Assessing the Quality of Models of the Ambient Solar Wind.

In this paper we present an assessment of the status of models of the global Solar Wind in the inner heliosphere. We limit our discussion to the class of models designed to provide solar wind forecasts, excluding those designed for the purpose of testing physical processes in idealized configurations. In addition, we limit our discussion to modeling of the 'ambient' wind in the absence of coronal mass ejections. In this assessment we cover use of the models both in forecast mode and as tools for scientific research. We present a brief history of the development of these models, discussing the range of physical approximations in use. We discuss the limitations of the data inputs available to these models and its impact on their quality. We also discuss current model development trends.

Coronal mass ejections are not coherent magnetohydrodynamic structures.

Coronal mass ejections (CMEs) are episodic eruptions of solar plasma and magnetic flux that travel out through the solar system, driving extreme space weather. Interpretation of CME observations and their interaction with the solar wind typically assumes CMEs are coherent, almost solid-like objects. We show that supersonic radial propagation of CMEs away from the Sun results in geometric expansion of CME plasma parcels at a speed faster than the local wave speed. Thus information cannot propagate across the CME. Comparing our results with observed properties of over 400 CMEs, we show that CMEs cease to be coherent magnetohydrodynamic structures within 0.3 AU of the Sun. This suggests Earth-directed CMEs are less like billiard balls and more like dust clouds, with apparent coherence only due to similar initial conditions and quasi homogeneity of the medium through which they travel. The incoherence of CMEs suggests interpretation of CME observations requires accurate reconstruction of the ambient solar wind with which they interact, and that simple assumptions about the shape of the CMEs are likely to be invalid when significant spatial/temporal gradients in ambient solar wind conditions are present.

Global solar wind variations over the last four centuries.

The most recent "grand minimum" of solar activity, the Maunder minimum (MM, 1650-1710), is of great interest both for understanding the solar dynamo and providing insight into possible future heliospheric conditions. Here, we use nearly 30 years of output from a data-constrained magnetohydrodynamic model of the solar corona to calibrate heliospheric reconstructions based solely on sunspot observations. Using these empirical relations, we produce the first quantitative estimate of global solar wind variations over the last 400 years. Relative to the modern era, the MM shows a factor 2 reduction in near-Earth heliospheric magnetic field strength and solar wind speed, and up to a factor 4 increase in solar wind Mach number. Thus solar wind energy input into the Earth's magnetosphere was reduced, resulting in a more Jupiter-like system, in agreement with the dearth of auroral reports from the time. The global heliosphere was both smaller and more symmetric under MM conditions, which has implications for the interpretation of cosmogenic radionuclide data and resulting total solar irradiance estimates during grand minima.

Probabilistic Solar Wind and Geomagnetic Forecasting Using an Analogue Ensemble or "Similar Day" Approach.

Effective space-weather prediction and mitigation requires accurate forecasting of near-Earth solar-wind conditions. Numerical magnetohydrodynamic models of the solar wind, driven by remote solar observations, are gaining skill at forecasting the large-scale solar-wind features that give rise to near-Earth variations over days and weeks. There remains a need for accurate short-term (hours to days) solar-wind forecasts, however. In this study we investigate the analogue ensemble (AnEn), or "similar day", approach that was developed for atmospheric weather forecasting. The central premise of the AnEn is that past variations that are analogous or similar to current conditions can be used to provide a good estimate of future variations. By considering an ensemble of past analogues, the AnEn forecast is inherently probabilistic and provides a measure of the forecast uncertainty. We show that forecasts of solar-wind speed can be improved by considering both speed and density when determining past analogues, whereas forecasts of the out-of-ecliptic magnetic field [ B N ] are improved by also considering the in-ecliptic magnetic-field components. In general, the best forecasts are found by considering only the previous 6 - 12 hours of observations. Using these parameters, the AnEn provides a valuable probabilistic forecast for solar-wind speed, density, and in-ecliptic magnetic field over lead times from a few hours to around four days. For B N , which is central to space-weather disturbance, the AnEn only provides a valuable forecast out to around six to seven hours. As the inherent predictability of this parameter is low, this is still likely a marked improvement over other forecast methods. We also investigate the use of the AnEn in forecasting geomagnetic indices Dst and Kp. The AnEn provides a valuable probabilistic forecast of both indices out to around four days. We outline a number of future improvements to AnEn forecasts of near-Earth solar-wind and geomagnetic conditions.

