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Oxytocin (OT) is a nonapeptide with an impressive variety of physiological functions. Among them, the 'prosocial' effects have been discussed in several recent reviews, but the direct effects on male and female sexual behavior did receive much less attention so far. As our contribution to honor the lifelong interest of Berend Olivier in the control mechanisms of sexual behavior, we decided to explore the role of OT in the present review. In the successive sections, some physiological mechanisms and the 'pair-bonding' effects of OT will be discussed, followed by sections about desire, female appetitive and copulatory behavior, including lordosis and orgasm. At the male side, the effects on erection and ejaculation are reviewed, followed by a section about 'premature ejaculation' and a possible role of OT in its treatment. In addition to OT, serotonin receives some attention as one of the main mechanisms controlling the effects of OT. In the succeeding sections, the importance of OT for 'the fruits of labor' is discussed, as it plays an important role in both maternal and paternal behavior. Finally, we pay attention to an intriguing brain area, the ventrolateral part of the ventromedial hypothalamic nucleus (VMHvl), apparently functioning in both sexual and aggressive behavior, which are at first view completely opposite behavioral systems., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Allergy is suggested to exacerbate impaired behaviour in children with neurodevelopmental disorders. We have previously shown that food allergy impaired social behaviour in mice. Dietary fatty acid composition may affect both the immune and nervous system. The aim of this study was to assess the effect of n-3 long chain polyunsaturated fatty acids (n-3 LCPUFA) on food allergy-induced impaired social behaviour and associated deficits in prefrontal dopamine (DA) in mice. Mice were fed either control or n-3 LCPUFA-enriched diet before and during sensitization with whey. Social behaviour, acute allergic skin response and serum immunoglobulins were assessed. Monoamine levels were measured in brain and intestine and fatty acid content in brain. N-3 LCPUFA prevented impaired social behaviour of allergic mice. Moreover, n-3 LCPUFA supplementation increased docosahexaenoic acid (DHA) incorporation into the brain and restored reduced levels of prefrontal DA and its metabolites 3,4-dihydroxyphenylacetic acid, 3-methoxytyramine and homovanillic acid in allergic mice. In addition to these brain effects, n-3 LCPUFA supplementation reduced the allergic skin response and restored decreased intestinal levels of serotonin metabolite 5-hydroxyindoleacetic acid in allergic mice. N-3 LCPUFA may have beneficial effects on food allergy-induced deficits in social behaviour, either indirectly by reducing the allergic response and restoring intestinal 5-HT signalling, or directly by DHA incorporation into neuronal membranes, affecting the DA system. Therefore, it is of interest to further investigate the relevance of food allergy-enhanced impairments in social behaviour in humans and the potential benefits of dietary n-3 LCPUFA supplementation., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

JNJ-37822681 is a potent, specific and fast dissociating dopamine D2 receptor antagonist intended for the treatment of schizophrenia. Its nonclinical toxicological profile was investigated in a series of general repeat dose toxicity studies in cynomolgus monkeys and Sprague-Dawley rats. The maximum duration of treatment was 9 and 6 months, respectively. Interspecies differences were noted in the response to JNJ-37822681 in terms of extrapyramidal (EPS)-like clinical signs and prolactin-mediated tissue changes in the mammary gland. Monkeys showed severe EPS-like clinical signs such as abnormal posture, abnormal eye movements and hallucination-like behavior at relatively low exposures compared to those associated with EPS in patients with schizophrenia. The high sensitivity of the monkey to JNJ-37822681-induced EPS-like signs was unexpected based on the fast dissociating properties of the compound. Rats, however, were not prone to EPS. Elevated serum prolactin levels were found in rats and monkeys. While rats showed slight to moderate prolactin-related tissue changes upon histopathological examination in all studies, which among others affected the mammary gland, only minor mammary gland tissue changes were noted in monkeys. Prolactin levels were only slightly increased in patients with schizophrenia receiving relatively high dose levels of JNJ-37822681. The monkey toxicology studies did not provide an exposure-based safety margin, while in rats adverse effects were only noted at exposures considerably higher than those achieved at efficacious plasma concentrations in the clinic. Overall, the available data suggest that the cynomolgus monkey showed better predictivity towards the nature of JNJ-37822681-associated adverse events in humans than the Sprague-Dawley rat., (Copyright © 2013 John Wiley & Sons, Ltd.)

Kidney epithelial sodium channels (ENaCs) are known to be inactivated by high sodium concentrations (feedback inhibition). Recently, the endothelial sodium channel (EnNaC) was identified to control the nanomechanical properties of the endothelium. EnNaC-dependent endothelial stiffening reduces the release of nitric oxide, the hallmark of endothelial dysfunction. To study the regulatory impact of sodium on EnNaC, endothelial cells (EA.hy926 and ex vivo mouse endothelium) were incubated in aldosterone-free solutions containing either low (130 mM) or high (150 mM) sodium concentrations. By applying atomic force microscopy-based nanoindentation, an unexpected positive correlation between increasing sodium concentrations and cortical endothelial stiffness was observed, which can be attributed to functional EnNaC. In particular, an acute rise in sodium concentration (+20 mM) was sufficient to increase EnNaC membrane abundance by 90% and stiffening of the endothelial cortex by 18%. Despite the absence of exogenous aldosterone, these effects were prevented by the aldosterone synthase inhibitor FAD286 (100 nM) or the mineralocorticoid receptor (MR)-antagonist spironolactone (100 nM), indicating endogenous aldosterone synthesis and MR-dependent signaling. Interestingly, in the presence of high-sodium concentrations, FAD286 increased the transcription of the MR by 69%. Taken together, a novel feedforward activation of EnNaC by sodium is proposed that contrasts ENaC feedback inhibition in kidney., (© FASEB.)

Purpose: Elevated expression of eukaryotic protein synthesis initiation factor 4E (eIF4E) in histologically cancer-free margins of resected head and neck squamous cell carcinomas (HNSCCs) is mediated by mammalian target of rapamycin complex 1 (mTORC1) and has been associated with increased risk of disease recurrence. Preclinically, inhibition of mTORC1 with everolimus sensitizes cancer cells to cisplatin and radiation., Methods and Materials: This was single-institution phase 1 study to establish the maximum tolerated dose of daily everolimus given with fixed dose cisplatin (30 mg/m(2) weekly × 6) and concurrent intensity modulated radiation therapy for patients with locally and/or regionally advanced head-and-neck cancer. The study had a standard 3 + 3 dose-escalation design., Results: Tumor primary sites were oral cavity (4), salivary gland (4), oropharynx (2), nasopharynx (1), scalp (1), and neck node with occult primary (1). In 4 of 4 cases in which resected HNSCC surgical pathology specimens were available for immunohistochemistry, elevated expression of eIF4E was observed in the cancer-free margins. The most common grade ≥3 treatment-related adverse event was lymphopenia (92%), and dose-limiting toxicities (DLTs) were mucositis (n=2) and failure to thrive (n=1). With a median follow up of 19.4 months, 2 patients have experienced recurrent disease. The maximum tolerated dose was everolimus 5 mg/day., Conclusions: Head-and-neck cancer patients tolerated everolimus at therapeutic doses (5 mg/day) given with weekly cisplatin and intensity modulated radiation therapy. The regimen merits further evaluation, especially among patients who are status post resection of HNSCCs that harbor mTORC1-mediated activation of eIF4E in histologically negative surgical margins., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Cetuximab is typically administered on a weekly schedule for patients with recurrent or metastatic head and neck squamous cell cancer (HNSCC). This study explores cetuximab administered every 2 weeks (q2w). In this multicenter randomized prospective phase II study, eligible patients (≤2 prior cytotoxic chemotherapy regimens for recurrent or metastatic disease; ECOG performance status ≤2) were randomized to receive cetuximab q2w at 500 mg/m(2) (Group A) or 750 mg/m(2) (Group B). The primary end point was response rate (RECIST 1.0). Sixty-one patients were enrolled: 35 in Group A and 26 in Group B, which was closed early for lack of efficacy. Confirmed partial response rates were 11% for Group A (4/35) and 8% for Group B (2/26) according to intention to treat analysis. Partial responses occurred only among patients whose primary tumors were in the oral cavity or larynx. Median progression-free survival (PFS) and median overall survival (OS) were similar for both groups (PFS, 2.2 and 2.0 months; OS, 7.0 and 9.4 months; Groups A and B, respectively). The most common cetuximab-related adverse events (all grades) among treated subjects included rash, fatigue, and hypomagnesemia. Cetuximab, 500 mg/m(2), q2w achieves similar efficacy as conventional dosing for patients with recurrent or metastatic HNSCC. Escalating the dose to 750 mg/m(2) q2w offers no obvious therapeutic advantage.

