Non-ohmic conduction in sodium bismuth titanate: the influence of oxide-ion conduction.

A nominal Bi-excess starting composition of sodium bismuth titanate, Na0.5Bi0.51TiO3.015 (NB0.51T) produces dielectric ceramics that exhibit mixed n-type and oxide-ion conductivity with an ionic transport number of ∼0.1 at ≥600 °C. The bulk electrical conductivity, σb, of NB0.51T ceramics under a dc bias field of ≤100 V cm-1 has been investigated by impedance spectroscopy. Over the temperature range ∼550 to 750 °C, σb increases by up to one order of magnitude under the dc bias and returns to its initial value on removal of the bias. The enhancement of conductivity is dependent on temperature, atmosphere, dc bias field and the electrode materials. A maximum conductivity enhancement of >2000% is achieved at 600 °C in nitrogen using Pt electrodes. This is in contrast to that observed for other n-type perovskite titanates and oxygen-deficient rutile where σb is suppressed under a dc bias. This 'unusual' non-ohmic behaviour is attributed mainly to the influence of highly mobile oxygen vacancies in NB0.51T. The field-enhanced σb is best described to be a consequence of increased pumping of oxygen from the cathode to the anode, in which the electrode reactions play an important role. In addition, dissociation of defect clusters may also contribute to the enhanced σb under a dc bias. The high, fast and reversible response to the dc bias voltage may expand the potential application of NBT-based materials to memory devices.

Enhanced inhibitory control by neuropeptide Y Y5 receptor blockade in rats.

RATIONALE: The neuropeptide Y (NPY) system acts in synergy with the classic neurotransmitters to regulate a large variety of functions including autonomic, affective, and cognitive processes. Research on the effects of NPY in the central nervous system has focused on food intake control and affective processes, but growing evidence of NPY involvement in attention-deficit/hyperactivity disorder (ADHD) and other psychiatric conditions motivated the present study. OBJECTIVES: We tested the effects of the novel and highly selective NPY Y5 receptor antagonist Lu AE00654 on impulsivity and the underlying cortico-striatal circuitry in rats to further explore the possible involvement of the NPY system in pathologies characterized by inattention and impulsive behavior. RESULTS: A low dose of Lu AE00654 (0.03 mg/kg) selectively facilitated response inhibition as measured by the stop-signal task, whereas no effects were found at higher doses (0.3 and 3 mg/kg). Systemic administration of Lu AE00654 also enhanced the inhibitory influence of the dorsal frontal cortex on neurons in the caudate-putamen, this fronto-striatal circuitry being implicated in the executive control of behavior. Finally, by locally injecting a Y5 agonist, we observed reciprocal activation between dorsal frontal cortex and caudate-putamen neurons. Importantly, the effects of the Y5 agonist were attenuated by pretreatment with Lu AE00654, confirming the presence of Y5 binding sites modulating functional interactions within frontal-subcortical circuits. CONCLUSIONS: These results suggest that the NPY system modulates inhibitory neurotransmission in brain areas important for impulse control, and may be relevant for the treatment of pathologies such as ADHD and drug abuse.

Measuring airway dimensions during bronchoscopy using anatomical optical coherence tomography.

Airway dimensions are difficult to quantify bronchoscopically because of optical distortion and a limited ability to gauge depth. Anatomical optical coherence tomography (aOCT), a novel imaging technique, may overcome these limitations. This study evaluated the accuracy of aOCT against existing techniques in phantom, excised pig and in vivo human airways. Three comparative studies were performed: 1) micrometer-derived area measurements in 10 plastic tubes were compared with aOCT-derived area; 2) aOCT-derived airway compliance curves from excised pig airways were compared with curves derived using an endoscopic technique; and 3) airway dimensions from the trachea to subsegmental bronchi were measured using aOCT in four anaesthetised patients during bronchoscopy and compared with computed tomography (CT) measurements. Measurements in plastic tubes revealed aOCT to be accurate and reliable. In pig airways, aOCT-derived compliance measurements compared closely with endoscopic data. In human airways, dimensions measured with aOCT and CT correlated closely. Bland-Altman plots showed that aOCT diameter and area measurements were higher than CT measurements by 7.6% and 15.1%, respectively. Airway measurements using aOCT are accurate, reliable and compare favourably with existing imaging techniques. Using aOCT with conventional bronchoscopy allows real-time measurement of airway dimensions and could be useful clinically in settings where knowledge of airway calibre is required.

