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.

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.

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.

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.

Chronic administration of the triazolobenzodiazepine alprazolam produces opposite effects on corticotropin-releasing factor and urocortin neuronal systems.

In view of the substantial preclinical evidence that supports a seminal role of central corticotropin-releasing factor (CRF) neuronal systems in the physiology and pathophysiology of stress and anxiety, it is reasonable to suggest that the anxiolytic properties of benzodiazepines are mediated, at least in part, via regulation of CRFergic function. To begin to test this complex hypothesis, we examined the effects of acute and chronic administration of the triazolobenzodiazepine agonist alprazolam on CRF peptide concentrations, receptor-binding density, and mRNA expression in the CNS. Additionally, we measured mRNA expression for urocortin, a recently discovered neuropeptide that is generally considered to be a second endogenous ligand for CRF receptors. Both acute and chronic alprazolam administration was found to decrease CRF concentrations within the locus coeruleus. Furthermore, chronic alprazolam decreased basal activity of the hypothalamic-pituitary-adrenal axis, CRF mRNA expression in the central nucleus of the amygdala, and CRF(1) mRNA expression and receptor binding in the basolateral amygdala. In marked contrast, urocortin mRNA expression in the Edinger-Westphal nucleus and CRF(2A) receptor binding in the lateral septum and ventromedial hypothalamus were increased. Similar findings of an inverse relationship between the CRF(1) and CRF(2A) receptor systems have been reported in an anxiety model based on adverse early-life experience, suggesting the intriguing possibility that CRF neuronal systems may be comprised of two separate, but interrelated, subdivisions that can be coordinately and inversely regulated by stress, anxiety, or anxiolytic drugs.

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.

Reduced corticotropin releasing factor binding sites in the frontal cortex of suicide victims.

Previous studies have provided evidence that corticotropin releasing factor (CRF) is hypersecreted in patients with major depression. This CRF hypersecretion is believed to contribute at least in part to hyperactivity of the hypothalamic-pituitary-adrenal axis in depressed patients. If CRF is chronically hypersecreted in depressed patients, then, due to down-regulation, a reduced number of CRF receptor binding sites should be present in patients with profound depressive disorder. To test this hypothesis, we measured the number and affinity of CRF binding sites in the frontal cortex of 26 suicide victims and 29 controls who died of a variety of causes. There was a marked (23%) reduction in the number of CRF binding sites in the frontal cortex of the suicide victims compared with the controls. These data are consistent with the hypothesis that CRF is hypersecreted in depression.

Cerebrospinal fluid concentrations of somatostatin and biogenic amines in grown primates reared by mothers exposed to manipulated foraging conditions.

BACKGROUND: In an earlier study, infant primates were nursed by mothers randomly assigned to variable foraging demand (VFD) or nonvariable foraging conditions (non-VFD). A group of grown VFD-reared subjects demonstrated elevations of cisternal cerebrospinal fluid (CSF) corticotropin-releasing factor concentrations and decreased CSF cortisol levels vs non-VFD counterparts. To further characterize neurobiological sequelae of disturbed early rearing, CSF concentrations of serotonin, dopamine, and norepinephrine metabolites (5-hydroxyindoleacetic acid, homovanillic acid, and 3-methoxy-4-hydroxyphenethyleneglycol [MHPG], respectively) and of somatostatin were determined. METHODS: Second CSF taps were obtained from the previously studied cohort of 30 subjects and from 28 age-matched ad libitum-reared control subjects. Relevant assays were performed. RESULTS: All neurochemicals assayed except MHPG were elevated in the VFD-reared compared with non-VFD subjects. In the VFD group, statistically significant positive correlations between corticotropin-releasing factor and each neurochemical was found, except for MHPG. In the non-VFD subjects, no significant correlations with corticotropin-releasing factor were observed. No effect of age was evident. CONCLUSIONS: Reducing the predictability of maternal foraging demand during early rearing was associated with elevations of cisternal somatostatin and of serotonin and dopamine metabolite concentrations in grown offspring. The corticotropin-releasing factor elevations reported previously were positively correlated with all the elevated CSF parameters of the current study. The findings support the notion that adverse early rearing experiences in primates have longstanding and complex effects on a range of neurochemicals relevant to emotional regulation. Replication in prospective age-controlled studies is warranted.

Persistent changes in corticotropin-releasing factor neuronal systems induced by maternal deprivation.