Selective adsorption of C60 on nanoscale Ge areas can be achieved, while neighboring Si(111) areas remain uncovered, if the whole surface is initially terminated by Bi. Fullerene chemisorption is found at Bi vacancies which form due to partial thermal desorption of the Bi surfactant. The growth rate and temperature dependence of the C60 adsorption were measured using scanning tunneling microscopy and are described consistently by a rate equation model. The selectivity of the C60 adsorption can be traced back to an easier vacancy formation in the Bi layer on top of the Ge areas compared to the Si areas. Furthermore, it is also possible to desorb C60 from Ge areas, allowing the use of C60 as a resist on the nanoscale.

We present a multitip scanning tunneling microscope (STM) where four independent STM units are integrated on a diameter of 50 mm. The coarse positioning of the tips is done under the control of an optical microscope or scanning electron microscopy in vacuum. The heart of this STM is a new type of piezoelectric coarse approach called KoalaDrive. The compactness of the KoalaDrive allows building a four-tip STM as small as a single-tip STM with a drift of less than 0.2 nm/min at room temperature and lowest resonance frequencies of 2.5 kHz (xy) and 5.5 kHz (z). We present as examples of the performance of the multitip STM four point measurements of silicide nanowires and graphene.

Plasma sodium, slightly above normal and in presence of aldosterone, stiffens vascular endothelium and reduces nitric oxide release with the consequence of endothelial dysfunction. This process is mediated by epithelial sodium channels (ENaC) and, most likely, the endothelial Na(+)/K(+)-ATPase. Both, ENaC and Na(+)/K(+)-ATPase, are located in the plasma membrane of endothelial cells and embedded in the endothelial glycocalyx (eGC). This negatively charged biopolymer is directly exposed to the blood stream and selectively buffers sodium ions. We hypothesize that the glycocalyx could interfere with endothelial sodium transport when extracellular sodium varies in the physiological range. Therefore, we modeled the endothelial cell as a pump-leak system measuring changes of intracellular sodium in cultured human endothelial cells. Experiments were performed under low/high extracellular sodium conditions before and after enzymatic eGC removal, and with inhibition of Na(+)/K(+)-ATPase and ENaC, respectively. Three major observations were made: (1) eGC removal by heparinase treatment facilitates sodium to enter/exit the endothelial cells. (2) The direction of net sodium movement across the endothelial plasma membrane depends on the concentration of extracellular sodium which regulates both the Na(+)/K(+)-ATPase and ENaC activity. (3) Removal of eGC and inhibition of sodium transport modify the electrical resistance of endothelial cells. We conclude that the eGC serves as a potential "firewall" preventing uncontrolled access of sodium to the pump-leak system of the endothelial cell. After eGC removal, sodium access to the system is facilitated. Thus the pump-leak system could be regulated by ambient sodium and control vascular permeability in pathophysiological conditions.

Sodium overload stiffens vascular endothelial cells in vitro and promotes arterial hypertension in vivo. The hypothesis was tested that the endothelial glycocalyx (eGC), a mesh of anionic biopolymers covering the surface of the endothelium, participates in the stiffening process. By using a mechanical nanosensor, mounted on an atomic force microscope, height (∼400 nm) and stiffness (∼0.25 pN/nm) of the eGC on the luminal endothelial surface of split-open human umbilical arteries were quantified. In presence of aldosterone, the increase of extracellular sodium concentration from 135 to 150 mM over 5 days (sodium overload) led the eGC shrink by ∼50% and stiffening by ∼130%. Quantitative eGC analyses reveal that sodium overload caused a reduction of heparan sulphate residues by 68% which lead to destabilization and collapse of the eGC. Sodium overload transformed the endothelial cells from a sodium release into a sodium-absorbing state. Spironolactone, a specific aldosterone antagonist, prevented these changes. We conclude that the endothelial glycocalyx serves as an effective buffer barrier for sodium. Damaged eGC facilitates sodium entry into the endothelial cells. This could explain endothelial dysfunction and arterial hypertension observed in sodium abuse.

With the steadily increasing number of publications in the field of stress research it has become evident that the conventional usage of the stress concept bears considerable problems. The use of the term 'stress' to conditions ranging from even the mildest challenging stimulation to severely aversive conditions, is in our view inappropriate. Review of the literature reveals that the physiological 'stress' response to appetitive, rewarding stimuli that are often not considered to be stressors can be as large as the response to negative stimuli. Analysis of the physiological response during exercise supports the view that the magnitude of the neuroendocrine response reflects the metabolic and physiological demands required for behavioural activity. We propose that the term 'stress' should be restricted to conditions where an environmental demand exceeds the natural regulatory capacity of an organism, in particular situations that include unpredictability and uncontrollability. Physiologically, stress seems to be characterized by either the absence of an anticipatory response (unpredictable) or a reduced recovery (uncontrollable) of the neuroendocrine reaction. The consequences of this restricted definition for stress research and the interpretation of results in terms of the adaptive and/or maladaptive nature of the response are discussed., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Cheyne-Stokes respiration (CSR) in patients with chronic heart failure (CHF) is of major prognostic impact and expresses respiratory instability. Other parameters are daytime pCO₂, VE/VCO₂-slope during exercise, exertional oscillatory ventilation (EOV), and increased sensitivity of central CO₂ receptors. Adaptive servoventilation (ASV) was introduced to specifically treat CSR in CHF. Aim of this study was to investigate ASV effects on CSR, cardiac function, and respiratory stability. A total of 105 patients with CHF (NYHA ≥ II, left ventricular ejection fraction (EF) ≤ 40%) and CSR (apnoea-hypopnoea index ≥ 15/h) met inclusion criteria. According to adherence to ASV treatment (follow-up of 6.7 ± 3.2 months) this group was divided into controls (rejection of ASV treatment or usage <50% of nights possible and/or <4 h/night; n = 59) and ASV (n = 56) adhered patients. In the ASV group, ventilator therapy was able to effectively treat CSR. In contrast to controls, NYHA class, EF, oxygen uptake, 6-min walking distance, and NT-proBNP improved significantly. Moreover, exclusively in these patients pCO₂, VE/VCO₂-slope during exercise, EOV, and central CO₂ receptor sensitivity improved. In CHF patients with CSR, ASV might be able to improve parameters of SDB, cardiac function, and respiratory stability.

