Observation of Microcanonical Atom Number Fluctuations in a Bose-Einstein Condensate.

Quantum systems are typically characterized by the inherent fluctuation of their physical observables. Despite this fundamental importance, the investigation of the fluctuations in interacting quantum systems at finite temperature continues to pose considerable theoretical and experimental challenges. Here we report the characterization of atom number fluctuations in weakly interacting Bose-Einstein condensates. Technical fluctuations are mitigated through a combination of nondestructive detection and active stabilization of the cooling sequence. We observe fluctuations reduced by 27% below the canonical expectation for a noninteracting gas, revealing the microcanonical nature of our system. The peak fluctuations have near linear scaling with atom number ΔN_{0,p}^{2}∝N^{1.134} in an experimentally accessible transition region outside the thermodynamic limit. Our experimental results thus set a benchmark for theoretical calculations under typical experimental conditions.

Bypassing proximal health care facilities for acute care: a survey of patients in a Ghanaian Accident and Emergency Centre.

OBJECTIVE: To characterise the population that presents to the Accident and Emergency Centre (AEC) at Komfo Anokye Teaching Hospital (KATH) and to identify risk factors associated with bypassing proximal care facilities. METHODS: A structured questionnaire was verbally administered to patients presenting to the AEC over 2 weeks. The questionnaire focused on the use of health care resources and characteristics of current illness or injury. Measures recorded include demographics, socioeconomic status, chief complaint, transportation and mobility, reasons for choosing KATH and health care service utilisation and cost. RESULTS: The total rate of bypassing proximal care was 33.9%. On multivariate analysis, factors positively associated with bypassing included age older than 38 years (OR: 2.18, P 0.04) and prior visits to facility (OR 2.88, P 0.01). Bypassers were less likely to be insured (OR 0.31, P 0.01), to be seeking care due to injury (OR 0.42, P 0.03) and to have previously sought care for the problem (OR 0.10, P < 0.001). CONCLUSIONS: Patients who bypass facilities near them to seek care at an urban AEC in Ghana do so for a combination of reasons including familiarity with the facility, chief complaint and insurance status. Understanding bypassing behaviour is important for guiding health care utilisation policy decisions and streamlining cost-effective, appropriate access to care for all patients.

Tracing nitrate sources with a combined isotope approach (δ15NNO3, δ18ONO3 and δ11B) in a large mixed-use watershed in southern Alberta, Canada.

Rapid population growth and land-use intensification over the last century have resulted in a substantial increase in nutrient loads degrading marine and freshwater ecosystems worldwide. In mixed-use watersheds, elevated nitrogen loads from wastewater treatment plant (WWTP) effluent or agricultural runoff often drive the eutrophication of waterways. Accordingly, the objective of this research was to identify sources of riverine nitrate (NO3), a deleterious dissolved species of nitrogen, with a combined isotopic tracing technique in the Bow River and the Oldman River in Alberta, Canada. Riverine NO3 and boron (B) concentrations, mean daily flux and δ15NNO3, δ18ONO3, and δ11B values were determined at 17 mainstem sites during high and low discharge periods in 2014 and 2015. The data for mainstem sites were then compared to results for effluent from seven WWTPs, eight synthetic fertilizers, cow manure, and three predominantly agricultural tributary sites to estimate point and non-point NO3 sources. The NO3 flux, δ15NNO3 and δ18ONO3 values indicated the city of Calgary's Bonnybrook WWTP effluent accounts for the majority of the NO3 flux in the Bow River downstream of Calgary. δ15NNO3 and δ11B values in the Bow River highlighted an increase in agricultural NO3 loading downstream of irrigation return-flows. A three-fold decrease in the NO3:B flux ratio indicated NO3-removal processes are active in the lower reaches of the Bow River. For the Oldman River, δ11B values revealed elevated nutrient loading from the Lethbridge WWTP effluent (10% of downstream B flux). Furthermore, the agricultural tributaries contributed 25% of the local B flux to the Oldman River. Overall, δ11B was proven to be an effective co-tracer for discriminating between urban and agricultural sources of NO3 in these large mixed-use watersheds. This combined isotope tracing approach has significant potential to identify point and non-point NO3 sources driving eutrophication around the world.

