Ultrasound-aided diagnosis of an insulinoma in a cat.

A 15-year old, neutered female, domestic shorthaired cat was presented for evaluation of a 3-month history of paroxysmal falling over and trembling. In laboratory work the cat displayed a mild hypoglycemia. Ultrasound revealed a nodule in the left pancreatic lobe and surgical excision was performed. The histological diagnosis was an insulinoma. To the authors knowledge this is the first ultrasound description of an insulinoma in a cat. Up to date the cat has a survival time of 32 months without recurrence of symptoms.

[Computed tomography in cats with craniofacial trauma with regard to maxillary and orbital fractures]. / Computertomographische Untersuchung des Schädels von Katzen mit kraniofazialem Trauma im Hinblick auf Maxilla- und Orbitafrakturen.

OBJECTIVE: Computed tomographic examination of the skull of cats with craniofacial trauma. Analysis of diagnostic findings with regard to the occurrence of isolated and combined maxillary and orbital fractures. MATERIAL AND METHODS: Prospective study (August 2006 - June 2010): Computed tomography (CT) of the skull of cats with craniofacial trauma. RESULTS: Thirty-eight cats met the inclusion criteria. Breeds were 36 Domestic Shorthair cats, one Maine Coon and one Somali cat. Age at admission ranged from 11 to 187 months. The ratio of the numbers of males to females was 22:16 (1.4). Computed tomographic examination revealed a maxillary fracture in 27 (71%) animals. Sixteen (42%) cats had multiple maxillary fractures (≥2). Twenty-eight animals (74%) displayed orbital fractures. Combined maxillary and orbital fractures occurred in 26 (68%) patients. The odds ratio of this combined occurrence was 87 (p<0.001). Sixteen (57%) of 28 cats with orbital fractures showed multiple orbital fractures (≥2). The incidence of bilateral orbital fractures was 67% (25 patients). The medial orbital wall was the most commonly fractured orbital wall (66%), and the orbital floor the second most common (61%). CONCLUSION: Computed tomographic examination of the skull of cats with craniofacial trauma showed that maxillary and orbital fractures are more common than previously described. Combined maxillary and orbital fractures occurred in more than half of the patients. In cats, orbital fractures mainly affect the medial orbital wall and the orbital floor. CLINICAL RELEVANCE: Cats with craniofacial trauma often have maxillary and orbital fractures. The additional information taken from the computed tomographic examination could lead to an optimised therapeutical concept.

Observer variability and sensitivity of radiographic diagnosis of canine medial coronoid disease.

OBJECTIVE: Medial coronoid disease (MCD) is a very common form of elbow joint disease and it's radiographic diagnosis can be challenging since it is frequently based on the detection of rather subtle primary or secondary changes than on a large primary lesion. We hypothesized that accuracy of radiographic diagnosis of MCD is highly dependent on training and experience level. METHODS: Radiographs of 102 canine elbows were evaluated for MCD by four observers with different levels of training and experience. All elbows underwent CT scans and arthroscopy. Sensitivity and specificity of radiographic and CT interpretation was determined using arthroscopy as a gold standard. Interobserver and intraobserver agreement (reliability and repeatability) were assessed by using Cohen's Kappa (κ) statistic. RESULTS: The sensitivity (92.4-96.7%) of the two experienced observers was almost comparable to that of CT (100%) and significantly higher than that of the two less experienced observers (77.2-80.4%). Reliability of the radiographic diagnosis of MCD was better between observers with higher experience level (κ= 0.74) than between observers of lower or different experience levels (κ=0.07-0.42). Repeatability was better in experienced (κ= 0.73-0.88) than in less experienced observers (κ= 0.31-0.42). CONCLUSION: Our results confirm that training and experience play important roles in reaching high sensitivity, reliability and repeatability for the radiographic diagnosis of MCD. CLINICAL RELEVANCE: Although radiography is inferior to CT in imaging of the medial coronoid process itself, sensitivity of radiographic diagnosis MCD can be significantly improved with observer experience almost reaching that of CT. Therefore, it is advised that radiographic screening for MCD should be performed by specialists experienced in the radiographic evaluation of elbow joint disease.

Immune challenge induces differential corticosterone and interleukin-6 responsiveness in rats bred for extremes in anxiety-related behavior.