Potent bronchodilation and reduced stiffness by relaxant stimuli under dynamic conditions.

Airway relaxation in response to isoprenaline, sodium nitroprusside (SNP) and electrical field stimulation (EFS) was compared under static and dynamic conditions. The capacity of relaxants to reduce airway stiffness and, thus, potentially contribute to bronchodilation was also investigated. Relaxation responses were recorded in fluid filled bronchial segments from pigs under static conditions and during volume oscillations simulating tidal and twice tidal manoeuvres. Bronchodilation was assessed from the reduction in carbachol-induced lumen pressure, at isovolume points in pressure cycles produced by volume oscillation, and stiffness was assessed from cycle amplitudes. Under static conditions, all three inhibitory stimuli produced partial relaxation of the carbachol-induced contraction. Volume oscillation alone also reduced the contraction in an amplitude-dependent manner. However, maximum relaxation was observed when isoprenaline or SNP were combined with volume oscillation, virtually abolishing contraction at the highest drug concentrations. The proportional effects of isoprenaline and EFS were not different under static or oscillating conditions, whereas relaxation to SNP was slightly greater in oscillating airways. All three inhibitory stimuli also strongly reduced carbachol-induced airway stiffening. The current authors conclude that bronchoconstriction is strongly suppressed by combining the inhibitory stimulation of airway smooth muscle with cyclical mechanical strains. The capacity of airway smooth muscle relaxants to also reduce stiffness may further contribute to bronchodilation.

Airway mechanics and methods used to visualize smooth muscle dynamics in vitro.

Contraction of airway smooth muscle (ASM) is regulated by the physiological, structural and mechanical environment in the lung. We review two in vitro techniques, lung slices and airway segment preparations, that enable in situ ASM contraction and airway narrowing to be visualized. Lung slices and airway segment approaches bridge a gap between cell culture and isolated ASM, and whole animal studies. Imaging techniques enable key upstream events involved in airway narrowing, such as ASM cell signalling and structural and mechanical events impinging on ASM, to be investigated.

Haemochromatosis protein is expressed on the terminal web of enterocytes in proximal small intestine of the rat.

The haemochromatosis protein (HFE) is an important regulator of body iron stores. In the liver, HFE is required for appropriate expression of hepcidin, a humoral mediator of iron absorption. HFE is also present in enterocytes, though its function in the intestine is unknown; it is not intrinsically required for iron absorption, but can augment iron absorption when over-expressed-independent of hepcidin regulation by the liver. In this study, an antibody was raised against rat HFE and validated by enzyme-linked immunosorbent assay, Western blot and quenching of antibody function by the immunising peptide. The sub-cellular location of HFE in enterocytes of iron-deficient and control rats was determined by double-labelling experiments with markers for the microvillus membrane, terminal web, early endosomes, lysosomes and the transferrin receptor. Parallel studies were performed for the primary iron absorption protein, divalent metal transporter 1 (DMT1). HFE co-localised exclusively with the terminal web of intestinal enterocytes. HFE expression was increased in iron deficiency, consistent with a second regulatory role for HFE in iron absorption, independent of hepcidin from the liver. DMT1 was localised primarily on the microvillus membrane, but did partially co-localise with HFE raising the possibility that the two proteins may interact to regulate iron absorption.

Dopamine-mediated regulation of striatal neuronal and network interactions.

The dopaminergic system exerts dynamic modulation of glutamatergic afferent drive that is dependent on the temporal pattern of the dopaminergic input and the subtypes of striatal neurons affected. The differences in feedforward inhibition between striatal neurons comprising the direct and indirect output pathway confer distinct response-pattern differences in their respective targets,supporting brief bursts of activity in Type-I neurons but attenuating repetitive activity in Type-II cells. This temporal patterning is further modulated by NO-mediated signaling, and by tonic and phasic dopamine-mediated stimulation, which exerts preferential actions on indirect and direct output neurons, respectively. As a result,the striatal network is forced into state-dependent patterns of activity that differentially regulate muscle tone and voluntary motor activity via distinct output projections from the striatum.

Striatal nitric oxide signaling regulates the neuronal activity of midbrain dopamine neurons in vivo.