Ensemble downscaling in coupled solar wind-magnetosphere modeling for space weather forecasting.

Advanced forecasting of space weather requires simulation of the whole Sun-to-Earth system, which necessitates driving magnetospheric models with the outputs from solar wind models. This presents a fundamental difficulty, as the magnetosphere is sensitive to both large-scale solar wind structures, which can be captured by solar wind models, and small-scale solar wind "noise," which is far below typical solar wind model resolution and results primarily from stochastic processes. Following similar approaches in terrestrial climate modeling, we propose statistical "downscaling" of solar wind model results prior to their use as input to a magnetospheric model. As magnetospheric response can be highly nonlinear, this is preferable to downscaling the results of magnetospheric modeling. To demonstrate the benefit of this approach, we first approximate solar wind model output by smoothing solar wind observations with an 8 h filter, then add small-scale structure back in through the addition of random noise with the observed spectral characteristics. Here we use a very simple parameterization of noise based upon the observed probability distribution functions of solar wind parameters, but more sophisticated methods will be developed in the future. An ensemble of results from the simple downscaling scheme are tested using a model-independent method and shown to add value to the magnetospheric forecast, both improving the best estimate and quantifying the uncertainty. We suggest a number of features desirable in an operational solar wind downscaling scheme. KEY POINTS: Solar wind models must be downscaled in order to drive magnetospheric models Ensemble downscaling is more effective than deterministic downscaling The magnetosphere responds nonlinearly to small-scale solar wind fluctuations.

Continuous expression of corticotropin-releasing factor in the central nucleus of the amygdala emulates the dysregulation of the stress and reproductive axes.

An increase in corticotropin-releasing factor (CRF) is a putative factor in the pathophysiology of stress-related disorders. As CRF expression in the central nucleus of the amygdala (CeA) is important in adaptation to chronic stress, we hypothesized that unrestrained synthesis of CRF in CeA would mimic the consequences of chronic stress exposure and cause dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, increase emotionality and disrupt reproduction. To test this hypothesis, we used a lentiviral vector to increase CRF-expression site specifically in CeA of female rats. Increased synthesis of CRF in CeA amplified CRF and arginine vasopressin peptide concentration in the paraventricular nucleus of the hypothalamus, and decreased glucocorticoid negative feedback, both markers associated with the pathophysiology of depression. In addition, continuous expression of CRF in CeA also increased the acoustic startle response and depressive-like behavior in the forced swim test. Protein levels of gonadotropin-releasing hormone in the medial preoptic area were significantly reduced by continuous expression of CRF in CeA and this was associated with a lengthening of estrous cycles. Finally, sexual motivation but not sexual receptivity was significantly attenuated by continuous CRF synthesis in ovariectomized estradiol-progesterone-primed females. These data indicate that unrestrained CRF synthesis in CeA produces a dysregulation of the HPA axis, as well as many of the behavioral, physiological and reproductive consequences associated with stress-related disorders.Molecular Psychiatry (2009) 14, 37-50; doi:10.1038/mp.2008.91; published online 12 August 2008.

Neurotensin and dopamine interactions.

