learn the tasks than mice with normal vision and did not reach the criterion of 70% correct. Mice with retinal degeneration (C3H/HeJ, FVB/NJ, MOLF/Ei and SJL/J) performed only at chance levels as did the three strains with unknown visual abilities (CAST/Ei, SM/J and SPRET/Ei). Because many behavioral tasks for rodents rely on visual cues, we suggest that the visual abilities of mice should be evaluated before they are tested in commonly used visuo-spatial learning and memory tasks.

Analysis of Variance↗
PubMed2006

Costs of detection and treatment of cervical cancer, cervical dysplasia and genital warts in the UK.

OBJECTIVE: Infection with human Papillomavirus (HPV) is a necessary cause of cervical cancer (CC) and genital warts (GW). HPV vaccination studies have shown excellent efficacy against HPV-induced lesions. To assess the cost-effectiveness of a HPV quadrivalent (6, 11, 16 and 18) vaccine it is necessary to estimate the costs of managing current levels of HPV-related diseases. This study estimates the annual 2003 expenditures in the UK for CC screening, follow-up of abnormal findings, CC treatment and GW treatment. DESIGN AND METHODS: CC screening programmes provided the annual number of screening tests, their results and use of colposcopy procedures in women with abnormal findings. Incident CC cases and hospital admissions for CC in 2003 were used to estimate CC costs. Health Protection Agency data provided the annual number of new, recurrent or persistent cases of GW treated in Genitourinary Medicine (GUM) clinics. Treatment patterns for managing GW were estimated by GUM clinicians. The annual physician visits, tests, procedures, hospital admissions and topical genital wart medications were costed to estimate the total annual expenditures for CC and GW. RESULTS: There were 4.8 million screening tests and 230 303 colposcopy procedures. Estimated costs for screening, management of abnormal and inadequate findings were 138.5 million pounds sterlings. Annual management costs for incident and prevalent CC cases were 46.8 million pounds sterlings. There were an estimated 76 457 incident and 55 657 recurrent/persistent GW cases in 2003. The costs for managing these cases were approximately 22.4 million pounds sterlings. Total annual estimated costs for CC screening, management and treatment of GW were 208 million pounds sterlings and ranged from 186.9 pounds sterlings to 214 million pounds sterlings based upon sensitivity analyses. CONCLUSIONS: The direct medical costs for the NHS associated with detection and management of CC, cervical dysplasia and treatment of GW in the UK are substantial. These medical costs are invaluable for future cost-effectiveness analyses of a quadrivalent HPV vaccine programme.

Adult↗
PubMed2005

Methylphenidate differentially regulates c-fos and fosB expression in the developing rat striatum.

Methylphenidate (MPH, Ritalin) is a psychostimulant drug used in very young children with attention deficit hyperactivity disorder (ADHD). To explore the central effects of MPH, we compared repeated MPH treatments on c-fos and fosB expression in the striatum of immature and adult rats. Prepubertal (PD25-38) or adult (PD53-66) male rats were treated once daily for: (a) 14 days with either saline or MPH (2 or 10 mg/kg) or (b) 13 days with saline followed by a single dose of MPH (2 or 10 mg/kg) on day 14. To determine long-term effects of MPH, another group of prepubertal rats was allowed a drug-free period of 4 weeks following the initial 14 days of treatment, and received a challenge dose of MPH at adulthood. All rats were sacrificed 2 h post-injection on the final day. Expression of c-fos and fosB was quantified by densitometric analysis of cFOS and FOSB-immunoreactivity (-ir). We demonstrated that FOSB-ir was increased by a single dose of MPH in the prepubertal and adult striatum, and this effect was further elevated by chronic MPH in prepubertal rats, in contrast to the inhibitory effect of MPH (2 and 10 mg/kg) on cFOS-ir. In adult rats, repeated MPH down-regulated cFOS-ir only at the higher dose (10 mg/kg), while fosB expression remained at levels comparable to acute MPH. The reduction in cFOS-ir observed in prepubertal rats given repeated MPH (10 mg/kg) persisted in the adult striatum following MPH challenge at adulthood. Our results suggest that (1) repeated MPH treatment differentially regulates c-fos and fosB expression in the immature and adult brain; (2) MPH-induced changes in gene expression may be enduring, and (3) the immature brain is more sensitive to the stimulant effects of MPH than the adult. Thus, our findings have implications for the long-term use of MPH in ADHD.