DOV 216,303 belongs to a new class of antidepressants, the triple reuptake inhibitors (TRIs), that blocks serotonin, norepinephrine and dopamine transporters and thereby increases extracellular brain monoamine concentrations. The aim of the present study was to measure extracellular monoamine concentrations both in the prefrontal cortex (PFC) and dorsal hippocampus (DH) after chronic administration of DOV 216,303 in the OBX animal model of depression and to compare the effects with acute drug treatment. OBX animals showed lower dopamine levels in PFC upon acute administration of DOV 216,303 than sham animals for up to five weeks after surgery. No such changes were observed in the DH. Unexpectedly, a DOV 216,303 challenge in chronic DOV 216,303 treated sham animals resulted in a blunted dopamine response in the PFC compared to the same challenge in vehicle treated animals. This blunted response probably reflects pharmacokinetic adaptations and/or pharmacodynamic changes, since brain and plasma concentrations of DOV 216,303 were significantly lower after chronic administration compared to acute administration. Surprisingly, and in contrast what we have reported earlier, chronic DOV 216,303 treatment was unable to normalize the hyperactivity of the OBX animals. Interestingly, by measuring the drug plasma and brain levels, it was demonstrated that at the time of behavioral testing (24 h after last drug treatment) DOV 216,303 was not present anymore in either plasma or brain. This seems to indicate that this putative antidepressant drug has no lasting antidepressant-like behavioral effects in the absence of the drug in the brain., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Rationale: Stress-related disorders are associated with dysfunction of both serotonergic and GABAergic pathways, and clinically effective anxiolytics act via both neurotransmitter systems. As there is evidence that the GABA(A) and the serotonin receptor system interact, a serotonergic component in the anxiolytic actions of benzodiazepines could be present., Objectives: The main aim of the present study was to investigate whether the anxiolytic effects of (non-)selective alpha subunit GABA(A) receptor agonists could be reversed with 5-HT(1A) receptor blockade using the stress-induced hyperthermia (SIH) paradigm., Results: The 5-HT(1A) receptor antagonist WAY-100635 (0.1-1 mg/kg) reversed the SIH-reducing effects of the non-alpha-subunit selective GABA(A) receptor agonist diazepam (1-4 mg/kg) and the GABA(A) receptor alpha(3)-subunit selective agonist TP003 (1 mg/kg), whereas WAY-100635 alone was without effect on the SIH response or basal body temperature. At the same time, co-administration of WAY-100635 with diazepam or TP003 reduced basal body temperature. WAY-100635 did not affect the SIH response when combined with the preferential alpha(1)-subunit GABA(A) receptor agonist zolpidem (10 mg/kg), although zolpidem markedly reduced basal body temperature., Conclusions: The present study suggests an interaction between GABA(A) receptor alpha-subunits and 5-HT(1A) receptor activation in the SIH response. Specifically, our data indicate that benzodiazepines affect serotonergic signaling via GABA(A) receptor alpha(3)-subunits. Further understanding of the interactions between the GABA(A) and serotonin system in reaction to stress may be valuable in the search for novel anxiolytic drugs.

Background: Cognitive function might be affected by the subjects' emotional reactivity. We assessed whether behavior in different tests of emotional reactivity is correlated with performance in aversively motivated learning tasks, using four strains of rats generally considered to have a different emotional reactivity., Methods: The performance of male Brown Norway, Lewis, Fischer 344, and Wistar Kyoto rats in open field (OF), elevated plus-maze (EPM), and circular light-dark preference box (cLDB) tasks, which are believed to provide measures of emotional reactivity, was evaluated. Spatial working and reference memory were assessed in two aversively motivated learning and memory tasks: the standard and the "repeated acquisition" versions of the Morris water maze escape task, respectively. All rats were also tested in a passive avoidance task. At the end of the study, levels of serotonin (5-HT) and 5-hydroxyindoleacetic acid, and 5-HT turnover in the hippocampus and frontal cortex were determined., Results: Strain differences showed a complex pattern across behavioral tests and serotonergic measures. Fischer 344 rats had the poorest performance in both versions of the Morris water escape task, whereas Brown Norway rats performed these tasks very well but the passive avoidance task poorly. Neither correlation analysis nor principal component analysis provided convincing support for the notion that OF, EPM, and cLDB tasks measure the same underlying trait., Conclusions: Our findings do not support the hypothesis that the level of emotional reactivity modulates cognitive performance in aversively motivated tasks. Concepts such as "emotional reactivity" and "learning and memory" cannot adequately be tapped with only one behavioral test. Our results emphasize the need for multiple testing.

Darwin's largest contribution to science is without doubt the mechanism of natural selection, an evolutionary game with players, strategies, and pay-offs. Game theory, which attempts to mathematically capture behaviour in situations where an organism's success in making choices depends on the choices of others, is not only important for economists, but also for biologists, veterinarians and other scientists, as it increases understanding of why individual differences exist. John Maynard Smith showed that the success of an individual's behaviour often depends on others and his Hawk-Dove model is one of the best known examples of game theory: the 'hawk' initiates aggressive behaviour (not stopping until injured or until the opponent backs down); the 'dove' retreats immediately if the opponent initiates aggressive behaviour and will not fight under any circumstances. Simultaneous hawkish behaviour has the worst pay-off for both players, whereas hawkish behaviour with a dove opponent has the best pay-off. Maynard Smith showed that natural selection will work towards an evolutionarily stable strategy that, when used by an entire population, is resistant to invasion by new mutant strategies. Thus, natural selection actually favours a particular ratio of aggressive hawkish and non-aggressive dovish behaviours in order to maintain a balance of different characteristics in the population. Natural selection has sculpted physiology and behaviour differently in hawks and doves, each in their own way so as to maintain stability of the internal environment through change--a process which is defined as allostasis. In the short term, allostasis has benefits, but in the long run it produces costs. Farm animals have been genetically selected by man for increased product quantity and quality, such as increased muscle volume, lean meat and egg shell quality, accompanied by altered steroid balance (such as more testosterone and less corticosteroids) and lower brain monoamine concentrations (serotonin and dopamine). It is hypothesised that such genetic selection results in the production of farm animals that prefer the hawk behavioural strategy. There is a growing body of evidence that hawk-like animals (such as laying hens and pigs) are more vulnerable to the development of increased impulsivity and compulsivity (stereotypies) as well as violent behaviour.

The cellular prion protein (PrP(C)), a copper binding protein has a primary role in the pathogenesis of in prion diseases. In these diseases alterations in the levels of copper and manganese have been described but how these alterations are involved in the pathogenesis is still unknown. Here we analysed synaptosomes of scrapie infected mice and observed a significant reduction in the amount of copper and an increase of the manganese content at day 100 after infection. Moreover a reduction of the copper content in mouse brains induced by application of copper poor diets was found to reduce the survival time of scrapie infected mice significantly, whereas enhanced administration of copper induced a significant delay in prion disease onset. Interestingly a significant higher amount of PrP(C) full length and misfolded PK-resistant PrP was observed in mice that were treated with an enhanced copper diet compared to controls. Moreover we could demonstrate that in healthy mock infected mice, a Cu(2+) rich/Mn(2+) poor diet induced a significantly decreased cleavage capability of PrP(C) compared to control mice. These new findings suggest that the copper content in mouse brains exerts an influence on the amount of PrP(C) and its cleavage properties and may affect the PrP conversion by depleted availability of functional PrP full length.