There is considerable evidence that CRF-containing neurons integrate the endocrine, autonomic, immune, and behavioral responses to stress. In this study we examined long term effects of early stress on developing hypothalamic and extrahypothalamic CRF neural systems in the rat brain and subsequent responses to stress in the adult. Specifically, we sought to determine whether adult male rats previously isolated for 6 h daily during postnatal days 2-20 react in a biochemically distinct manner to a mild foot shock stress compared to controls. Four treatment groups were examined: nondeprived (NDEP)/no shock, NDEP/shock, deprived (DEP)/no shock, and DEP/shock. Compared to the NDEP group, DEP rats exhibited an increase in both basal and stress-induced ACTH concentrations. Moreover, DEP rats exhibited a 125% increase in immunoreactive CRF concentrations in the median eminence and a reduction in the density of CRF receptor binding in the anterior pituitary compared to those in all NDEP rats. Alterations in extrahypothalamic CRF systems were also apparent in DEP vs. NDEP animals, with an observed 59% increase in the number of CRF receptor-binding sites in the raphe nucleus and an 86% increase in immunoreactive CRF concentrations in the parabrachial nucleus. These results indicate that maternal deprivation before weaning in male rats produces effects on CRF neural systems in both the central nervous system and pituitary that are apparent several months later and are probably associated with persistent alterations in behavioral response in adult rats.

Role for brain corticotropin-releasing factor in the weight-reducing effects of chronic fenfluramine treatment in rats.

Fenfluramine is an amphetamine derivative which is used as a weight-reducing agent in the treatment of obesity. It has been postulated that fenfluramine affects brain serotonin (5HT) neurons resulting in decreased food intake and altered autonomic outflow which, in turn, increases metabolism. CRF decreases food intake and, in addition, has been demonstrated to reduce body weight in genetically obese rats through selective activation of sympathetic and inhibition of parasympathetic outflows. Because 5HT is a potent CRF secretagogue, we tested the hypothesis that the weight-reducing effects of fenfluramine administration may be mediated, in part, through altered CRF secretion. Chronic fenfluramine treatment (1-24 mg/kg sc, twice daily, 4 days) resulted in a dose-dependent decrease in hypothalamic CRF concentration at 30 min after the final drug injection and was accompanied by a significant reciprocal increase in plasma corticosterone concentration. These data suggest that the decrease in hypothalamic CRF was a consequence of increased CRF secretion. These changes in hypothalamic CRF and plasma corticosterone correlated with brain fenfluramine levels. In contrast, high dose fenfluramine treatment significantly increased hippocampus, midbrain, and spinal cord CRF concentrations whereas levels in cerebral cortex, caudate putamen, thalamus, pons/medulla, and cerebellum were unaffected. There was no effect of this fenfluramine treatment protocol on regional brain TRH or neurotensin concentrations. In keeping with the well known development of tolerance to the weight-reducing effects of fenfluramine, chronic fenfluramine treatment resulted in lesser increases in corticosterone secretion than after acute treatment. Whereas weight loss observed after chronic fenfluramine treatment was associated with stimulation of hypothalamic-pituitary-adrenocortical hormone secretion, the weight-recovery phase after cessation of drug treatment was associated with decreased levels of plasma corticosterone. These data, demonstrating fenfluramine-induced alterations in brain CRF and plasma corticosterone, suggest that CRF may represent an important endogenous transmitter which mediates the weight-reducing effects of the drug.

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.

Paroxetine binding to the rat norepinephrine transporter in vivo.

BACKGROUND: The norepinephrine transporter (NET)/uptake site is an antidepressant-sensitive transporter located on plasma membranes of noradrenergic neurons and other specialized cells that remove norepinephrine (NE) from the synapse to terminate the actions of NE. The antidepressant paroxetine is believed to produce its therapeutic effects primarily by acting as a highly selective antagonist of the serotonin transporter (SERT). However, in vitro data indicates that paroxetine inhibits the NET. The present study was designed to determine whether paroxetine inhibits in NET in vivo. METHODS: Rats were administered paroxetine (6.5, 10.0, or 15.0 mg/kg/day) via osmotic minipumps for 1 week. Following attainment of steady state serum concentrations, cortical NET function was assessed by both [3H]-nisoxetine binding and [3H]-norepinephrine uptake assays conducted ex vivo. RESULTS: In unwashed brain homogenates, serum paroxetine concentrations greater than 100 ng/mL were positively correlated with the observed Kd for [3H]-nisoxetine. At [3H]-nisoxetine concentrations associated with 50% transporter occupancy in vehicle treated rats, [3H]-nisoxetine binding was decreased 21% and 34% in rats exhibiting serum paroxetine concentrations > 100 ng/mL and > 500 ng/mL, respectively. CONCLUSIONS: Although paroxetine is a very potent inhibitor of the SERT, paroxetine also inhibits the NET at serum concentrations > 100 ng/mL. This novel finding may underlie the broad therapeutic utility of paroxetine in mood and anxiety disorders.