Interactions between the classical monoamine neurotransmitter dopamine (DA) and the peptide neurotransmitter neurotensin (NT) in the central nervous system (CNS) have now been investigated for over two decades. Interest in this topic has been sustained, primarily because of the potential clinical relevance of these interactions to schizophrenia and drug abuse. In the past five years, important new discoveries in the NT field have markedly expanded our previous database. Additional NT receptors have been cloned, and novel and refined techniques have contributed to a more detailed description of the anatomy of the CNS NT system. Additionally, lipophilic NT receptor antagonists, active in the CNS after peripheral administration, have rendered more facile the investigation of the physiologic importance of endogenous NT at electrophysiologic, neurochemical, and behavioral levels. In the present review, the discussion of NT/DA interactions will progress from a discussion of the anatomical interactions between these two systems, to electrophysiologic and neurochemical interactions, and finally to behavioral implications-always with focus toward the potential clinical relevance of the data. The discussion of interactions between NT and DA systems will be limited to those occurring within the CNS. Moreover, because the DA projections from the midbrain to the striatum account for the bulk of the DA innervation in the CNS, we will focus on NT/DA interactions within these brain regions. Last, because of the extensive literature on NT/DA interactions available in the rat, our discussion will be based primarily on studies using this species.

The role of neurotensin in the pathophysiology of schizophrenia and the mechanism of action of antipsychotic drugs.

It has become increasingly clear that schizophrenia does not result from the dysfunction of a single neurotransmitter system, but rather pathologic alterations of several interacting systems. Targeting of neuropeptide neuromodulator systems, capable of concomitantly regulating several transmitter systems, represents a promising approach for the development of increasingly effective and side effect-free antipsychotic drugs. Neurotensin (NT) is a neuropeptide implicated in the pathophysiology of schizophrenia that specifically modulates neurotransmitter systems previously demonstrated to be dysregulated in this disorder. Clinical studies in which cerebrospinal fluid (CSF) NT concentrations have been measured revealed a subset of schizophrenic patients with decreased CSF NT concentrations that are restored by effective antipsychotic drug treatment. Considerable evidence also exists concordant with the involvement of NT systems in the mechanism of action of antipsychotic drugs. The behavioral and biochemical effects of centrally administered NT remarkably resemble those of systemically administered antipsychotic drugs, and antipsychotic drugs increase NT neurotransmission. This concatenation of findings led to the hypothesis that NT functions as an endogenous antipsychotic. Moreover, typical and atypical antipsychotic drugs differentially alter NT neurotransmission in nigrostriatal and mesolimbic dopamine (DA) terminal regions, and these effects are predictive of side effect liability and efficacy, respectively. This review summarizes the evidence in support of a role for the NT system in both the pathophysiology of schizophrenia and the mechanism of action of antipsychotic drugs.

Second-generation SSRIs: human monoamine transporter binding profile of escitalopram and R-fluoxetine.

BACKGROUND: Single isomers of the selective serotonin reuptake inhibitors citalopram (escitalopram, S-citalopram) and fluoxetine (R-fluoxetine) are currently under development for the treatment of depression and other psychiatric disorders. Previous studies conducted in laboratory animals have revealed that the biological effects on serotonin reuptake for citalopram reside in the S enantiomer. In contrast, both enantiomers of fluoxetine contribute to its biological activity. METHODS: In the present study, the potency and selectivity of escitalopram, R-fluoxetine, and all of the other currently available selective serotonin reuptake inhibitors were compared for binding affinity at the human serotonin, norepinephrine, and dopamine transporters and several select neurotransmitter receptors using radioligand binding assays. RESULTS: Both escitalopram and R-fluoxetine were potent inhibitors of the serotonin transporter (K(i) = 1.1 and 1.4 nmol/L, respectively). Escitalopram was the most serotonin transporter-selective compound tested and was approximately 30-fold more potent than R-citalopram. CONCLUSIONS: As noted previously, paroxetine and sertraline possess moderate affinity (<50 nmol/L) for the human norepinephrine transporter and dopamine transporter, respectively. R-Fluoxetine, unlike the other selective serotonin reuptake inhibitors, possesses moderate affinity (K(i) = 64 nmol/L) for the serotonin 2C receptor. Potential clinical correlates of these unique attributes of escitalopram and R-fluoxetine are discussed.

Variable foraging demand rearing: sustained elevations in cisternal cerebrospinal fluid corticotropin-releasing factor concentrations in adult primates.