Rationale: The stress-induced hyperthermia (SIH) model is an anxiety model that uses the transient rise in body temperature in response to acute stress. Benzodiazepines produce anxiolytic as well as sedative side effects through nonselective binding to GABA(A) receptor subunits. The GABA(A) receptor alpha(1) subunit is associated with sedation, whereas the GABA(A) receptor alpha(2) and alpha(3) subunits are involved in anxiolytic effects., Objectives: We therefore examined the effects of (non)subunit-selective GABA(A) receptor agonists on temperature and locomotor responses to novel cage stress., Results: Using telemetric monitoring of temperature and locomotor activity, we found that nonsubunit-selective GABA(A) receptor agonist diazepam as well as the alpha(3) subunit-selective receptor agonist TP003 dose-dependently attenuated SIH and locomotor responses. Administration of GABA(A) receptor alpha(1)-selective agonist zolpidem resulted in profound hypothermia and locomotor sedation. The GABA(A) receptor alpha(1)-selective antagonist betaCCt antagonized the hypothermia, but did not reverse the SIH response attenuation caused by diazepam and zolpidem. These results suggest an important regulating role for the alpha(1) subunit in thermoregulation and sedation. Ligands of extrasynaptic GABA(A) receptors such as alcohol and nonbenzodiazepine THIP attenuated the SIH response only at high doses., Conclusions: The present study confirms a putative role for the GABA(A) receptor alpha(1) subunit in hypothermia and sedation and supports a role for alpha(2/3) subunit GABA(A) receptor agonists in anxiety processes. In conclusion, we show that home cage temperature and locomotor responses to novel home cage stress provide an excellent tool to assess both anxiolytic and sedative effects of various (subunit-selective) GABA(A)ergic compounds.

Background: Olfactory bulbectomy (OBX) in rats causes several behavioral and neurochemical changes. However, the extent and onset of physiological and behavioral changes induced after bulbectomy have been little examined., Methods: Male Sprague-Dawley rats received telemetric implants. Before and immediately after OBX surgery, basal and stress-induced heart rate, body temperature, and locomotor activity were measured in the home cage in sham (n=9) and OBX animals (n=11). Stress was induced using novel cage stress or witness stress., Results: Bulbectomized animals differed physiologically and behaviorally from shams. Nocturnally, OBX animals were significantly more active compared with shams, had a higher core body temperature and displayed a decreased heart rate variability. During the light period, OBX animals had a significantly lower basal heart rate and a reduced heart rate variability. These effects became apparent 2-3 days after OBX surgery, and were stable over time. After witness stress, OBX animals showed smaller autonomic (body temperature and heart rate) responses compared with shams, but showed no difference in locomotor responses. In contrast, novel cage stress led to increased locomotor responses in OBX rats compared with sham rats, while no differences were found in autonomic responses., Conclusion: Removal of the olfactory bulbs results in rapid, stable and persistent changes in basal locomotor activity, body temperature, heart rate and heart rate variability. Although the sleep-wake cycle of these parameters is not altered, increases in circadian amplitude are apparent within 3 days after surgery. This indicates that physiological changes in the OBX rat are the immediate result of olfactory bulb removal. Further, stress responsivity in OBX rats depends on stressor intensity. Bulbectomized rats display smaller temperature and heart rate responses to less intense witness stress compared with sham rats. Increased locomotor responses to more intense novel cage stress are present in the home cage as well as the open field. The present study shows that olfactory bulbectomy has rapid and persistent influence on basal and stress-induced physiological parameters.

The present study examined the effects of the intravenous administration of the anxiolytic drug brotizolam on the behavioral and physiological responsiveness of calves to novelty in a dose response fashion. Holstein Friesian heifer calves (39-41 weeks of age; body weight 200-300 kg) received an intravenous injection of either a vehicle control (12 calves) or one of four doses of brotizolam (8 calves per dose): 0.0125, 0.05, 0.2 and 0.8 mg/100 kg body weight. They were then individually subjected to a 'combined' test involving exposure to a novel environment (open field, OF) for 5 min followed by the sudden introduction of a novel object (NO) that remained in place for a further 10 min. Behavioral, heart rate and plasma cortisol responses were recorded in all animals. Compared to vehicle treatment, the highest dose of brotizolam dose-dependently and significantly increased the time spent in locomotion and the distance travelled near the NO, as well as the time spent in contact with the NO. In addition, post-test plasma cortisol concentrations changed in a dose-dependent manner over time: they decreased between 0 and 10 min after the test in calves that had received the two highest doses of brotizolam, whereas they increased in vehicle-treated and low-dosage calves. There were no effects of brotizolam on vocalization or locomotion during the OF phase of the test or on vocalization following introduction of the NO. These findings strongly support the notion that interaction with a novel object in a novel arena represents a behavioral index of fear and fearfulness in calves, and that vocalization and locomotion in an OF reflect other independent characteristics.

Olfactory bulbectomy (OBX) in rats causes several behavioral and neurochemical CNS changes, reminiscent of symptoms of human depression. Such depression-like behavior after OBX can be reversed with antidepressants. Recently, a connection between the vasopressin 1b (V1b) receptor and the development of depression has been suggested; therefore, a vasopressin V1b receptor antagonist (SSR149415) was investigated in the OBX model. Male rats received olfactory bulbectomy or sham surgery. After recovery, animals received 14 consecutive daily doses of SSR149415 (10 or 30 mg/kg), imipramine (20 mg/kg), or vehicle (5% hydroxy-propyl methylcellulose). Animals were tested in an open field after acute treatment, on days 7 and 14 of treatment and 1 week after cessation of treatment. Similar to imipramine, repeated, but not acute, administration of SSR149415 completely reversed OBX-induced hyperactivity, leaving activity in shams unaffected. This reversal of OBX-induced hyperactivity in the SSR149415 treated rats was still present 7 days after cessation of treatment. Although the behavioral effects of treatment with SSR149415 were specific for the OBX animals, adrenal gland weights were reduced in both sham and OBX animals treated with 30 mg/kg SSR149415. Chronic but not acute administration of SSR149415 normalizes OBX-induced hyperactivity up to 1 week after cessation of treatment, suggesting that a V1b receptor antagonist may have long-lasting antidepressant activity.

Identification of transcripts at key development stages of preimplantation embryos is critical for a better understanding of early embryogenesis. The current study had two aims. The first was to characterize the relative abundance of multiple transcripts during several developmental stages, namely, metaphase II-stage oocytes (MPII), as well as 2-cell, precompact morula (PCM) and in vitro-produced blastocyst (IVTBL) stage embryos. The second was to characterize differences in the relative abundance of transcripts present in in vivo- (IVVBL), in vitro- (IVTBL), and nuclear transfer-derived (NTBL) blastocysts. It was hypothesized that the identification of differentially represented transcripts from these embryos would reveal not only developmentally important genes, but also genes that might be aberrantly expressed due to embryo production techniques. Individual clusters from a large bovine expressed sequence tag (EST) library (http://genome.rnet.missouri.edu/bovine/) of female reproductive tissues and embryos were compared using Fisher's Exact Test weighted by number of transcripts per tissue by gene. Of the 3,144 transcripts that were present during embryogenesis, 125 were found to be differentially represented (P < or = 0.01) in at least one pairwise comparison. Fifteen of these transcripts were selected for further examination using quantitative real-time PCR (qRTPCR) to determine differences in transcript abundance. Twelve of the 15 transcripts were differentially represented (n = 9, P < or = 0.01; n = 3, P < or = 0.05) in at least one pairwise comparison. In summary, identification of differentially represented transcripts in early embryo development, which are modulated by in vitro techniques, should provide markers to ensure the production of embryos closer to those developed in vivo.