Disturbances in mood such as anxiety and depression are often associated with altered hypothalamo-pituitary-adrenal (HPA) axis reactivity, but also with changes in cytokine production, such as interleukin-6 (IL-6), an essential immune factor produced by macrophages and lymphocytes during inflammatory processes. The reciprocal relationship between the HPA axis and the immune system is now well established. In order to understand better the endocrine reactivity of anxious individuals faced with an immune challenge, a model of innate anxiety-related behavior, HAB and LAB rats (HABs, high and LABs, low anxiety-related behavior) was used in this study. We sought to determine whether injection of lipopolysaccharide (LPS) induced a differential HPA axis reactivity and plasma IL-6 release in HABs and LABs. After LPS injection, the plasma adrenal corticotrophic hormone increase did not differ between HABs and LABs, whereas a larger increase in plasma corticosterone levels occurred in HABs than in LABs at 2 h after injection. Moreover, basal IL-6 levels were lower in HABs than in LABs, leading to a higher IL-6 2 h/basal ratio in HABs. In conclusion, we propose for the first time a link between the endocrine and immune systems of HABs and LABs and suggest that IL-6 could be a neuroendocrine correlate of trait anxiety in HABs.

Differential effects of periodic maternal separation on adult stress coping in a rat model of extremes in trait anxiety.

We studied interactions of genetic and environmental factors shaping adult emotionality and stress coping, and tested the hypothesis that repeated periodic maternal deprivation (PMD) exerts differential effects on adult behavioral and neuroendocrine stress responsiveness in dependence on the genetic predisposition to either hyper- or hypo-anxiety. Exposure of male Wistar rats bidirectionally bred for either high (HAB) or low (LAB) anxiety-related behavior to PMD between postnatal days 2 and 15 resulted in a behavioral approximation of the selected lines. This was reflected by test-dependent signs of reduced anxiety-related behavior in adult HAB rats and of enhanced levels of anxiety in LAB rats compared with their corresponding unstressed controls. In addition to behavioral parameters, differential effects of PMD were also seen with respect to the responsiveness of the hypothalamo-pituitary-adrenocortical axis to acute stressor exposure (novel environment) in adulthood. The corticotrophin (ACTH) and corticosterone hyper-responses seen in control rats of the HAB line compared with those of the LAB line became attenuated in PMD-HAB rats, whereas PMD did not significantly alter neuroendocrine responses in LAB rats. Thus, as a result of PMD, both ACTH and corticosterone responses became indistinguishable between HAB and LAB rats. Although HAB dams spent more time on the nest with the litter compared with LAB dams during the first 5 days postpartum, licking and grooming behavior did not differ between the lines prior to separation, and was found to be increased to the same extent in both HAB and LAB dams during the first hour immediately after reunion with the pups. In contrast to early life stress, exposure of adult HAB and LAB rats to a 10-day unpredictable stress schedule failed to alter their emotional measures. The mitigating effect of PMD on both behavioral and neuroendocrine parameters in rats representing extremes in trait anxiety might reflect an evolutionary benefit as the genetic variability among individuals of a species is sustained while allowing adequate responses to potentially dangerous stimuli in adulthood dependent on early life conditions.

Two Wistar rat lines selectively bred for anxiety-related behavior show opposite reactions in elevated plus maze and fear-sensitized acoustic startle tests.

Two Wistar rat lines selectively bred for high (HAB), and low anxiety-related behavior (LAB) on the elevated plus maze were tested for the fear-sensitized acoustic startle response. The study of male rats from the F9 generation revealed a higher anxiety level of HAB rats on the elevated plus maze. However, the LAB rats displayed a higher baseline and fear-sensitized acoustic startle response compared to HAB rats, although the two rat lines did not differ in freezing duration during the interstimulus intervals in the startle experiment (neither before, nor after, footshocks). Counts of neurons immunoreactive for corticotropin-releasing factor and neuropeptide Y in amygdaloid nuclei did not reveal any differences between the two lines, which is in marked contrast to findings in the Roman rat lines. The data indicate that opposite types of anxiety/fear responses are elicited in HAB/LAB rats in the elevated plus maze and fear-sensitized startle tests. Moreover, the animals displayed a differential fear response in the startle experiment, as assessed by measuring the fear-sensitized startle response and freezing.

Born to be anxious: neuroendocrine and genetic correlates of trait anxiety in HAB rats.