Age Factors↗
PubMed2005

Methylphenidate regulates c-fos and fosB expression in multiple regions of the immature rat brain.

Methylphenidate (Ritalin, MPH) is a common psychostimulant used to treat childhood attention-deficit hyperactivity disorder (ADHD). Little is known about the long-term developmental effects on gene expression and behavior, which may occur with extended MPH use. We reported previously that the striatum is a major target of MPH, consistent with human MRI studies. In the present study, we tested the hypothesis that MPH is likely to have widespread effects in extra-striatal regions of the brain. We used the expression of two immediate early genes, c-fos and fosB, as probes to map the response of the immature rat brain to single (1 day) versus repeated (14 days) MPH treatment (2 or 10 mg/kg; s.c.) from postnatal day 25 to 38. Consistent with previous reports, the striatum is a major target of acute MPH action, as indicated by elevated levels of cFOS-immunoreactivity (-ir). Increases in c-fos expression were also seen in the nucleus accumbens, cingulate/frontal cortex and piriform cortex, and Islands of Calleja. FosB expression was elevated only in the striatum following a single stimulation. Chronic MPH treatment (10 mg/kg/day for 14 days) resulted in an attenuation of c-fos expression in the striatum and Islands of Calleja. However, levels of cFOS-ir remained elevated in the nucleus accumbens and frontal cortex. In contrast to the inhibitory effect of repeated MPH exposure on c-fos expression, FOSB-ir was further elevated in the striatum, and an increase was observed in the cingulate/frontal and piriform cortices. Thus, chronic MPH differentially regulated expression of c-fos and fosB in several brain regions. Our data suggest that MPH may exert its stimulant effects at multiple sites in the immature brain, which has implications for long-term treatment in children.

Analysis of Variance↗
PubMed2005

Cost-effectiveness comparison of current proton-pump inhibitors to treat gastro-oesophageal reflux disease in the UK.

OBJECTIVE: Gastro-oesophageal reflux disease (GORD) is a recurring condition with many patients requiring long-term maintenance therapy. Therefore initial choice of treatment has long-term cost implications. The aim was to compare the costs and effectiveness of treatment of GORD the (unconfirmed by endoscopy) with seven proton pump inhibitors (PPIs: esomeprazole, lansoprazole (capsules and oro-dispersible tablets), omeprazole (generic and branded), pantoprazole and rabeprazole), over one year. DESIGN AND METHODS: A treatment model was developed of 13 interconnected Markov models incorporating acute treatment of symptoms, long-term therapy and subsequent decisions to undertake endoscopy to confirm diagnosis. Patients were allowed to stop treatment or to receive maintenance treatment either continuously or on-demand depending on response to therapy. Long-term dosing schedule (high dose or step-down dose) was based on current market data. Efficacy of treatments was based on clinical trials and follow-up studies, while resource use patterns were determined by a panel of physicians. MAIN OUTCOME MEASURES: The model predicts total expected annual costs, number of symptom-free days and quality-adjusted life-years (QALY). RESULTS: Generic omeprazole and rabeprazole dominated (i.e. cost less and resulted in more symptom-free days and higher QALY gains) the other PPIs. Rabeprazole had a favourable cost-effectiveness ratio of 3.42 pounds per symptom-free day and 8308 pounds/quality-adjusted life-year gained when compared with generic omeprazole. Rabeprazole remained cost-effective independent of choice of maintenance treatment (i.e. proportion of patients remaining on continuous treatment versus on-demand treatment). CONCLUSIONS: Economic models provide a useful framework to evaluate PPIs in realistic clinical scenarios. Our findings show that rabeprazole is cost-effective for the treatment of GORD.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed2004

Orexins/hypocretins cause sharp wave- and theta-related synaptic plasticity in the hippocampus via glutamatergic, gabaergic, noradrenergic, and cholinergic signaling.