Current antidepressants have a delayed onset of action and disturbing side effects, including inhibition of sexual behavior. It is hypothesized that novel drugs, hitting multiple disease-relevant targets, may yield a new generation of superior antidepressants. One such approach is simultaneous inhibition of serotonin, norepinephrine and dopamine transporters. We tested the triple uptake inhibitor (TUI), DOV 216,303 (5, 10 and 20 mg/kg) after 1, 7 and 14 days administration in the olfactory bulbectomized (OBX) rat depression model, and in a model of rat sexual behavior to detect putative sexual side effects. Chronic, but not acute treatment of DOV 216,303 (20 mg/kg) normalized OBX-induced hyperactivity in the open field, similar to the effect of imipramine (20 mg/kg). None of the doses of DOV 216,303 had any effect on sexual behavior at any time point. The results indicate that DOV 216,303 displays antidepressant efficacy and is devoid of sexual side effects.

Ethnopharmacological Relevance: Dry sex refers to the use of plants to dry and contract the vagina, a popular practice in Africa that damages vaginal tissue and facilitates the spread of sexually transmitted diseases. Here we show that dry-sex practices are not limited to Africa. Afro-Surinamese women frequently use genital steam baths that contain drying and tightening herbs., Aim of the Study: To assess the possible health consequences of this tradition, we quantified the diversity and trade in steam-bath ingredients and described the reasons why Surinamese women use them., Materials and Methods: We collected botanical vouchers of steam-bath herbs, carried out a market survey and interviewed 140 women who used these baths., Results: No less than 177 different plant species were employed in vaginal steam baths, not only for dry sex, but also to cleanse the uterus after childbirth and menstruation. Prohibiting the use of these baths is not an option. Moreover, they may save lives by preventing womb infection and puerperal fever., Conclusions: The lively trade in steam-bath herbs plays a role in the rapid increase in HIV among Surinamese citizens and migrants. We also have reasons to believe that dry-sex practices are more widespread in the Caribbean than previously thought.

The aim of this study was to develop an animal model of major depression. Since two thirds of depressive patients are women, it is important to develop specific female animal models of depression. We therefore determined the consequences of chronic social defeat in individually housed prepubertal female pigs confronted with a dominant, older pig. Repeated defeat increased the salivary cortisol level, measured immediately after the confrontations, but this effect diminished after repeated confrontations. Neither organ weights nor the number of glucocorticoid (GR) and mineralocorticoid (MR) receptors in the ventral hippocampus were affected by repeated defeat. Serotonin turnover in the dorsal hippocampus was also unaffected. Behavioral analysis revealed that across confrontations, the pigs reduced the time spent actively attacking the dominant pigs, whereas the time increased in which the pigs passively underwent aggression and/or actively avoided aggression. Therefore, we conclude that the repeated social defeat paradigm does not induce long-lasting depression-like neuroendocrine effects as a consequence of behavioral adaptations (changes in the fighting strategy) in the young female pigs.

A caudal forebrain area of zebra finches that comprises a part of the caudal nidopallium and a part of the intermediate arcopallium is highly activated during courtship. This activation is thought to reflect the processing of information that is necessary for the choice of an appropriate mate. In addition to the information on the potential mate, control of courtship behavior includes motivational aspects. Being involved in the integration of external input and previously stored information, as well as in adding motivational factors, the caudal nidopallium and intermediate arcopallium should be integrative areas receiving input from many other regions of the brain. Our results indeed show that the caudal nidopallium receives input from a variety of telencephalic regions including the secondary visual and auditory areas. The intermediate arcopallium is recipient of input from intermediate and caudal nidopallium, mesopallium and densocellular hyperpallium. Regions closely associated with the song control nuclei also innervate both regions. There are also specific visual and auditory thalamic inputs, while specific motivating catecholaminergic mesencephalic afferents include the ventral tegmental area, the substantia nigra and the locus coeruleus. In addition, non-specific activation reaches these areas from the mesencephalic reticular formation. Bilateral innervation by ventral intermediate arcopallium indicates links with sensori-motor pathways, while the projection from the caudal nidopallium to intermediate arcopallium suggests monosynaptic and disynaptic input to downstream motor pathways. These findings support the idea of an involvement of the caudal nidopallium and the intermediate arcopallium in the control of courtship behavior.

Macrophage-activating lipopeptide-2 (MALP-2) from Mycoplasma fermentans has been identified as a pathogen-associated molecular pattern of Mycoplasmas that causes activation of the innate immune system through the activation of the heterodimeric Toll-like receptors (TLRs)-2 and -6. The aim of this study was to characterize the ability of MALP-2 and a synthetic analog fibroblast-stimulating lipopeptide-1 (FSL-1; represents the NH2-terminal sequence of a lipoprotein from M. salivarium) to act as exogenous pyrogens, to induce formation of cytokines (endogenous pyrogens), and to cause sickness behavior, such as depressed motor activity, anorexia, and adipsia. For this purpose, body temperature, activity, food intake, and water intake were recorded for 3 days by use of telemetry devices in several groups of rats treated with MALP-2/FSL-1 or the respective control solutions. Intraperitoneal injections of FSL-1 caused fever at doses of 10 or 100 microg/kg, which was preceded by a pronounced phase of hypothermia in response to a dose of 1,000 microg/kg. The maximal fever (a peak of 1.5 degrees C above baseline) was caused by the 100 microg/kg dose with almost identical responses to both MALP-2 and FSL-1. Fever was accompanied by pronounced rises of the proinflammatory cytokines TNF and IL-6 in plasma. Treatment with the TLR-2 and -6 agonists further induced a dose-dependent manifestation of anorexia and adipsia, as well as a reduction of motor activity. We could thus demonstrate that activation of TLR-2 and -6 can induce systemic inflammation in rats accompanied by the classical signs of brain-controlled illness responses.

During systemic inflammation, cytokines are released by immune-competent cells into the circulation, which in turn signal the brain to mediate brain-controlled signs of illness. Cytokine-responsive brain cells can be mapped by histological analysis of cytokine-induced transcription factors or transcription factor-associated molecules revealing different cell phenotypes that respond to activation of the immune system. Critical sites mediating cytokine-dependent immuneffector functions can be divided into two groups, one group of responding cells situated along a tight blood-brain barrier (BBB), and a second cell group in structures with an open BBB, e.g., the sensory circumventricular organs (CVOs). Previous reports from our group suggest that activation of the signal transducer and activator of transcription factor 3 (STAT3) during lipopolysaccharide (LPS)-induced systemic inflammation is mediated by interleukin-6 (IL-6) and occurs in astrocytes of the rat CVOs. Here we show in the guinea pig a time-dependent marked LPS-induced STAT3 activation within astrocytes and endothelial cells of the CVOs, within astrocytes located in brain structures with a functional BBB and within the brain endothelium of the entire brain. In addition, systemic treatment of rats with either rat recombinant IL-6 or LPS induced STAT3 activation in brain endothelial cells in a similar way as observed in the guinea pig brain, stressing the involvement of IL-6 in this phenomenon in a more generalized way. The STAT3-activated brain cells are located in critical target structures mediating cytokine action during LPS-induced inflammation. STAT3-controlled transcriptional activation with yet unknown cell-specific functional consequences seems to be involved in this process., ((c) 2005 Wiley-Liss, Inc.)