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.

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.

Effects of gender and social isolation on electroencephalogram and neuroendocrine parameters in rats.

Social separation/isolation from either maternal or peer influence can induce a biobehavioral response in rodents and nonhuman primates seeming to mimic certain aspects of human psychopathology. To further explore this paradigm, the effects of 6 weeks of social isolation on electroencephalographic (EEG) recordings and hypothalamic-pituitary-adrenal (HPA) functioning were studied in male and female adult rats. Gender differences were observed in EEG and HPA axis functioning in these rats. Female rats, overall, were found to have higher levels of EEG slow-wave activity over the entire recording period, suggesting more intense levels of slow-wave sleep in those animals. Female rats were also observed to have overall higher plasma corticosterone concentrations and a lower anterior pituitary corticotropin-releasing factor (CRF) receptor density compared with male rats. The male rats, however, showed greater changes in response to social isolation than female rats. EEG power was increased as a result of social isolation in the male animals during the first 30-100 min of the recording. Reductions in the number of CRF receptors were also observed in the brains of the socially isolated rats in several cortical areas; however, again this effect was more prominent in the male animals. These studies suggest that gender is an important variable in determining the biobehavioral response to social isolation.

Preliminary studies of 6 beta-hydroxydexamethasone and its importance in the DST.

The role of the metabolites of dexamethasone (DEX) in the dexamethasone suppression test (DST) has never been fully elucidated. We report here our preliminary studies of 6 beta-hydroxydexamethasone (6 OH-Dex), a known metabolite of DEX, on the hypothalamic-pituitary-adrenal (HPA) axis of the rat; its activity in the most commonly used radioimmunoassay for plasma DEX; and its plasma concentrations in a normal human subject during the standard 1.0 mg DST. Six OH-Dex administered subcutaneously to rats at a dose of 1 mg/kg was able to completely suppress corticosterone production for at least 3 hr. In the IgG Corp. radioimmunoassay for plasma DEX, 6 OH-Dex was moderately cross-reactive yielding a 50% cross-reactivity of 10%. Gas chromatographic coupled mass spectroscopic analysis of human plasma samples, obtained 12 to 20 hr after the oral ingestion of 1.0 mg DEX, demonstrated similar plasma concentrations for both the parent compound and the 6-hydroxyl metabolite. The relevance of these findings, particularly to pharmacokinetic studies of the DST, is 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.

Reduced brain serotonin transporter availability in major depression as measured by [123I]-2 beta-carbomethoxy-3 beta-(4-iodophenyl)tropane and single photon emission computed tomography.

BACKGROUND: Prior research has suggested reductions in the density of serotonin transporter (SERT) binding sites in blood platelets and post-mortem brain tissue of depressed patients. We sought to determine whether patients with unipolar major depression have diminished SERT availability as assessed by both brainstem [123I] beta-CIT SPECT and platelet [3H]paroxetine binding. METHODS: Drug-free depressed and healthy subjects were injected with 211 +/- 22 MBq [123I] beta-CIT and imaged 24 +/- 2 h later under equilibrium conditions. A ratio of specific to nonspecific brain uptake (V3" = (brainstem-occipital)/occipital), a measure proportional to the binding potential (Bmax/Kd), was used for all comparisons. RESULTS: Results showed a statistically significant reduction in brainstem V3" values in depressed as compared to healthy subjects (3.1 +/- .9 vs. 3.8 +/- .8, p = .02). Platelet [3H]paroxetine binding was not altered (Bmax = 2389 +/- 484 vs. 2415 +/- 538 fmol/mg protein, p = .91) and was not significantly correlated with brainstem [123I] beta-CIT binding (r = -0.14, p = .48). CONCLUSIONS: These data are the first to suggest reductions in the density of brain SERT binding sites in living depressed patients. These findings provide further support for a preeminent role for alterations in serotonergic neurons in the pathophysiology of depression.