BACKGROUND: The authors previously reported elevated cerebrospinal fluid (CSF) corticotropin-releasing factor (CRF) concentrations in juvenile primates nursed by mothers undergoing experimentally imposed unpredictable foraging conditions in comparison to normally reared controls. The purpose of the present study was to determine if these changes would endure into young adulthood. METHODS: Cisternal CSF samples were obtained from those unpredictably reared young adult primates who had been previously studied as juveniles and age-matched ad libitum normally reared controls. Samples were assayed for CSF CRF. RESULTS: Concentrations of CSF CRF were significantly elevated in the unpredictably reared sample in comparison to the ad libitum-reared control group. A significant positive correlation was noted between juvenile and young adult CSF CRF values within the unpredictably reared cohort. CONCLUSIONS: Disturbances of maternal-infant attachment processes have an enduring impact on primate CRF function into young adulthood. The CRF elevations following unpredictable maternal foraging conditions appear traitlike in nature.

Effects of sodium valproate on corticotropin-releasing factor systems in rat brain.

We hypothesized that divalproex sodium, an anticonvulsant effective in the acute treatment of mania, may act upon neuropeptide systems that utilize corticotropin-releasing factor (CRF). Pharmacokinetic studies demonstrated that valproate has an apparent elimination half life of 17 minutes in rats after acute administration and that there is a nonlinear relationship between chronic dose and serum drug concentration. Acute valproate treatment neither altered plasma adrenocorticotropic hormone (ACTH) or corticosterone concentrations nor produced changes in CRF concentration in any of 10 brain regions examined. Subchronic treatment via SC-implanted osmotic minipumps (875 mg/kg/day x 7 days) resulted in decreased CRF concentrations in the median eminence and raphe nuclei. Moreover, CRF mRNA expression was decreased in the central nucleus of the amygdala (CeA) and paraventricular nucleus (PVN) of the hypothalamus. The benzodiazepine alprazolam, also a positive modulator of GABAergic function, similarly decreases CRF mRNA expression in the CeA. These results suggest that the mood stabilizing effects of valproic acid may be mediated in part by alterations in CRF neuronal activity.

Synthesis and characterization of fluorinated and iodinated pyrrolopyrimidines as PET/SPECT ligands for the CRF1 receptor.

Fluorine-18 labeled fluorobutyl[2,5-dimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo [2,3-d] pyrimidin-4-yl]ethylamine (FBPPA) and iodine-123 labeled butyl[2,5-dimethyl-7-(4-iodo-2,6-dimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]ethyl-amine (IBPPA) were synthesized in the development of a CRF receptor ligand. The methods of synthesis, in vitro binding assays, radiolabeling and in vivo tissue distribution in rats are described. Fluorine-18 labeled FBPPA was prepared with high specific activity (3 x 10(4) Ci/mmol) by nucleophilic displacement with an average radiochemical yield of 6% (EOB). Iodine-123 labeled IBPPA was prepared by electrophilic iododestannylation with good yield (60%) and high specific activity (3.3 x 10(3) Ci/mmol). The retention of FBPPA and IBPPA in the pituitary was good (1.16% i.d./g and 2.35% i.d./g respectively at 60 min). However, the accumulation of radioactivity in the brain for both radiotracers was very low at all time points of the study, which demonstrated the difficulties for these radiopharmaceuticals to penetrate the blood brain barrier (BBB).

Neurokinin(1) receptor antagonists as potential antidepressants.

Selective, nonpeptide antagonists for tachykinin receptors first became available ten years ago. Of the three known tachykinin receptors, drug development has focused most intensively on the substance P-preferring receptor, neurokinin(1) (NK(1)). Although originally studied as potential analgesic compounds, recent evidence suggests that NK(1) receptor antagonists may possess antidepressant and anxiolytic properties. If confirmed by further controlled clinical studies, this will represent a mechanism of action distinct from all existing antidepressant agents. As reviewed in this chapter, the existing preclinical and clinical literature is suggestive of, but not conclusive, concerning a role of substance P and NK(1) receptors in the pathophysiology of depression and/or anxiety disorders. The ongoing clinical trials with NK(1) receptor antagonists have served as an impetus for much needed, basic research in this field.

