The NK1R-/- mouse phenotype suggests that small body size, with a sex- and diet-dependent excess in body mass and fat, are physical biomarkers for a human endophenotype with vulnerability to attention deficit hyperactivity disorder.

The abnormal behaviour of NK1R-/- mice (locomotor hyperactivity, inattentiveness and impulsivity in the 5-Choice Serial Reaction-Time Test) is arguably analogous to that of patients with attention deficit hyperactivity disorder (ADHD). Evidence suggests that small body size and increased body weight are risk factors for ADHD. Here, we compared the body size, body mass and body composition of male and female NK1R-/- mice and their wildtypes that had been fed either standard laboratory chow or a high-fat (45%: 'Western') diet. Male NK1R-/- mice from both cohorts were approximately 7% shorter than wildtypes. A similar trend was evident in females. Male NK1R-/- mice fed the normal diet weighed less than wildtypes but the 'body mass index' ('mBMI': weight (mg)/length (cm)(2)) of female NK1R-/- mice was higher than wildtypes. When given the high-fat diet, the mBMI of both male and female NK1R-/- mice was higher than wildtypes. There were no consistent genotype or sex differences in protein, ash or water content of mice from the two cohorts. However, the fat content of male NK1R-/- mice on the Western diet was considerably (35%) higher than wildtypes and resembled that of females from both genotypes. We conclude that a lack of functional NK1R is associated with small body size but increases vulnerability to an increase in mBMI and fat content, especially in males. This phenotype could also be evident in ADHD patients with polymorphism(s) of the TACR1 gene (the human equivalent of Nk1r)

Atomoxetine reduces hyperactive/impulsive behaviours in neurokinin-1 receptor 'knockout' mice.

Mice with functional ablation of the neurokinin-1 receptor gene (NK1R(-/-)) display behavioural abnormalities which resemble the hyperactivity, inattention and impulsivity seen in Attention Deficit Hyperactivity Disorder (ADHD). Here, we investigated whether the established ADHD treatment, atomoxetine, alleviates these abnormalities when tested in the light/dark exploration box (LDEB) and 5-Choice Serial Reaction-Time Task (5-CSRTT)

Catecholamines: Knowledge and Understanding in the 1960s, now, and in the future

The late 1960s was a heyday for catecholamine research. Technological developments made it feasible to study the regulation of sympathetic neuronal transmission and to map the distribution of noradrenaline and dopamine in the brain. At last, it was possible to explain the mechanism of action of some important drugs that had been used in the clinic for more than a decade (e.g. the first generation of antidepressants) and to contemplate the rational development of new treatments (e.g. l-dihydroxyphenylalanine therapy, to compensate for the dopaminergic neuropathy in Parkinson’s disease, and β1-adrenoceptor antagonists as antihypertensives). The fact that drug targeting noradrenergic and/or dopaminergic transmission are still the first-line treatments for many psychiatric disorders (e.g. depression, schizophrenia, and attention deficit hyperactivity disorder) is a testament to the importance of these neurotransmitters and the research that has helped us to understand the regulation of their function. This article celebrates some of the highlights of research at that time, pays tribute to some of the subsequent landmark studies, and appraises the options for where it could go next

Contrasting changes in extracellular dopamine and glutamate along the rostrocaudal axis of the anterior cingulate cortex of the rat following an acute d-amphetamine or dopamine challenge.

There is evidence for functional specificity of subregions along the rostrocaudal axis of the anterior cingulate cortex (ACC). The subregion-specific distribution of dopaminergic afferents and glutamatergic efferents along the ACC make these obvious candidates for coding such regional responses. We investigated this possibility using microdialysis in freely-moving rats to compare changes in extracellular dopamine and glutamate in the rostral ('rACC: Cg1 and Cg3 (prelimbic area)) and caudal ('cACC': Cg1 and Cg2) ACC induced by systemic or local administration of d-amphetamine. Systemic administration of d-amphetamine (3 mg/kg, i.p.) caused a transient increase in extracellular dopamine in the rACC, but an apparent increase in the cACC of the same animals was less clearly defined. Local infusion of d-amphetamine increased dopamine efflux in the rACC, only. Glutamate efflux in the rACC was increased by local infusion of dopamine (5-50 μM), which had negligible effect in the cACC, but only systemic administration of d-amphetamine into the cACC increased glutamate efflux. The asymmetry in the neurochemical responses within the rACC and cACC, to the same experimental challenges, could help explain why different subregions are recruited in the response to specific environmental and somatosensory stimuli and should be taken into account when studying the regulation of neurotransmission in the ACC. This article is part of a Special Issue entitled 'CNS Stimulants'

A closer look at chaotic advection in the stratosphere: part II: statistical diagnostics

Statistical diagnostics of mixing and transport are computed for a numerical model of forced shallow-water flow on the sphere and a middle-atmosphere general circulation model. In particular, particle dispersion statistics, transport fluxes, Liapunov exponents (probability density functions and ensemble averages), and tracer concentration statistics are considered. It is shown that the behavior of the diagnostics is in accord with that of kinematic chaotic advection models so long as stochasticity is sufficiently weak. Comparisons with random-strain theory are made

The behavioural response of NK1R-/- mice to guanfacine resembles its clinical profile in treatment of ADHD.