Household decision-making about delivery in health facilities: evidence from Tanzania.

This study investigated how partners' perceptions of the healthcare system influence decisions about delivery-location in low-resource settings. A multistage population-representative sample was used in Kasulu district, Tanzania, to identify women who had given birth in the last five years and their partners. Of 826 couples in analysis, 506 (61.3%) of the women delivered in the home. In multivariate analysis, factors associated with delivery in a health facility were agreement of partners on the importance of delivering in a health facility and agreement that skills of doctors are better than those of traditional birth attendants. When partners disagreed, the opinion of the woman was more influential in determining delivery-location. Agreement of partners regarding perceptions about the healthcare system appeared to be an important driver of decisions about delivery-location. These findings suggest that both partners should be included in the decision-making process regarding delivery to raise rates of delivery at facility.

Economic evaluation of surgically trained assistant medical officers in performing major obstetric surgery in Mozambique.

OBJECTIVE: To compare the training and deployment costs and surgical productivity of surgically trained assistant medical officers (técnicos de cirurgia) and specialist physicians (surgeons and obstetrician/gynaecologists) in Mozambique in order to inform health human resource planning in a developing country with low availability of obstetric care and severe physician shortages. Técnicos de cirurgia have been previously shown to have quality of care outcomes comparable to physicians. DESIGN: Economic evaluation of costs and productivity of surgically trained assistant medical officers and specialist physicians. SETTING: Hospitals and health science training institutions in Mozambique. POPULATION: Surgically trained assistants, medical officers, surgeons and obstetrician/gynaecologists in Mozambique. METHODS: The costs of training and deploying the two cadres of health workers were derived from a review of budgets, annual expenditure reports, enrolment registers, and accounting statements from training institutions and interviews with directors and administrators. Productivity estimates were based on a hospital survey of physicians and técnicos de cirurgia. MAIN OUTCOME MEASURES: Cost per major obstetric surgical procedure over 30 years in 2006 US dollars. RESULTS: The 30-year cost per major obstetric surgery was $38.9 for técnicos de cirurgia and $144.1 for surgeons and obstetrician/gynaecologists. Doubling the salaries of técnicos de cirurgia resulted in a smaller but still substantial difference in cost per surgery between the groups ($60.3 versus $144.1 per procedure). One-way sensitivity analysis to test the impact of varying other inputs did not substantially change the magnitude of the cost advantage of técnicos de cirurgia. CONCLUSION: Training more mid-level health workers in surgery can be part of the response to the health worker shortage, which today threatens the achievement of the health Millennium Development Goals in developing countries.

On the benefits of living in clumps: a case study on Polytrichastrum formosum.

The study concerns the mechanics and water relationships of clumps of a species of endohydric moss, Polytrichastrum formosum. Anatomical and morphological studies were done using optical and scanning electron microscopy. Experiments on waterdrop capture and their distribution to adjacent shoots within a moss clump were performed with the experimental set-up for the droplet collision phenomena and ultra-high speed camera. The mechanical strength of the moss clump was tested on an electromechanical testing machine. During the process of moss clump wetting, the falling water drops were captured by the apical stem part or leaves, then flowed down while adhering to the gametophore and never lost their surface continuity. In places of contact with another leaf, the water drop stops there and joins the leaves, enabling their hydration. Mathematical analysis of anatomical images showed that moss stems have different zones with varying cell lumen and cell wall/cell radius ratios, suggesting the occurrence of a periodic component structure. Our study provides evidence that the reaction of mosses to mechanical forces depends on the size of the clump, and that small groups are clearly stronger than larger groups. The clump structure of mosses acts as a net for falling rain droplets. Clumps of Polytrichastrum having overlapping leaves, at the time of loading formed a structure similar to a lattice. The observed reaction of mosses to mechanical forces indicates that this phenomenon appears to be analogous to the 'size effect on structural strength' that is of great importance for various fields of engineering.