A major component of the cortical regulation of the nigrostriatal dopamine (DA) system is known to occur via activation of striatal efferent systems projecting to the substantia nigra. The potential intermediary role of striatal nitric oxide synthase (NOS)-containing interneurons in modulating the efferent regulation of DA neuron activity was examined using single-unit recordings of DA neurons performed concurrently with striatal microdialysis in anesthetized rats. The response of DA neurons recorded in the substantia nigra to intrastriatal artificial cerebrospinal fluid (ACSF) or drug infusion was examined in terms of mean firing rate, percent of spikes fired in bursts, cells/track, and response to electrical stimulation of the orbital prefrontal cortex (oPFC) and striatum. Intrastriatal infusion of NOS substrate concurrently with intermittent periods of striatal and cortical stimulation increased the mean DA cell population firing rate as compared with ACSF controls. This effect was reproduced via intrastriatal infusion of a NO generator. Infusion of either a NOS inhibitor or NO chelator via reverse microdialysis did not affect basal firing rate but increased the percentage of DA neurons responding to striatal stimulation with an initial inhibition followed by a rebound excitation (IE response) from 40 to 74%. NO scavenger infusion also markedly decreased the stimulation intensity required to elicit an IE response to electrical stimulation of the striatum. In single neurons in which the effects of electrical stimulation were observed before and after drug delivery, NO antagonist infusion was observed to decrease the onset latency and extend the duration of the initial inhibitory phase induced by either oPFC or striatal stimulation. This is the first report showing that striatal NO tone regulates the basal activity and responsiveness of DA neurons to cortical and striatal inputs. These studies also indicate that striatal NO signaling may play an important role in the integration of information transmitted to basal ganglia output centers via corticostriatal and striatal efferent pathways.

Making a difference: immunizing infants and children.

Childhood immunizations, particularly for those under the age of two, is a major health issue. Since the measles epidemic in 1989-1991, the American Nurses Association/Foundation has collaborated with Every Child By Two (ECBT) to protect the nation's youngest from the ravages of vaccine preventable disease. Immunizations are the first line of prevention for infants and children. Healthy People 2000, together with the Presidential Administration's Childhood Immunization Initiative has mandated a goal of 90% immunizations for children under the age of two by the year 2000. As a nation, we are very close to meeting that goal.

The regulation of forebrain dopamine transmission: relevance to the pathophysiology and psychopathology of schizophrenia.

Since the discovery that the therapeutic efficacy of antipsychotic drugs was significantly correlated to their ability to block dopamine D2 receptors, abnormal dopamine transmission in the forebrain has been postulated to underlie psychosis in schizophrenia. In the past 15 years, an impressive amount of clinical and basic research aimed at the study of schizophrenia has indicated that prefrontal and temporal cortical abnormalities may be more important in the etiology of many of the symptoms of schizophrenia, including psychosis. However, the cortical systems that appear to have structural and/or metabolic abnormalities in schizophrenia patients potently regulate forebrain dopamine transmission through a number of mechanisms. In turn, dopamine modulates excitatory transmission mediated by frontal and temporal cortical projections to the basal ganglia and other regions. The present review summarizes the multiple interactions between forebrain DA systems and frontal and temporal corticostriatal transmission. It then examines the role of these interactions in normal behaviors and the psychopathology of schizophrenia.

Nitric oxide and potassium chloride-facilitated striatal dopamine efflux in vivo: role of calcium-dependent release mechanisms.

Previous studies investigating the calcium-dependency of nitric oxide-facilitated striatal dopamine efflux have produced conflicting results. In the current study, we have investigated the role of extracellular calcium in nitric oxide and potassium chloride-evoked striatal dopamine efflux in vivo using microdialysis. Dialysis probes were implanted in the anterior dorsal striatum of chloral hydrate-anesthetized rats. Intrastriatal infusion (20 min fraction) of the nitric oxide generators sodium nitroprusside (200 microM, 500 microM, or 1 mM) and 3-morpholinosydnonimine (1 mM) increased extracellular dopamine levels. The facilitatory effects of 3-morpholinosydnonimine and potassium chloride on dopamine efflux were attenuated following pretreatment (100 min) and co-infusion of calcium free artificial cerebral spinal fluid containing magnesium chloride. Local potassium chloride infusion (100 mM) administered alone elevated striatal dopamine efflux to a similar degree as potassium chloride (100 mM) delivered 60 min after 3-morpholinosydnonimine infusion. These results demonstrate that like potassium chloride, nitric oxide facilitates striatal dopamine efflux in vivo via a mechanism largely dependent on extracellular calcium. Also, as intrastriatal potassium chloride infusion evoked similar increases in extracellular dopamine levels in controls and subjects receiving pretreatment with the NO-generator 3-morpholinosydnonimine, it is unlikely that the functional integrity of DA nerve terminals is compromised via a neurotoxic disruption of plasma membrane potential following enhanced striatal NO production.