Orexins (OX), also called hypocretins, are bioactive peptides secreted from glucose-sensitive neurons in the lateral hypothalamus linking appetite, arousal and neuroendocrine-autonomic control. Here, OX-A was found to cause a slow-onset long-term potentiation of synaptic transmission (LTPOX) in the hippocampus of young adult mice. LTPOX was induced at Schaffer collateral-CA1 but not mossy fiber-CA3 synapses, and required transient sharp wave-concurrent population field-burst activity generated by the autoassociative CA3 network. Exogenous long theta-frequency stimulation of Schaffer collateral axons erased LTPOX in intact hippocampal slices but not mini slices devoid of the CA3 region. Pharmacological analysis revealed that LTPOX requires co-activation of ionotropic and metabotropic glutamatergic, GABAergic, as well as noradrenergic and cholinergic receptors. Together these data indicate that OX-A induces a state-dependent metaplasticity in the CA1 region associated with sharp-wave and theta rhythm activity as well as glutamatergic, GABAergic, aminergic, and cholinergic transmission. Thus, orexins not only regulate arousal threshold and body weight but also threshold and weight of synaptic connectivity, providing a molecular prerequisite for homeostatic and behavioral state-dependent control of neuronal plasticity and presumably memory functions.

Acetylcholine↗
PubMed2004

A phenotypic and molecular characterization of the fmr1-tm1Cgr fragile X mouse.

Fragile X Syndrome is the most common form of inherited mental retardation. It is also known for having a substantial behavioral morbidity, including autistic features. In humans, Fragile X Syndrome is almost always caused by inactivation of the X-linked FMR1 gene. A single knockout mouse model, fmr1-tm1Cgr, exists. In this report we further characterize the cognitive and behavioral phenotype of the fmr1-tm1Cgr Fragile X mouse through the use of F1 hybrid mice derived from two inbred strains (FVB/NJ and C57BL/6J). Use of F1 hybrids allows focus on the effects of the fmr1-tm1Cgr allele with reduced influence from recessive alleles present in the parental inbred strains. We find that the cognitive phenotype of fmr1-tm1Cgr mice, including measures of working memory and learning set formation that are known to be seriously impacted in humans with Fragile X Syndrome, are essentially normal. Further testing of inbred strains supports this conclusion. Thus, any fmr1-tm1Cgr cognitive deficit is surprisingly mild or absent. There is, however, clear support presented for a robust audiogenic seizure phenotype in all strains tested, as well as increased entries into the center of an open field. Finally, a molecular examination of the fmr1-tm1Cgr mouse shows that, contrary to common belief, it is not a molecular null. Implications of this finding for interpretation of the phenotype are discussed.

Animals↗
PubMed2003

Marked differences in olfactory sensitivity and apparent speed of forebrain neuroblast migration in three inbred strains of mice.

In the adult forebrain, new neuroblasts constantly migrate from the subventricular zone along the rostral migratory stream to the olfactory bulb, where many become neurons. It is unclear whether this process is different in commonly used mouse strains and whether it is related to olfactory function. Adult male BALB/c, C57BL/6, and 129/S1 (formerly 129SV) mice were tested for olfactory sensitivity plus discrimination, using male mouse urine from the two other strains. BALB/c mice had the greatest olfactory sensitivity, followed by 129/S1, and C57BL/6 mice, by an order of magnitude each. Newly formed cells were pulse-labeled for 3 h with i.p. 5-bromo-2'-deoxyuridine (BrdU) injections and the animals analyzed 24 h later. In 129/S1 mice, a greater proportion of neuroblasts were present closer to the olfactory bulb than in BALB/c mice, followed by C57BL/6 mice. The total number of BrdU-labeled cells did not differ, suggesting differences in migration and not proliferation. The impaired olfactory function in C57BL/6 mice might be caused by the reduced number of neuroblasts that reach the olfactory bulbs. However, olfactory function in BALB/c and 129/S1 mice did not correlate with their putative migration speed, suggesting a more complex nature of cellular processes that contribute to olfactory function. These results caution against comparing studies of olfactory function or neural precursors that use different strains of mice, and question the use of C57BL/6 mice as a "normal" strain or as transgenic background. Perhaps more importantly, the results point to an opportunity to identify genes that regulate olfactory function and neuroblast behavior.