Neurochemical characterization of hypothalamic neurons involved in attack behavior: glutamatergic dominance and co-expression of thyrotropin-releasing hormone in a subset of glutamatergic neurons.

The electrical stimulation of a specific hypothalamic area rapidly evokes attacks in rats. Noteworthy, attack-related hypothalamic structures were identified in all species studied so far. The area has been extensively mapped in rats, and its anatomical connections have been studied in detail. However, technical difficulties precluded earlier the precise identification of the neural elements mediating the aggressive effects of stimulation. It now appears that a dense and distinct group of glutamatergic cells expressing vesicular glutamate transporter 2 mRNA extends over the entire hypothalamic attack area. Rostral parts overwhelmingly contained glutamatergic neurons. In more caudal parts, glutamatergic and fewer GABAergic neurons were found. The remarkable similarity in the distribution of hypothalamic attack area and glutamatergic cell groups suggests that these cells mediate the aggressive effects of stimulation. Surprisingly, thyrotropin releasing hormone mRNA was co-localized in a subset of glutamatergic neurons. Such neurons were present at all rostro-caudal levels of the hypothalamic attack area, except for that part of the hypothalamic attack area extending into the ventro-lateral part of the ventromedial hypothalamic nucleus. Earlier data on the projections of hypothalamic thyrotropin releasing hormone neurons suggest that this subpopulation plays a specific role in attack behavior. Thus, we identified three neuronal phenotypes in the hypothalamic structure that is involved in the induction of attacks: glutamatergic neurons co-expressing thyrotropin releasing hormone, glutamatergic neurons without thyrotropin releasing hormone, and GABAergic neurons dispersed among the glutamatergic cells. Assessing the specific roles and connections of these neuron subpopulations would contribute to our understanding of the mechanisms underlying attack behavior and aggression.

Ethology and pharmacology of hypothalamic aggression in the rat.

Stimulation of a restricted area of the rat's hypothalamus elicits unprovoked violent attacks of a species-specific and strain-specific nature. Serotonergic drugs affecting 5HT1 receptors, propranolol, the 5HT re-uptake inhibitor fluvoxamine, and the anxiolytic oxazepam, inhibit hypothalamic attack selectively. However, hypothalamic attack is extremely unsensitive for many drugs that do affect attack provoked by natural stimuli. The pharmacology, the form, the impulsive nature, the absence of preliminaries, the insensitivity for contexts and ultimate aims of aggressive behaviour, suggest that a mechanism with the limited function of damaging adversaries of any kind is activated in the hypothalamus. This hypothalamic attack release mechanism (harm) requires specific sensory input for the expression of specific motor components, such as biting and kicking. The back and dorsal part of the opponent's head are the important attack releasing and directing stimuli. Attacks of this nature are part of the "aggressive" repertoire of the rat in natural settings. "Lateral" or "sideways" postures, specific for intermale fighting cannot be induced by hypothalamic stimulation. Drug, lesion, and stimulation studies suggest that attack and "sideways" postures are under the control of different central mechanisms. These results suggest new ways to describe the patterning of aggressive behaviour. There are interesting ethopharmacological similarities between hypothalamic responses and obsessive compulsive disorders (OCD) in man. It is suggested that further study of the ethopharmacology of hypothalamic responses may shed light on the pathophysiology of impulsive behavioural symptoms which in man seem to be beyond the control of appraisal or context.

Catecholaminergic involvement in the control of aggression: hormones, the peripheral sympathetic, and central noradrenergic systems.