Enhanced neurotensin neurotransmission is involved in the clinically relevant behavioral effects of antipsychotic drugs: evidence from animal models of sensorimotor gating.

To date, none of the available antipsychotic drugs are curative, all have significant side-effect potential, and a receptor-binding profile predictive of superior therapeutic ability has not been determined. It has become increasingly clear that schizophrenia does not result from the dysfunction of a single neurotransmitter system, but rather from an imbalance between several interacting systems. Targeting neuropeptide neuromodulator systems that concertedly regulate all affected neurotransmitter systems could be a promising novel therapeutic approach for schizophrenia. A considerable database is concordant with the hypothesis that antipsychotic drugs act, at least in part, by increasing the synthesis and release of the neuropeptide neurotensin (NT). In this report, we demonstrate that NT neurotransmission is critically involved in the behavioral effects of antipsychotic drugs in two models of antipsychotic drug activity: disrupted prepulse inhibition of the acoustic startle response (PPI) and the latent inhibition (LI) paradigm. Blockade of NT neurotransmission using the NT receptor antagonist 2-[[5-(2,6-dimethoxyphenyl)-1-(4-(N-(3-dimethylaminopropyl)-N-methylcarbamoyl)-2-isopropylphenyl)-1H- pyrazole-3-carbonyl]-amino]-adamantane-2-carboxylic acid, hydrochloride (SR 142948A) prevented the normal acquisition of LI and haloperidol-induced enhancement of LI. In addition, SR 142948A blocked the PPI-restoring effects of haloperidol and the atypical antipsychotic drug quetiapine in isolation-reared animals deficient in PPI. We also provide evidence of deficient NT neurotransmission as well as a left-shifted antipsychotic drug dose-response curve in isolation-reared rats. These novel findings, together with previous observations, suggest that neurotensin receptor agonists may represent a novel class of antipsychotic drugs.

The effects of glutamate receptor agonists on neurotensin release using in vivo microdialysis.

In the present study, extracellular concentrations of neurotensin were measured from the striatum, nucleus accumbens and the medial prefrontal cortex in the awake, freely moving rat. Using a highly sensitive solid phase radioimmunoassay, basal concentrations of neurotensin were 2-5 pg/sample. In each region, glutamate receptor agonists, N-methyl-D-aspartate (NMDA) and kainic acid, increased neurotensin release 2-3-fold. Preincubation with the Na(+) channel blocker tetrodotoxin abolished the glutamate receptor agonist-induced increases except in the striatum following kainic acid infusion. These findings indicate that activation of glutamate receptors may indirectly stimulate neurotensin release.

The effects of acute antipsychotic drug administration on the neurotensin system of the developing rat brain.

The effects of antipsychotic drugs on the neurotensin (NT) system have been well characterized in adult male animals. There is considerable evidence that the NT system undergoes distinct age-related changes during development of the rat brain. This observation in conjunction with antipsychotic pharmacotherapy in children and breast feeding women led us to characterize the effects of antipsychotic drug administration in neonatal rats. The effects of a single subcutaneous injection of haloperidol (2.0 mg/kg) on the developing NT system were determined between postnatal days 10 and 21. Haloperidol significantly increased NT/neuromedin N (NT/NN) mRNA expression and NT concentrations in the caudate/putamen as early as postnatal day 10. Haloperidol did not increase NT/NN mRNA expression in the nucleus accumbens until postnatal day 15 and did not increase NT concentrations in this brain region until postnatal day 21. These results demonstrate that there is a critical time point in development before which the NT system does not respond to antipsychotic drug administration in the same manner as the mature rat.

Cerebrospinal fluid corticotropin-releasing hormone in healthy humans: effects of yohimbine and naloxone.