Animals↗
PubMed2002

Male and female C57BL/6 mice respond differently to diazepam challenge in avoidance learning tasks.

Benzodiazepines (BZ) impair learning and memory performance of animals. The goal of this study was to examine sex differences in the effects of diazepam on learning and memory of C57BL/6 mice in avoidance paradigms. Male and female C57BL/6 mice were tested in the one-way active avoidance, step-down passive avoidance, and foot-shock pain threshold tasks, following administration of vehicle or diazepam (1 mg/kg). No substantial sex or drug effects on the threshold of the pain response to shock were found. There were no significant differences in avoidance performance between vehicle-treated male and female mice while 1 mg/kg of diazepam produced opposite effects on performance of males and females in both tasks. Diazepam-treated females learned faster in the active avoidance task and showed stronger retention in the passive avoidance task. In contrast, diazepam impaired learning of males in the active avoidance task and had no effect on their performance in the passive avoidance task. Diazepam-induced impairment in males was not due to higher sensitivity to the sedative effect of diazepam as females were more sedated than males on the first trial of the passive avoidance task. Our data showed that sedative and amnesic effects of BZs are not tightly linked. This study also suggests that cognitive effects of BZs in rodents could be sex dependent and highlight the importance of using both sexes in studies on behavioral effects of psychoactive drugs.

Animals↗
PubMed2002

Strain differences in activity and emotionality do not account for differences in learning and memory performance between C57BL/6 and DBA/2 mice.

This study examined emotionality, activity, learning and memory, as well as the influence of emotionality and activity on learning and memory performance in C57BL/6 and DBA/2 mice using a mouse-test battery. DBA/2 mice performed more poorly than C57BL/6 mice in complex learning tasks such as the water maze and object recognition tasks. In contrast, C57BL/ 6 mice showed attenuated habituation tonovelty in the open field apparatus and poorer performance in the step-down passive avoidance task. The C57BL/6 mice were less exploratory and more anxious than the DBA/ 2 mice. The anxiety score (open arm entries in the elevated plus maze) was significantly correlated with all measures of learning and memory in the object recognition task, and some measures in the passive avoidance and water maze tasks. Analysis of covariance (with open arm entries as a covariate) revealed that some measures on trial 1 of the object recognition task, but not the memory scores on trial 2,were confounded by anxiety. No confounding factors of anxiety were found in the water maze or passive avoidance tasks. Similar results were obtained with the activity scores (line crossing and rearing in the open field). In conclusion, strain differences in activity and anxiety did not account for strain differences in learning and memory performance of C57BL/6 and DBA/2 mice. Nonetheless, the importance of using complete behavioural test batteries should be stressed to ensure that strain differences in learning and memory tasks are not confounded by non-cognitive factors.

Animals↗
PubMed2002

Cost effectiveness of eptifibatide in acute coronary syndromes; an economic analysis of Western European patients enrolled in the PURSUIT trial. The Platelet IIa/IIb in unstable Angina: Receptor Suppression Using Integrilin Therapy.

AIMS: To assess the direct medical costs and cost effectiveness of routine eptifibatide use amongst patients with unstable angina and myocardial infarction without persistent ST-segment elevation in the Western European subgroup of the PURSUIT trial. METHODS AND RESULTS: Health care resources were collected for the Western European PURSUIT trial patients (n=3697). Unit costs for major resources were developed within six countries using a consistent bottom-up methodology. Resource consumption from the Western European population was used to calculate the average direct medical costs per patient in the eptifibatide and placebo arms of the trial. Eptifibatide was estimated to cost 524 Euros per treatment. Long-term survival estimated from the 6-month trial survival data and combined with the cost data was used to calculate cost-effectiveness ratios. Additionally, cost per death and non-fatal myocardial infarction at 30 days was calculated. Sensitivity analyses were conducted on the discount rate and resource consumption. Cost-effectiveness ratios ranged from 9603 Euros to 18 115 Euros per year of life saved with 3% discount. Using resource consumption based on countries with low coronary arteriography rates, the cost per year of life saved was between 3329 Euros and 10 079 Euros. Using resource consumption based on high coronary arteriography rate countries, the cost per year of life saved was between 17 089 Euros and 24 099 Euros. Assuming no difference in treatment costs except for the addition of eptifibatide, the incremental cost per year of life saved was 23 818 Euros. CONCLUSIONS: Routine eptifibatide use was associated with a reduction in the combined end-point of death and myocardial infarction at 30 days, which was sustained at 6 months. Long-term projections indicate a modest increase in survival in eptifibatide patients. These data translate into cost-effectiveness ratios that compare favourably with other new technologies that are currently in use.