Noradrenaline is involved in many different functions, which all are known to affect behaviour profoundly. In the present review we argue that noradrenaline affects aggression on three different levels: the hormonal level, the sympathetic autonomous nervous system, and the central nervous system (CNS), in different, but functionally synergistic ways. Part of these effects may arise in indirect ways that are by no means specific to aggressive behaviour, however, they are functionally relevant to it. Other effects may affect brain mechanisms specifically involved in aggression. Hormonal catecholamines (adrenaline and noradrenaline) appear to be involved in metabolic preparations for the prospective fight; the sympathetic system ensures appropriate cardiovascular reaction, while the CNS noradrenergic system prepares the animal for the prospective fight. Indirect CNS effects include: the shift of attention towards socially relevant stimuli; the enhancement of olfaction (a major source of information in rodents); the decrease in pain sensitivity; and the enhancement of memory (an aggressive encounter is very relevant for the future of the animal). Concerning more aggression-specific effects one may notice that a slight activation of the central noradrenergic system stimulates aggression, while a strong activation decreases fight readiness. This biphasic effect may allow the animal to engage or to avoid the conflict, depending on the strength of social challenge. A hypothesis is presented regarding the relevance of different adrenoceptors in controlling aggression. It appears that neurons bearing postsynaptic alpha2-adrenoceptors are responsible for the start and maintenance of aggression, while a situation-dependent fine-tuning is realised through neurons equipped with beta-adrenoceptors. The latter phenomenon may be dependent on a noradrenaline-induced corticosterone secretion. It appears that by activating very different mechanisms the systems working with adrenaline and/or noradrenaline prepare the animal in a very complex way to answer the demands imposed by, and to endure the effects caused by, fights. It is a challenge for future research to elucidate how precisely these mechanisms interact to contribute to functionally relevant and adaptive aggressive behaviour.

Phamacokinetic-pharmacodynamic modelling of behavioural responses.

Drug concentrations at the site of action in studies on behavioural pharmacology, are seldom constant. Therefore, observed changes in behaviour can be due to the natural time course of behavioural processes, but equally to changes in drug concentration, and it is therefore crucial to separate the former from the latter. One solution is keeping drug concentrations constant. However, one can also exploit the variation in drug concentration caused by absorption, distribution and elimination of a drug. This is done by simultaneous measurement of drug effect and concentration, while the drug enters and leaves a biologically relevant compartment, such as blood or cerebrospinal fluid. The concept of determining concentration-effect curves in individual animals, by monitoring in parallel drug effect and changes in concentration in one single experiment, has not yet found wide application in behavioural studies. The fact that behavioural processes, like any other physiological process, change over time, may have contributed to the scarcity of pharmacokinetic-pharmacodynamic (PK/PD) studies in behavioural pharmacology. However, there are now mathematical techniques that allow PK/PD modelling even if the effect parameter changes over time or cannot be properly assessed in every instance. Here we use PK/PD modelling to characterize fear-induced ultrasonic vocalizations and the anxiolytic effect of buspirone. This approach reduces the number of animals required to assess concentration-effect relationships. More importantly, it allows the identification of differences in individual drug response over a wide range of concentrations. Consequently, we suggest that PK/PD modelling can be used as a tool to study drug-induced changes in behavioural response. An introduction in PK/PD modelling is presented.

Acute effects of glucocorticoids: behavioral and pharmacological perspectives.

There has been evidence since the early eighties that glucocorticoids, apart from their well known chronic effects, may have acute, short-term effects. However, a lack of understanding of the molecular mechanisms of action has hampered appreciation of these observations. Mounting evidence over the years has continued to confirm the early observations on a fast corticosterone control of acute behavioral responses. We summarize experimental data obtained mainly in rats but also in other species which show: (1) that glucocorticoid production is sufficiently quick to affect ongoing behavior; (2) that there exist molecular mechanisms that could conceivably explain the fast neuronal effects of glucocorticoids (although these are still insufficiently understood); (3) that glucocorticoids are able to stimulate a wide variety of behaviors within minutes; and (4) that acute glucocorticoid production (at least in the case of aggressive behavior) is linked to the achievement of the behavioral goal (winning). The achievement of the behavioral goal reduces glucocorticoid production. It is argued that glucocorticoids are regulatory factors having a well-defined behavioral role. Both the acute (stimulatory) effects and the chronic (inhibitory) effects are adaptive in nature. The acute control of behavior by corticosterone is a rather unknown process that deserves further investigation. The pharmacologic importance of the acute glucocorticoid response is that it may readily affect the action of pharmacologic agents. An interaction between acute glucocorticoid increases and noradrenergic treatments has been shown in the case of offensive and defensive agonistic behavior. Non-behavioral data demonstrate that acute increases in glucocorticoids may interfere with other neurotransmitter systems (e.g., with the 5HT system) as well. These observations show the importance of taking into account endocrine background and endocrine responsiveness in behavior pharmacological experiments.