CRH neurons projecting from the paraventricular nucleus (PVN) of the hypothalamus to the median eminence control hypothalamic-pituitary-adrenal (HPA) axis activity. However, CRH neurons outside the PVN as well as PVN neurons projecting to sites other than the median eminence also contribute to the stress response and may play a role in mood and anxiety disorders. We have attempted to investigate possible noradrenergic and opioid regulation of these non-HPA CRH neurons. We hypothesized that yohimbine (an alpha2-adrenergic antagonist) would have stimulatory action on non-HPA CRH neurons, whereas naloxone (a mu-opioid receptor antagonist) would not have this effect. Adult normal volunteers received i.v. yohimbine (n = 5; 0.4 microg/kg), naloxone (n = 4; 125 microg/kg), or placebo (n = 3; 0.9% saline). Cerebrospinal fluid (CSF) was collected continuously, and concentrations of CSF CRH, CSF norepinephrine (NE), and plasma cortisol were measured. Administration of either yohimbine or naloxone caused significant increases in plasma cortisol concentrations over time. Although yohimbine robustly increased CSF NE levels and appeared to increase CSF CRH levels, these effects were not seen after naloxone or placebo administration. Intraindividual correlations were not observed between the measured concentrations of plasma cortisol and CSF CRH for any of the subjects. The results support the idea that CSF CRH concentrations reflect the activity of non-HPA CRH neurons. Although both yohimbine and naloxone stimulated the HPA axis, only yohimbine appeared to have stimulatory effects on central NE and non-HPA CRH.

The neurobiology of urocortin.

Urocortin (UCN) is a recently isolated 40 amino acid-containing neuropeptide that is the second endogenous mammalian ligand for the corticotropin-releasing factor (CRF) receptors. While UCN and CRF both display a similar high affinity for the CRF(1) receptor, the affinity of UCN for the CRF(2) receptor is more than 10-fold higher than that of rat/human CRF. UCN mRNA expression is highest in the Edinger-Westphal nucleus and lateral superior olive, with the most prominent terminal fields found in the lateral septum. Because of the higher relative affinity of UCN for the CRF(2) receptor and the corresponding neuroanatomical distribution of the highest density of UCN expression and innervation to brain regions preferentially expressing the CRF(2) receptor subtype, it has been hypothesized that UCN is the preferred endogenous ligand for the CRF(2) receptor. Following central administration, UCN has been demonstrated to produce behavioral and physiological effects that are qualitatively similar to CRF. Quantitatively, however, UCN appears to be a more potent suppressor of ingestive behavior (food and water intake) and a less potent inducer of anxiogenic behavior than CRF.

Effects of acute and subchronic administration of typical and atypical antipsychotic drugs on the neurotensin system of the rat brain.

The acute and subchronic effects of a variety of doses of a prototype typical (haloperidol) or one of several atypical antipsychotic drugs (clozapine, olanzapine, risperidone, quetiapine, or sertindole) on regional brain neurotensin (NT) tissue concentrations, and NT receptor binding were examined. Acute administration of haloperidol, clozapine, olanzapine, and risperidone dose-dependently increased NT tissue concentrations in the nucleus accumbens. Haloperidol, olanzapine, risperidone, and sertindole also increased NT tissue concentrations in the caudate nucleus. NT tissue concentrations in the nucleus accumbens and caudate remained elevated after 14-day administration of haloperidol, olanzapine, sertindole, and risperidone. In contrast, at the doses studied, quetiapine decreased NT tissue concentrations in the nucleus accumbens; clozapine had no effect. Haloperidol significantly increased NT receptor binding in the substantia nigra after 14-day administration. All of the atypical antipsychotic drugs decreased NT receptor binding in the nucleus accumbens and in the substantia nigra. Although these studies do not conclusively support the hypothesis that increased NT neurotransmission is involved in the clinically relevant effects of all antipsychotic drugs, the extant evidence clearly suggests that further study is warranted. Inconsistencies in the data suggest that differential effects of antipsychotic drug administration on subpopulations of NT neurons must be scrutinized further.