Inhibition of glutamate reuptake potentiates endogenous nitric oxide-facilitated dopamine efflux in the rat striatum: an in vivo microdialysis study.

The current study investigated the effects of the nitric oxide synthase (NOS) substrate, N(G)-hydroxy-L-arginine (H-ARG) and the selective glutamate (GLU) reuptake inhibitor (2S)-trans-pyrrolidine-2,4-dicarboxylic acid (PDC) on striatal dopamine (DA) and glutamate (GLU) efflux in vivo. Concentric microdialysis probes were stereotaxically implanted in the anterior-medial striatum of chloral hydrate-anesthetized rats. Intra-striatal infusion of PDC (200 microM) elevated extracellular (EC) DA and GLU levels concurrently over a 10 fraction collecting period without affecting EC asparagine levels. Infusion of H-ARG (200 microM) for six 20-min fractions, also significantly elevated EC DA levels. In the presence of PDC (200 microM), co-perfusion of H-ARG (200 microM) resulted in supra-additive increases in EC DA levels. The synergistic effect of PDC and H-ARG infusion on DA efflux was attenuated by co-infusion of the NOS inhibitor, 7-nitroindazole (100-200 microM). These results suggest that while both endogenous NO and GLU regulate striatal DA efflux via facilitatory influences, enhanced glutamatergic tone on striatal NOS-containing neurons may potentiate NO-synthesis and subsequently NO-induced DA efflux.

Endogenous nitric oxide facilitates striatal dopamine and glutamate efflux in vivo: role of ionotropic glutamate receptor-dependent mechanisms.

We have investigated the influence of the nitric oxide synthase (NOS) substrate, NG-hydroxy-L-arginine (H-ARG) on dopamine (DA) and glutamate (GLU) efflux in vivo using concentric microdialysis probes implanted in the anterior-medial striatum of chloral hydrate-anesthetized rats. Intrastriatal infusion of H-ARG (100 microM, 200 microM, or 1 mM for 120 min) increased DA efflux in a dose-dependent fashion. The facilitatory effect of H-ARG (1 mM) on DA efflux was abolished following pretreatment (80 min) with the constitutive NOS inhibitor 7-nitroindazole (7-NI, 10 microM) but unaffected by L-NG(1-iminoethyl) lysine (100 microM) infusion. As both H-ARG (1 mM) and the NO-generator (+/-)-S-nitroso-N-acetylpenicillamine (1 mM) were observed to increase GLU efflux concurrently with the effect on DA efflux, we evaluated the potential intermediary role of GLU in NO-facilitated DA efflux using ionotropic GLU receptor antagonists. Local infusion of dizocilpine maleate (10 microM) or (+/-)-2-amino-3-[3-(carboxymethoxy)-5-methyl-isoxazol-4-yl] propionic acid (100 microM), attenuated the H-ARG (1 mM)-induced elevation of extracellular DA levels. Conversely, similar treatment with the kainate receptor antagonist d-gamma-glutamyl-aminomethanesulfonic acid did not alter H-ARG-induced DA efflux. To evaluate the regulatory influence of striatal NO on NMDA receptor activation, NMDA (100 microM) was co-perfused with either H-ARG (2 mM) or 7-NI (10 microM). While co-perfusion with 7-NI potentiated NMDA-induced DA efflux, similar treatment with H-ARG (2 mM) abolished the effect. These results demonstrate that endogenous NO production, stimulated via H-ARG-dependent activation of type 1 NOS, enhances striatal DA efflux via an increase in glutamatergic tone on ionotropic GLU-receptors. At higher levels of NOS activation (following H-ARG (2 mM) or NMDA infusion), NO may block glutamatergic neurotransmission via inhibition of NMDA receptor function.

Intrastriatal infusion of (+/-)-S-nitroso-N-acetylpenicillamine releases vesicular dopamine via an ionotropic glutamate receptor-mediated mechanism: an in vivo microdialysis study in chloral hydrate-anesthetized rats.