Neuropharmacology of brain-stimulation-evoked aggression.

Evidence is reviewed concerning the brain areas and neurotransmitters involved in aggressive behavior in the cat and rodent. In the cat, two distinct neural circuits involving the hypothalamus and PAG subserve two different kinds of aggression: defensive rage and predatory (quiet-biting) attack. The roles played by the neurotransmitters serotonin, GABA, glutamate, opioids, cholecystokinin, substance P, norepinephrine, dopamine, and acetylcholine in the modulation and expression of aggression are discussed. For the rat, a single area, largely coincident with the intermediate hypothalamic area, is crucial for the expression of attack; variations in the rat attack response in natural settings are due largely to environmental variables. Experimental evidence emphasizing the roles of serotonin and GABA in modulating hypothalamically evoked attack in the rat is discussed. It is concluded that significant progress has been made concerning our knowledge of the circuitry underlying the neural basis of aggression. Although new and important insights have been made concerning neurotransmitter regulation of aggressive behavior, wide gaps in our knowledge remain.

The hypothalamus: cross-roads of endocrine and behavioural regulation in grooming and aggression.

Anatomical and functional studies show that the hypothalamus is at the junction of mechanisms involved in the exploratory appraisal phase of behaviour and mechanisms involved in the execution of specific consummatory acts. However, the hypothalamus is also a crucial link in endocrine regulation. In natural settings it has been shown that behavioural challenges produce large and fast increases in circulating hormones such as testosterone, prolactin, corticotropin and corticosterone. The behavioural function and neural mechanisms of such fast neuroendocrine changes are not well understood. We suggest that behaviourally specific hypothalamic mechanisms, at the cross-roads of behavioural and endocrine regulation, play a role in such neuroendocrine changes. Mild stimulation of the hypothalamic aggressive area, produces stress levels of circulating prolactin, corticotropin, and corticosterone. Surprisingly luteinizing hormone does not change. This increase in stress hormones is due to the stimulation itself, and not caused by the stress of fighting. Similar increases in corticosterone are observed during electrical stimulation of the hypothalamic self-grooming area. The corticosterone response during self-grooming-evoking stimulation is negatively correlated with the amount of self-grooming observed, suggesting that circulating corticosterone exerts a negative feedback control on grooming. Earlier literature, and preliminary data form our laboratory, show that circulating corticosterone exerts a fast positive feedback control over brain mechanisms involved in aggressive behaviour. Such findings suggest that the hormonal responses caused by the activity of behaviourally specific areas of the hypothalamus may be part of a regulation mechanism involved in facilitating or inhibiting the very behavioural responses that can be evoked from those areas. We suggest that studying such mechanisms may provide a new approach to behavioural dysfunctions associated with endocrine disorders and stress.

Efferent connections of the hypothalamic "aggression area" in the rat.

The efferent connections of the hypothalamic area of the rat, where attack behaviour can be elicited by electrical stimulation, were studied using iontophoretic injections of Phaseolus vulgaris-leucoagglutinin. Specificity for the hypothalamic "attack area" was investigated by comparison with efferents of hypothalamic sites outside the attack area. The hypothalamic attack area consists of the intermediate hypothalamic area and the ventrolateral pole of the ventromedial hypothalamic nucleus. Fibres from the hypothalamic attack area, as well as fibres from several other hypothalamic sites, form diffuse fibre "streams" running rostrally or caudally. Many varicosities that are found on the fibres suggest, that these fibres are capable of influencing many brain sites along their way. Projection sites were found throughout the brain. In the comparison between attack area efferents and controls, many overlapping brain sites were found. Hypothalamic efferents preferentially originating in the largest part of the attack area, i.e. the intermediate hypothalamic area, were found in the mediodorsal and parataenial thalamic nuclei. Within the septum, a spatial organization of hypothalamic innervation was found. Fibres from the attack area formed specialized "pericellular baskets" in the dorsolateral aspect of the intermediate part of the lateral septal nucleus. Fibres from other hypothalamic sites were found in other septal areas and did not form these septal baskets. Within the mesencephalic central gray, fibres from the attack area were found specifically in the dorsal part and dorsal aspect of the lateral part of the central gray. Physiological and pharmacological studies have shown that several brain sites are involved in different aspects of aggressive behaviour. Some of these areas, as for instance the dorsomedial thalamic nucleus, septum and central gray, are innervated by efferents from the hypothalamic attack area, whereas other sites, like ventral premammillary nucleus and ventral tegmental area, are not. It is concluded from the present findings, that a number of brain sites, that are known to be involved in agonistic behaviour, receive hypothalamic information preferentially from the hypothalamic attack area through diffusely arranged varicose fibres. The function of each connection in the regulation of specific behaviours remains to be further investigated.