Mice with functional ablation of substance P-preferring neurokinin-1 receptors (NK1R-/-) display behavioural abnormalities resembling those seen in Attention Deficit Hyperactivity Disorder (ADHD). Here, we investigated whether the ADHD treatment, guanfacine, alleviates the hyperactivity and impulsivity/inattention displayed by NK1R-/- mice in the light/dark exploration box (LDEB) and 5-Choice Serial Reaction-Time Task (5-CSRTT), respectively. Prompted by reports of comorbid anxiety in ADHD, we also investigated the effects of guanfacine on anxiety-like behaviour displayed by NK1R-/- and wildtype mice in the elevated plus-maze (EPM)

Depression in Visual Impairment Trial (DEPVIT): A Randomized Clinical Trial of Depression Treatments in People With Low Vision

Supported by Guide Dogs (Grant OR-2009 07b)

The Hubble Space Telescope Cluster Supernova Survey: II. The Type Ia Supernova Rate in High-Redshift Galaxy Clusters

We report a measurement of the Type Ia supernova (SN Ia) rate in galaxy clusters at 0.9 < z < 1.45 from the Hubble Space Telescope (HST) Cluster Supernova Survey. This is the first cluster SN Ia rate measurement with detected z > 0.9 SNe. Finding 8 +/- 1 cluster SNe Ia, we determine a SN Ia rate of 0.50 +0.23-0.19 (stat) +0.10-0.09 (sys) SNuB (SNuB = 10^-12 SNe L_{sun,B}^-1 yr^-1). In units of stellar mass, this translates to 0.36 +0.16-0.13 (stat) +0.07-0.06 (sys) SNuM (SNuM = 10^-12 SNe M_sun^-1 yr^-1). This represents a factor of approximately 5 +/- 2 increase over measurements of the cluster rate at z < 0.2. We parameterize the late-time SN Ia delay time distribution with a power law (proportional to t^s). Under the assumption of a cluster formation redshift of z_f = 3, our rate measurement in combination with lower-redshift cluster SN Ia rates constrains s = -1.41 +0.47/-0.40, consistent with measurements of the delay time distribution in the field. This measurement is generally consistent with expectations for the "double degenerate" scenario and inconsistent with some models for the "single degenerate" scenario predicting a steeper delay time distribution at large delay times. We check for environmental dependence and the influence of younger stellar populations by calculating the rate specifically in cluster red-sequence galaxies and in morphologically early-type galaxies, finding results similar to the full cluster rate. Finally, the upper limit of one host-less cluster SN Ia detected in the survey implies that the fraction of stars in the intra-cluster medium is less than 0.47 (95% confidence), consistent with measurements at lower redshifts.Comment: 29 pages, 14 figures. Accepted for publication in ApJ on 16 February 2011. See the HST Cluster Supernova Survey website at http://supernova.lbl.gov/2009ClusterSurvey for a version with full-resolution images and a complete listing of transient candidates from the survey. This version fixes a typo in the metadata; the paper is unchanged from v

Women and postfertilization effects of birth control: consistency of beliefs, intentions and reported use

BACKGROUND: This study assesses the consistency of responses among women regarding their beliefs about the mechanisms of actions of birth control methods, beliefs about when human life begins, the intention to use or not use birth control methods that they believe may act after fertilization or implantation, and their reported use of specific methods. METHODS: A questionnaire was administered in family practice and obstetrics and gynecology clinics in Salt Lake City, Utah, and Tulsa, Oklahoma. Participants included women ages 18–50 presenting for any reason and women under age 18 presenting for family planning or pregnancy care. Analyses were based on key questions addressing beliefs about whether specific birth control methods may act after fertilization, beliefs about when human life begins, intention to use a method that may act after fertilization, and reported use of specific methods. The questionnaire contained no information about the mechanism of action of any method of birth control. Responses were considered inconsistent if actual use contradicted intentions, if one intention contradicted another, or if intentions contradicted beliefs. RESULTS: Of all respondents, 38% gave consistent responses about intention to not use or to stop use of any birth control method that acted after fertilization, while 4% gave inconsistent responses. The corresponding percentages for birth control methods that work after implantation were 64% consistent and 2% inconsistent. Of all respondents, 34% reported they believed that life begins at fertilization and would not use any birth control method that acts after fertilization (a consistent response), while 3% reported they believed that life begins at fertilization but would use a birth control method that acts after fertilization (inconsistent). For specific methods of birth control, less than 1% of women gave inconsistent responses. A majority of women (68% or greater) responded accurately about the mechanism of action of condoms, abstinence, sterilization, and abortion, but a substantial percentage of women (between 19% and 57%) were uncertain about the mechanisms of action of oral contraceptives, intrauterine devices (IUDs), Depo-Provera, or natural family planning. CONCLUSION: Women who believe that life begins at fertilization may not intend to use a birth control method that could have postfertilization effects. More research is needed to understand the relative importance of postfertilization effects for women in other populations, and in relation to other properties of and priorities for birth control methods. However, many women were uncertain about the mechanisms of action of specific methods. To respect the principles of informed consent, some women may need more education about what is known and not known about the mechanisms of action of birth control methods