In guinea pigs, dose-dependent febrile responses were induced by injection of a high (100 microg/kg) or a low (10 microg/kg) dose of bacterial lipopolysaccharide (LPS) into artificial subcutaneously implanted Teflon chambers. Both LPS doses further induced a pronounced formation of prostaglandin E(2) (PGE(2)) at the site of localized subcutaneous inflammation. Administration of diclofenac, a nonselective cyclooxygenase (COX) inhibitor, at different doses (5, 50, 500, or 5,000 microg/kg) attenuated or abrogated LPS-induced fever and inhibited LPS-induced local PGE(2) formation (5 or 500 microg/kg diclofenac). Even the lowest dose of diclofenac (5 microg/kg) attenuated fever in response to 10 microg/kg LPS, but only when administered directly into the subcutaneous chamber, and not into the site contralateral to the chamber. This observation indicated that a localized formation of PGE(2) at the site of inflammation mediated a portion of the febrile response, which was induced by injection of 10 microg/kg LPS into the subcutaneous chamber. Further support for this hypothesis derived from the observation that we failed to detect elevated amounts of COX-2 mRNA in the brain of guinea pigs injected subcutaneously with 10 microg/kg LPS, whereas subcutaneous injections of 100 microg/kg LPS, as well as systemic injections of LPS (intra-arterial or intraperitoneal routes), readily caused expression of the COX-2 gene in the guinea pig brain, as demonstrated by in situ hybridization. Therefore, fever in response to subcutaneous injection of 10 microg/kg LPS may, in part, have been evoked by a neural, rather than a humoral, pathway from the local site of inflammation to the brain.

The prion protein (PrPC) has a primary role in the pathogenesis of transmissible spongiform encephalopathies. Here we analysed in detail the effect of recombinant PrPC and N- and C-terminal fragments of PrPC on the whole-cell current amplitude through voltage-gated calcium channels (VGCCs) of cultured wild-type cerebellar granule cells. With the application of full-length recombinant PrPC (50-500 nm), a highly significant reduction of the whole-cell current amplitude was observed in a dose-dependent manner. Amplitude reduction was abolished when cells were pre-incubated with nifedipine, a specific blocker of voltage-gated L-type calcium channels. N-terminal PrP fragments also led to a dose-dependent reduction of the maximal current amplitude, whereas a C-terminal fragment did not affect the current amplitude. These data demonstrate that nanomolar concentrations of PrPC modulate L-type VGCCs in mouse cerebellar granule cells, an effect that is dependent upon the copper-binding amino-terminal domain of PrPC.

Cu is thought to play an important role in the pathogenesis of several neurodegenerative diseases, such as Wilson's, Alzheimer's, and probably in prion protein diseases like Creutzfeld-Jakob's disease. Until now, no method existed to determine the concentration of this cation in vivo. Here, we present two possible approaches combined with a critical comparison of the results. The successful use of fluorescent ligands for the determination of Ca2+-concentrations in recent years encouraged us to seek a fluorophore which specifically reacts to Cu2+ and to characterize it for our purposes. We found that the emission of TSPP (tetrakis-(4-sulfophenyl)porphine) at an emission wavelength of 645 nm is in vitro highly specific to Cu2+ (apparent dissociation constant Kd=0.43 +/- 0.07 microM at pH 7.4). It does not react with the most common divalent cations in the brain, Ca2+ and Mg2+, unlike most of the other dyes examined. In addition, Zn2+ quenches TSPP fluorescence at a different emission wavelength (605 nm) with a Kd of 50 +/- 2.5 microM (pH 7.0). With these findings, we applied the measurement of Cu with TSPP to a biological system, showing for the first time in vivo that there is release of copper by synaptosomes upon depolarisation. Our findings were validated with a completely independent analytical approach based on ICP-MS (inductively-coupled-plasma mass-spectrometry).

In the European Union, legislation concerning animal housing is becoming stricter because of animal welfare concerns. Feather pecking (FP) in large group housing systems is a major problem. It has been suggested that corticosterone (CORT) response to manual restraint as a measure for stress is associated with FP behavior. The aim of the current study was to identify QTL involved in FP behavior and stress response in laying hens. An F2 population of 630 hens was established from a cross between two commercial lines of laying hens differing in their propensity to feather peck. The behavioral traits, measured at 6 and 30 wk of age, were gentle FP, severe FP, and aggressive pecking. Toe pecking was measured at 30 wk of age and CORT response to manual restraint was measured at 32 wk. All animals were genotyped for 180 microsatellite markers. A QTL analysis was performed using a regression interval mapping method. At 6 wk of age, a suggestive QTL on GGA10 was detected for gentle FP. At 30 wk of age, suggestive QTL were detected on GGA1 and GGA2 for gentle FP. A significant QTL was detected on GGA2 for severe FP. At 32 wk of age, a suggestive QTL was detected on GGA18 for CORT response to manual restraint. In addition, a suggestive QTL was detected on GGA5 with possible maternal parent-of-origin effect for CORT response.

Fear (i.e., decreased percentage time spent on open-arm exploration) in the elevated plus-maze can be potentiated by prior inescapable stressor exposure, but not by escapable stress. The use of fear-potentiated plus-maze behaviour has several advantages as compared to more traditional animal models of anxiety. (a) In contrast to the traditional (spontaneous) elevated plus-maze, which measures innate fear of open spaces, fear-potentiated plus-maze behaviour reflects an enhanced anxiety state (allostatic state). This "state anxiety" can be defined as an unpleasant emotional arousal in face of threatening demands or dangers. A cognitive appraisal of threat is a prerequisite for the experience of this type of emotion. (b) Depending on the stressor used (e.g., fear of shock, predator odour, swim stress, restraint, social defeat, predator stress (cat)), this enhanced anxiety state can last from 90 min to 3 weeks. Stress effects are more severe when rats are isolated in comparison to group housing. (c) Drugs can be administered in the absence of the original stressor and after stressor exposure. As a consequence, retrieval mechanisms are not affected by drug treatment. (d) Fear-potentiated plus-maze behaviour is sensitive to proven/putative anxiolytics and anxiogenics which act via mechanisms related to the benzodiazepine-gamma-aminobutyric acid receptor, but it is also sensitive to corticotropin-releasing receptor antagonists and glucocorticoid receptor antagonists and serotonin receptor agonists/antagonists complex (high predictive validity). (e) Fear-potentiated plus-maze behaviour is very robust, and experiments can easily be replicated in other labs. (f) Fear-potentiated plus-maze behaviour can be measured both in males and females. (g) Neural mechanisms involved in contextual fear conditioning, fear potentiation and state anxiety can be studied.Thus, fear-potentiated plus-maze behaviour may be a valuable measure in the understanding of neural mechanisms involved in the development of anxiety disorders and in the search for novel anxiolytics. Finally, the involvement of corticotropin-releasing factor and corticosteroid-corticotropin-releasing factor interactions in the production of fear-potentiated plus-maze behaviour are discussed.

A comparative study was performed to evaluate the differences in behavioral and physiological stress responses during milking between cows that were milked by an automated milking system (AM-cows) and cows that were milked in a conventional tandem parlor (TM-cows). In a randomized design, 36 primiparous Holstein-Friesian dairy cows were observed and blood sampled (1-min intervals) individually during milking. AM-cows spent less time standing with their heads outside the feeding trough than TM-cows and had a lower heart rate. In addition, AM-cows had lower maximum plasma adrenaline and noradrenaline concentrations during milking. No differences were found in the number of steps. After tactile stimulation of the teats either by hand or by the cleaning brush, mean oxytocin concentrations did not differ. In AM-cows, however, elevated oxytocin levels were prolonged at the end of milking. Averaged over the first five blood samples, AM-cows tended to have higher plasma cortisol concentrations than TM-cows, but median fecal concentrations of the cortisol metabolite dioxoandrostane were comparable. Maximum quarter milk flow, maximum udder milk flow and residual milk as a percentage of the total milk volume was comparable. From this study it is concluded that behavioral and physiological responses, both in automatically and in conventionally milked cows, were relatively low and were typical for cows being milked. We therefore conclude that, as far as the welfare of the dairy cow during milking is concerned, automatic milking and conventional milking are equally acceptable.