Pharmacodynamic interaction between phenytoin and sodium valproate changes seizure thresholds and pattern.

1. In this study we used cortical stimulation to assess the effects of phenytoin (PHT), sodium valproate (VPA), and their interaction on total motor seizure and on the constituent elements of the seizure. 2. PHT (40 mg kg(-1)) was administered as an intravenous bolus infusion to animals receiving either a continuous infusion of VPA or saline. VPA plasma concentration was maintained at levels that produced no detectable anticonvulsant effect. 3. Analysis of ictal components (eyes closure, jerk, gasp, forelimb, clonus, and hindlimb tonus) and their durations revealed both qualitative and quantitative differences in drug effects. 4. The anticonvulsant effect is represented by the increase in the duration of the stimulation required to reach a given seizure threshold. PHT significantly increased the duration of the stimulation and of the motor seizure. This increase was greatly enhanced by VPA. In addition, ictal component analysis revealed that the combination of PHT and VPA causes the reduction of a specific seizure component (JERK). 5. Neither the free fraction of PHT nor the biophase equilibration kinetics changes in the presence of VPA. It is concluded that the synergism may be due to a pharmacodynamic rather than a pharmacokinetic interaction.

Deviant forms of aggression in glucocorticoid hyporeactive rats: a model for 'pathological' aggression?

Deviant forms of aggressiveness have been associated with low plasma glucocorticoid concentrations in humans. Here, we report data on the development of aggressive behaviour in rats in which glucocorticoid secretion was inhibited by adrenalectomy. Such rats were compared with both sham operated rats and adrenalectomized rats in which the fight-induced elevation of plasma glucocorticoids was mimicked by acute injections. Low and stable corticosterone plasma concentrations were maintained by subcutaneous glucocorticoid pellets in adrenalectomized rats. The development of aggressive behaviour was followed over three trials performed at 2-day intervals. Adrenalectomy lead to high aggressiveness already at the first encounter, a decreased threatening (attack signalling) behaviour and a change in attack targeting. While control rats targeted biting attacks towards less vulnerable dorsal parts of the opponent's body, adrenalectomized rats attacked the head frequently. Corticosterone injections that mimicked the fight induced adrenocortical reaction abolished this behavioural pattern. Thus, a reduced responsiveness of the adrenocortical system may be causally linked to deviant forms of aggression in rats.

Chronic glucocorticoid deficiency-induced abnormal aggression, autonomic hypoarousal, and social deficit in rats.