Acute Disease↗
PubMed2001

Orexin/hypocretin excites the histaminergic neurons of the tuberomammillary nucleus.

The hypothalamic orexin (hypocretin) neuropeptides are associated with the regulation of sleep and feeding, and disturbances in orexinergic neurotransmission lead to a narcoleptic phenotype. Histamine has also been shown to play a role in the regulation of sleep and feeding. Therefore, we studied the relationship between the orexin and histamine systems of the CNS using electrophysiology, immunocytochemistry, and the reverse transcriptase (RT)-PCR method. Both orexin-A and orexin-B depolarized the histaminergic tuberomammillary neurons and increased their firing rate via an action on postsynaptic receptors. The depolarization was associated with a small decrease in input resistance and was likely caused by activation of both the electrogenic Na(+)/Ca(2+) exchanger and a Ca(2+) current. In a single-cell RT-PCR study using primers for the two orexin receptors, we found that most tuberomammillary neurons express both receptors and that the expression of the orexin-2 receptor is stronger than that of the orexin-1 receptor. Immunocytochemical studies show that the histamine and orexin neurons are often located very close to each other. The contacts between these two types of neurons seem to be reciprocal, because the orexin neurons are heavily innervated by histaminergic axons. These results suggest a functional connection between the two populations of hypothalamic neurons and that they may cooperate in the regulation of rapid-eye-movement sleep and feeding.

Animals↗
PubMed2001

The mechanism of spontaneous firing in histamine neurons.

Histaminergic neurons project to virtually the whole central nervous system and display regular firing related to behavioral state. Electrophysiological studies of histaminergic neurons show that these neurons fire in a beating pacemaker pattern, which is intrinsic to individual neurons. Onset of an action potential occurs as the result of a slow depolarizing potential, which consists of voltage dependent calcium current(s) and non-inactivating sodium current. The calcium component is a voltage-dependent current activated by the return to threshold following the afterhyperpolarization (AHP) while the sodium current appears to be persistent. The action potential is followed by an AHP, which limits firing rate. The AHP is due to two potassium currents, one voltage-, the other calcium-dependent; it determines the amount of voltage-dependent currents available for activation. We show original results indicating that calcium current can be activated during AHP-like ramps and that the amount of calcium current near threshold is strongly dependent on the membrane potential and on the size of the AHP. The amount of calcium entering during the action potential will determine the duration of the AHP and thus, the firing rate.

Animals↗
PubMed2001

Defective hippocampal mossy fiber long-term potentiation in endothelial nitric oxide synthase knockout mice.

Mossy fiber long-term potentiation (mfLTP) was compared in hippocampal slices prepared from wild-type mice and mice lacking functional endothelial nitric oxide synthase (eNOS(-/-) mice) using field potential recording. In the presence of D-2-amino-5-phosphonovaleric acid (AP5, 50 microM), the mfLTP induced by tetanic stimulation (100 Hz, 1 sec) was significantly reduced in knockouts (n = 8) in comparison with wild-type (n = 8). Similarly, potentiation induced by forskolin (30 microM) or 8-bromo-cyclic adenosine monophosphate (8-Br-cAMP, 100 microM) was less pronounced in knockouts. However, in wild-types the mfLTP-induced in the presence of the nonselective pharmacological inhibitor of NOS (N-nitro-L-Arginine, 100 microM, n = 6) was not significantly different from control (n = 8). Thus, eNOS is not directly involved in mfLTP, but lack of eNOS during development leads to a deficit downstream of adenylyl cyclase.

8-Bromo Cyclic Adenosine Monophosphate↗