Munc13 proteins form a family of three, primarily brain-specific phorbol ester receptors (Munc13-1/2/3) in mammals. Munc13-1 is a component of presynaptic active zones in which it acts as an essential synaptic vesicle priming protein. In contrast to Munc13-1, which is present in most neurons throughout the rat and mouse CNS, Munc13-3 is almost exclusively expressed in the cerebellum. Munc13-3 mRNA is present in granule and Purkinje cells but absent from glia cells. Munc13-3 protein is localized to the synaptic neuropil of the cerebellar molecular layer but is not found in Purkinje cell dendrites, suggesting that Munc13-3, like Munc13-1, is a presynaptic protein at parallel fiber-Purkinje cell synapses. To examine the role of Munc13-3 in cerebellar physiology, we generated Munc13-3-deficient mutant mice. Munc13-3 deletion mutants exhibit increased paired-pulse facilitation at parallel fiber-Purkinje cell synapses. In addition, mutant mice display normal spontaneous motor activity but have an impaired ability to learn complex motor tasks. Our data demonstrate that Munc13-3 regulates synaptic transmission at parallel fiber-Purkinje cell synapses. We propose that Munc13-3 acts at a similar step of the synaptic vesicle cycle as does Munc13-1, albeit with less efficiency. In view of the present data and the well established vesicle priming function of Munc13-1, it is likely that Munc13-3-loss leads to a reduction in release probability at parallel fiber-Purkinje cell synapses by interfering with vesicle priming. This, in turn, would lead to increases in paired-pulse facilitation and could contribute to the observed deficit in motor learning.

Previous studies have indicated that recombinant cellular prion protein (PrP(C)), as well as a synthetic peptide of PrP(C), affects intracellular calcium homeostasis. To analyze whether calcium homeostasis in neurons is also affected by a loss of PrP(C), we performed microfluorometric calcium measurements on cultured cerebellar granule cells derived from prion protein-deficient (Prnp(0/0)) mice. The resting concentration of intracellular free calcium [Ca(2+)](i) was found to be slightly, but significantly, reduced in Prnp(0/0) mouse granule cell neurites. Moreover, we observed a highly significant reduction in the [Ca(2+)](i) increase after high potassium depolarization. Pharmacological studies further revealed that the L-type specific blocker nifedipine, which reduces the depolarization-induced [Ca(2+)](i) increase by 66% in wild-type granule cell somas, has no effect on [Ca(2+)](i) in Prnp(0/0) mouse granule cells. Patch-clamp measurements, however, did not reveal a reduced calcium influx through voltage-gated calcium channels in Prnp(0/0) mice. These data clearly indicate that loss of PrP(C) alters the intracellular calcium homeostasis of cultured cerebellar granule cells. There is no evidence, though, that this change is due to a direct alteration of voltage-gated calcium channels.

Over the last 30 years concern about farm animal welfare has increased and has become a public issue in the Netherlands. Public discussion has stimulated research in this field, financed by both government and industry. Dutch society in general and consumers of animal products in particular, want to see high standards of welfare for production animals. Good animal welfare has gradually gained more impact in the total quality concept of the product. This will encourage scientists to continue to analyse the welfare status of animals and to come up with innovative solutions for the remaining problems. At ID-Lelystad much effort is put into farm animal welfare research. This research includes for example, the development of behavioural tests for quantifying and interpreting fear in cattle, investigations into the effects of dietary iron supply and a lack of roughage on behaviour, immunology, stress physiology, and pathology in veal calves, studies of the ontogeny of tail biting in finishing pigs and feather pecking in laying hens as well as evaluation of the welfare effects of automatic milking in dairy cows. The results of these projects contribute to concrete improvements in animal husbandry and expertise and support policy making and legislation. The animal industry as well as retailers should aim at the further implementation of this knowledge and to specify welfare standards to guarantee consumer acceptance of animal production.

Previously we showed that pigs reared in an enriched environment had higher baseline salivary cortisol concentrations during the light period than pigs reared under barren conditions. In the present experiment, it was investigated whether these higher baseline salivary cortisol concentrations were a real difference in cortisol concentration or merely represented a phase difference in circadian rhythm. The effects of different cortisol concentrations on the behavioral responses to novelty and learning and long-term memory in a maze test were also studied in enriched and barren housed pigs. At 9 weeks of age enriched and barren housed pigs did not differ in baseline salivary cortisol concentrations nor in circadian rhythm, but at 22 weeks of age barren housed pigs had a blunted circadian rhythm in salivary cortisol as compared to enriched housed pigs. The differences in baseline salivary cortisol concentrations between enriched- and barren-housed pigs are age-dependent, and become visible after 15 weeks of age. Enriched- and barren-housed piglets did not differ in time spent on exploration in the novel environment test. Barren-housed pigs had an impaired long-term memory in the maze test compared to enriched-housed pigs; however, no differences in learning abilities between enriched- and barren-housed pigs were found. Because blunted circadian cortisol rhythms are often recorded during states of chronic stress in pigs and rats or during depression in humans, it is suggested that the blunted circadian rhythm in cortisol in barren-housed pigs similarily may reflect decreased welfare.

This paper summarizes the current views on coping styles as a useful concept in understanding individual adaptive capacity and vulnerability to stress-related disease. Studies in feral populations indicate the existence of a proactive and a reactive coping style. These coping styles seem to play a role in the population ecology of the species. Despite domestication, genetic selection and inbreeding, the same coping styles can, to some extent, also be observed in laboratory and farm animals. Coping styles are characterized by consistent behavioral and neuroendocrine characteristics, some of which seem to be causally linked to each other. Evidence is accumulating that the two coping styles might explain a differential vulnerability to stress mediated disease due to the differential adaptive value of the two coping styles and the accompanying neuroendocrine differentiation.

Genetically selected short attack latency (SAL) and long attack latency (LAL) male wild house mice behave differently in the defensive burying test. When challenged, SAL males respond actively with more time spent on defensive burying, whereas LAL males are more passive with more time remaining immobile. The first aim of this study was to find out whether the nonpairing part of the Y chromosome (Y(NPAR)) affects the behavioral stress response in this paradigm. Second, to determine if the differential behavioral profile found in males is also present in females, SAL and LAL females were tested. Third, nonattacking and attacking LAL males were compared. Five behavioral elements were recorded: defensive burying, immobility, rearing, grooming, and exploration. Males were first tested for attack latency. The results show that the Y(NPAR) influences defensive burying. However, the size of this effect is overshadowed by the background of the mice. Furthermore, although females differed from males, they tended to demonstrate the same behavioral profile as males. Nongenetic factors may also play a role, as attacking LAL males showed more defensive burying than nonattacking LAL males.

The purpose of this investigation was to determine whether two-week-old rapidly growing broiler chickens with high metabolic activity have an increased risk of the development of heart failure three to five weeks later. The incidence of cardiac arrhythmias was assessed in broiler chickens with either a relatively high carbon dioxide tension (PCO2) or a low PCO2 in their venous blood. Their electrocardiograms (ECGS) were measured when the birds were between five and seven weeks old by means of a biotransplant which allowed them to move freely. Premature ventricular beats were observed in all the birds, but the largest numbers were observed in birds that had had a high PCO2 when they were two weeks old.