The existence of both nitric oxide synthase (NOS) immunoreactive interneurons and amino acid neurotransmitter-mediated nitric oxide (NO) release in the striatum suggests a role for NO in modulating striatal function. To explore the potential interaction between NO and dopaminergic neurotransmission, the NO-releasing agent (+/-)-S-nitroso-N-acetylpenicillamine (SNAP) was administered locally into the anterior medial striatum of chloral hydrate-anesthetized rats. SNAP, at 0.5, 1, and 2 mM concentrations, elevated striatal extracellular (EC) dopamine (DA) to 200 +/- 42, 472 +/- 120, and 2,084 +/- 496%, respectively, above baseline levels. Perfusion with (+/-)-penicillamine (PEN, 1 mM), the non-NO-containing carrier component of SNAP, was ineffective, indicating that PEN is not responsible for SNAP-mediated DA release. Additional microdialysis experiments suggest SNAP-mediated DA release is not due to NO-induced neurotoxicity or blockade of the DA transporter. The DA-releasing effect of SNAP was attenuated under calcium-free conditions and abolished in rats pretreated with reserpine (5 mg/kg), implicating a calcium-sensitive vesicular-dependent release process. To determine the mechanism of SNAP-mediated DA release, the guanylyl cyclase (GC) inhibitor LY 83583 (100 microM) was administered 100 min before and during the SNAP pulse. LY 83583 elevated EC DA levels approximately fivefold and potentiated the DA-releasing effect of SNAP to 2,598 +/- 551% above basal DA levels. Similar pretreatments with both the noncompetitive N-methyl-D-aspartate (NMDA) antagonist MK-801 (10 microM) and the competitive NMDA-receptor antagonist (+/-)-3-(carboxypiperazin-4-yl) propyl-1-phosphonic acid [(+/-)-CPP, 100 microM] blocked SNAP-mediated DA release. SNAP-mediated DA release was also significantly blunted by pretreatment and coperfusion with MgSO4 (10 mM) and 6,7-dinitroquinoxaline-2,3-dione (DNQX, 10 microM) but not (+)-2-amino-3-phosphonopropionic acid (AP-3, 10 microM). These results suggest that NO releases DA via a calcium-sensitive vesicular-dependent process that is independent of GC activation. In addition, NMDA and kainate/ (+/-)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-mediated mechanisms are implicated in NO-induced DA release.

Regulation of serotonin-facilitated dopamine release in vivo: the role of protein kinase A activating transduction mechanisms.

Recent neuroanatomical, biochemical, and electrophysiological studies suggest that serotonin (5HT) can modulate dopaminergic function at the level of the cell body and the nerve terminal. The receptor subtypes, regulatory processes, and intracellular transduction mechanisms mediating these interactions remain to be characterized. The potential involvement of cAMP in mediating 5HT-facilitated increases in extracellular levels of striatal dopamine (DA) was assessed using in vivo microdialysis. Local infusion of 0.4 nmol 5HT delivered via probes located in the anterior striata of chloral hydrate-anesthetized male rats significantly increased extracellular DA levels to approximately 700% of basal control levels. Local, intrastriatal infusion of either 2 nmol forskolin, 2 nmol rolipram, 100 nmol isobutylmethylxanthine, or 200 nmol dibutyryl cAMP significantly increased basal DA levels to 28 +/- 3%, 143 +/- 5%, 56 +/- 7%, and 52 +/- 3% above control levels, respectively. Additionally, coperfusion of any of these agents with 5HT significantly decreased the 5HT-facilitory effect on DA release to approximately 50% of observed 5HT controls. The current results suggest a role for the cAMP second-messenger systems in modulating 5HT-facilitated DA release.

Desensitization of 5-hydroxytryptamine-facilitated dopamine release in vivo.

Desensitization to serotonin (5-hydroxytryptamine, 5-HT)-facilitated dopamine release in vivo develops following either continuous or repeated pulses of 5-HT. For instance, an initial 20 min pulse of 5-HT (10 microM) produced a 715 +/- 150% increase in basal dopamine, an effect which steadily declined over 5 subsequent fractions to 222 +/- 80%. Also, secondary pulses (s2) of 5-HT administered 40 min following the primary pulse (s1), elicited a 327 +/- 16% increase in dopamine levels, significantly decreased from the primary s1 pulse. Augmentation of either protein kinase A or protein kinase C systems attenuated 5-HT-facilitated dopamine release, suggesting a role for protein kinases in regulating the desensitization process.