Certain aggression-related psychopathologies are associated with decreased glucocorticoid production and autonomic functions in humans. We have previously shown that experimentally-induced chronic glucocorticoid deficiency leads to abnormal forms of attack in rats. Here, we compared the effects of acute and chronic glucocorticoid deficiency on aggressive behaviour, autonomic responses to challenges, and anxiety. Glucocorticoid synthesis was blocked acutely by the glucocorticoid synthesis blocker metyrapone or chronically by adrenalectomy and low glucocorticoid replacement (ADXr). As shown previously, chronic glucocorticoid deficiency facilitated aberrant attacks directed towards the most vulnerable parts of the opponent's body. The acute inhibition of glucocorticoid synthesis lowered aggressive behaviour without affecting attack targeting. In a different experiment, ADXr rats and their sham-operated controls were exposed to different challenges whereas their heart rate and locomotion were telemetrically recorded. Autonomic responses to social challenges were lowered by chronic, but not by acute glucocorticoid deficiency. Autonomic responses to the elevated plus-maze were only slightly affected by chronic glucocorticoid deficiency. Locomotor behaviour was not affected in either challenge; thus, the altered autonomic reactions were not due to interference from workload. The behaviour of ADXr rats was similar to that of sham-operated controls in the elevated plus-maze, but ADXr rats showed reduced social interactions in the social interaction test. Our data demonstrate that, in rats, chronic but not acute glucocorticoid deficiency induces abnormal attack patterns, deviant cardiovascular responses and social deficits that are similar to those seen in abnormally violent humans. Thus, the similar correlations found in humans probably cover a causal relationship. Experimentally-induced glucocorticoid deficiency may be used to assess the mechanisms underlying glucocorticoid deficiency-induced abnormal forms of aggressiveness.

The active phase-related increase in corticosterone and aggression are linked.

Recently we demonstrated that corticosterone exerts an acute facilitatory effect on aggression in male rats. Corticosterone production reaches a maximum at the onset of the dark period, while male rats are more aggressive in the dark. Here we present evidence demonstrating that the corticosterone increase at the beginning of the dark period is causally linked to the increase in aggressiveness. We measured plasma corticosterone and quantified aggressive behaviour of male territorial rats at various time points of the day-night transition. Low aggression levels were observed in the full light period when plasma concentrations of corticosterone were low. An increase in plasma corticosterone occurred just prior to the dark phase, when aggressive responding was the highest. Aggressive behaviour remained high in the early dark period when corticosterone was still high. We found that blocking the high affinity mineralocorticoid receptor (MR) with spironolactone (5 or 10 mg/kg) during the early dark period dramatically and specifically reduced territorial aggression.

Ultradian corticosterone rhythm and the propensity to behave aggressively in male rats.

Ultradian fluctuations in plasma glucocorticoids have been demonstrated in a variety of species including humans. The significance of such rhythms is poorly known, although disorganized ultradian glucocorticoid rhythms have been associated with behavioural disorders. Here we report that ultradian glucocorticoid rhythms may establish the propensity to behave aggressively in male rats. Male rats were significantly more aggressive in the increasing phase of their corticosterone fluctuation when confronting a male intruder than counterparts in the decreasing phase of their corticosterone fluctuations facing such opponents. Corticosterone fluctuations were mimicked by a combination of treatments with the corticosterone synthesis inhibitor metyrapone and corticosterone. Again, males with increased plasma corticosterone levels were more aggressive than counterparts with a decreased plasma corticosterone concentration. These data suggest that the behavioural response to an aggressive challenge may vary in the same animal across the day due to the pulsating nature of corticosterone secretion. Aggressive behaviour is also episodic in humans; moreover, intermittent explosive behaviour is recognized as a psychological disorder. It can be hypothesized that a temporal coincidence between the occurrence of a challenge and a surge in plasma corticosterone concentration may be one of the factors that promote episodic aggressive outbursts.

Anticonvulsant drugs differentially suppress individual ictal signs: a pharmacokinetic/pharmacodynamic analysis in the cortical stimulation model in the rat.

Antiepileptic drugs can suppress seizures completely, but they may also modify the appearance of drug-resistant seizures. In this study, the effects of three antiepileptic drugs on a seizure pattern were assessed by means of population pharmacokinetic/pharmacodynamic (PK/PD) modeling, yielding estimates of baseline response, EC50, and Hill slope. Lamotrigine did not affect eye closure, although it did suppress the other ictal signs in a concentration-dependent fashion. Midazolam suppressed forelimb clonus less potently than the other ictal signs; the same was observed for tiagabine with respect to eye closure. This study shows that ictal component analysis (ICA) in combination with PK/PD modeling may facilitate drug selection and dose optimization. The application of ICA is not restricted to a single seizure type or anticonvulsant drug and can be used to identify drug combinations that have a complementary action.