In the present study we report the effect of corticosterone in the regulation of hippocampal muscarinic acetylcholine receptor immunoreactivity (mAChR-ir) expression in rats. Adrenalectomy (ADX) or a single injection of a mineralocorticoid antagonist RU-28318 (1.0 mg/100 g body weight (b.w.)) in adrenally intact rats 24 h prior to sacrifice revealed an increased mAChR-ir in hippocampal CA1 and CA3 areas. Corticosterone replacement (100 microg/100 g b.w.) prevented the increase in mAChR-ir of ADX animals. However, glucocorticoid receptor antagonist (RU38486) treatment in adrenally intact rats failed to affect the mAChR immunolabeling. These results point to a modulation of muscarinic receptors by corticosterone that is predominantly mediated by the mineralocorticoid receptor.

To study the effects of environmental enrichment on physiological responses to stressors and behavior in growing pigs, pigs were housed in either a poor environment (standard farrowing pens followed by standard rearing and fattening pens) or in an enriched environment (larger farrowing pens followed by larger rearing and fattening pens, provision of straw). Body temperature, heart rate and salivary cortisol were measured during baseline conditions and in response to relocation, isolation and restraint. Pigs housed in the poor environment performed more manipulative social behavior directed to penmates than pigs housed in the enriched environment. Physiological responses to the stressors were the same for enriched- and poor-housed pigs. Surprisingly, enriched-housed pigs had significantly higher baseline salivary cortisol concentrations, especially at 14 and 17 weeks of age. Moreover, enriched housed pigs had a lower baseline body temperature at 17 weeks of age. Thus, provision of straw has an effect on behavior, baseline HPA-axis activity and baseline body temperature in growing pigs.

The anxiolytic property of R-(+)-8-OSO2CF3-PAT(R-(+)-8- [[(trifluoromethyl)sulfonyl]oxy]-2-(n-propyl-amino)tetralin), a 5-HT1A receptor agonist, was evaluated in Wistar rats by means of animal models of anxiety, the conditioned defensive burying model and the conditioned stress-induced freezing response followed by the elevated plus-maze test, respectively. In addition, the 5-HIAA/5-HT ratio (5-hydroxy-indole acetic acid/5-hydroxytryptamine) of rat brain homogenates was studied. Acute drug administration resulted in abolition of the burying behaviour (3 mg/kg i.p.), a dose-dependent decrease of rearing and induction of hyperphagia. R-(+)-8-OSO2CF3-PAT had no effect on conditioned footshock-induced freezing behaviour but increased open-arm activity in the rats on the plus-maze. The 5-HIAA/5-HT ratio was decreased in the lateral septum (1 and 3 mg/kg), dorsal hippocampus (3 mg/kg) and somatosensory cortex (3 mg/kg), implying that R-(+)-8-OSO2CF3-PAT affects particularly the limbic system in anxiety-inducing situations.

The aim of the present study was to explore the neuroanatomic network that underlies the cardiovascular responses of reticular formation origin in the region of the cuneiform nucleus (CNF). The study was performed in urethane anesthetized male Wistar rats. The left iliac artery was supplied with a catheter for the measurement of systemic blood pressure. Low intensity electrical stimulation of the mesencephalic reticular formation (MRF) in the vicinity of the CNF always resulted in pressor and bradycardiac responses, whereas stimulation in the parabrachial nucleus (PB) and Kölliker-Fuse nucleus (KF) led to a pressor response and a small tachycardiac response. The cuneiform area may be placed in the center of a circuit that serves a specific autonomic response pattern to stress: parallel activation of the sympathetic (pressor response) and parasympathetic limb (bradycardia). The efferent connections of the effective stimulation sites in the MRF and the CNF area, were investigated by anterograde tracing with the lectin Phaseolus vulgaris leucoagglutine (PHA-L). The CNF sends descending fibers to the gigantocellular reticular nuclei (GI), the motor nucleus of the vagus (DMNV) and nucleus tractus solitarius (NTS). These projections are probably involved in the bradycardiac response to stimulation. The descending pathway to the NTS/DMNV and GI may therefore be the parasympathetic limb of the circuit. Furthermore, the CNF sends ascending fibers to limbic forebrain areas and descending fibers to the PB-KF complex. The KF in its turn projects to the rostroventrolateral medullary nucleus (RVLM) and the intermediolateral cell column (IML). These latter projections are partly involved in producing the pressor response and thereby represent the sympathetic limb of the circuit. Accordingly, the transection of the descending fibers from the CNF to the PB-KF complex resulted in a decreased pressor and an increased bradycardiac response. This suggests that a baroreceptor reflex-induced bradycardia which results from blood pressure increase can be excluded as the origin of the stimulation-induced bradycardia, and that the pressor and bradycardiac responses are two independent moieties. It cannot be excluded that ascending fibers from the CNF are also involved in producing the pressor response. On the basis of the present physiological and neuroanatomical study, a brain circuit has been proposed in which the cuneiform nucleus has a central position. The described brain circuit may serve a passive coping strategy to novel, painful or threatening stimuli during which the animals show orientation/attention or freezing behavior accompanied by a bradycardiac and pressor response.

Intracerebroventricularly (icv) administered corticotropin-releasing hormone (CRH) produces a dose-dependent increase in heart rate in association with behavioral activation. The present study was designed to investigate whether these CRH-induced responses are dependent on adrenal function. The effects of adrenalectomy (ADX) and subsequent corticosterone replacement were studied. Administration icv of 300 ng of CRH failed to produce behavioral activation and tachycardia in ADX rats. Corticosterone replacement restored the CRH-induced behavioral response to preoperative levels, whereas the CRH-induced tachycardia was partially restored. This latter result may be related to the fact that the baseline heart rate of ADX animals appeared to be significantly higher than that of corticosterone-treated ADX animals. It is concluded that circulating adrenal corticosterone in ADX rats is involved in the expression of the behavioral and cardiac effect of central CRH.

Plasma epinephrine (E), norepinephrine (NE), and corticosterone (CORT) concentrations were determined in the rat before, during, and after a 15-min exposure to a nonelectrified probe on day after receiving electric shock (1.5 mA) through a probe mounted on the wall of the home cage. Rats displayed burying (active coping) if sawdust was provided on the floor and immobility (passive coping) if bedding was absent both during training and testing. The conditioned burying was accompanied by high plasma NE but low E and CORT concentrations, whereas immobility was associated with high CORT and low NE levels. A forced switch from the active to passive coping (training with and testing without sawdust) led to the highest rise in E concentration. The 5-HT1A agonist ipsapirone, with anxiolytic properties, dose-dependently (0.5 and 2.5 mg/kg, IV) reduced defensive burying behavior and increased the amount of time spent on feeding behavior in the presence of bedding material. Both plasma E and CORT levels were further elevated by the higher dose of ipsapirone. In the absence of bedding material, ipsapirone failed to affect immobility behavior, but it dose-dependently elevated the stress-induced increase in E, NE, and CORT concentrations. Accordingly, the behavioral anxiolytic action of the 5-HT1A agonist ipsapirone was restricted to active coping, whereas neuroendocrine activation by the drug was present in all conditions. It is suggested that the effects of ipsapirone on behavioral coping and neuroendocrine regulation are produced by different populations of 5-HT1A receptors in the brain.