This review summarises behavioural, neuroendocrine, and genetic characteristics of Wistar rats bred for either high (HAB) or low (LAB) anxiety-related behaviour. Compared to LABs, HAB animals show signs of extreme trait anxiety in a variety of behavioural tests; they further prefer passive coping strategies, indicative of a genetically linked depression-like behaviour, and show signs of increased stress vulnerability. All behavioural parameters associated with trait anxiety are robust and consistent. Resembling psychiatric patients, HAB rats respond to exposure to ethologically relevant stressors with a hyper-reactivity of the hypothalamic-pituitary-adrenal axis and show a pathological outcome of the combined dexamethasone/corticotropin-releasing hormone (Dex/CRH) challenge test. Experimental evidence indicates that over-expression and -release of vasopressin in the hypothalamic paraventricular nucleus is responsible for these behavioural and neuroendocrine phenomena, making the neuropeptide gene a candidate gene of trait anxiety/depression. Indeed, preliminary molecular genetic approaches succeeded in identifying polymorphisms in the promoter structure of the vasopressin gene. This may have implications for understanding the molecular basis for individual variations in trait anxiety and for psychopathology.

Hypothalamic and hippocampal release of serotonin in rats bred for hyper- or hypo-anxiety.

Microdialysis for measurement of serotonin in the paraventricular nucleus of the hypothalamus (PVN) and the dorsal hippocampus was performed under both basal and stimulated conditions, known to elicit differential behavioral and neuroendocrine responses in rats with inborn high (HAB) or low (LAB) anxiety-related behavior. We studied the release of hypothalamic and hippocampal serotonin in response to elevated platform exposure and forced swim stress, a mild emotional and a combined emotional and physical stressor, respectively. The data suggest that serotonin release patterns may depend on the inborn level of anxiety, the brain area dialyzed, and the stressor the animals were exposed to. Under basal conditions, no differences in serotonin release in either the PVN or dorsal hippocampus were observed between HAB and LAB rats. While in the PVN open platform exposure failed to change the release of serotonin, forced swim stress induced an increase in both HAB (p = 0.0001) and LAB (p = 0.01) rats with a significantly greater effect in the former (p = 0.027). In the dorsal hippocampus, only LABs, but not HABs, responded to the elevated platform exposure by enhancing the release of serotonin (p = 0.01). Also, forced swim stress increased hippocampal serotonin only in LAB (p = 0.002), but not HAB, rats probably indicating an involvement of hippocampal serotonin in locomotion and active stress coping. It remains to be shown to what extent the differences in serotonin release contribute to neuroendocrine and behavioral differences between HAB and LAB rats.

Endogenous opioid regulation of stress-induced oxytocin release within the hypothalamic paraventricular nucleus is reversed in late pregnancy: a microdialysis study.

Oxytocin secretion into blood in response to swim stress is differentially regulated by endogenous opioids in virgin and pregnant rats. Here, the influence of endogenous opioids on oxytocin release within the hypothalamic paraventricular and supraoptic nuclei was investigated using microdialysis in virgin and pregnant (day 19-21) rats. Rats fitted with a U-shaped microdialysis probe 3 days before testing were injected with naloxone (5 mg/kg body weight, s.c.) or vehicle (sterile saline) and, 3 min later, were forced to swim (10 min at 19 degrees C). Within the paraventricular nucleus, basal and stimulated oxytocin release did not significantly differ between vehicle-treated virgin and pregnant rats. After naloxone, local oxytocin release in response to swimming was lowered in virgin rats (P<0.01), whereas it was further increased in pregnant rats (P<0.01). Within the supraoptic nucleus, basal oxytocin release was significantly lower in pregnant compared to virgin rats (P<0.01). Forced swimming induced a similar rise in intranuclear oxytocin release in both vehicle-treated virgin and pregnant rats, but peak levels were still higher in the virgin controls. In contrast to the paraventricular nucleus, naloxone did not alter swim-induced oxytocin release within the supraoptic nucleus either in virgin or pregnant rats. Vasopressin release in the paraventricular nucleus was also increased by forced swimming but there was no effect of pregnancy or naloxone on it. In summary, in pregnancy, basal and stress-induced oxytocin release within the paraventricular nucleus was not changed, whereas it was blunted within the supraoptic nucleus. Further, within the paraventricular nucleus the excitatory effect of endogenous opioids on local oxytocin release seen in virgins was switched into an inhibitory action in pregnancy. In contrast, endogenous opioids were evidently not involved in the regulation of swim-induced oxytocin release within the supraoptic nucleus either in virgin or pregnant rats. Thus, pregnancy-related neuroendocrine plasticity also includes site-specific functional alterations in opioid receptor-mediated actions in the hypothalamus.

Cross-fostering and cross-breeding of HAB and LAB rats: a genetic rat model of anxiety.

Recently, two Wistar rat lines, bred and selected for either high (HAB) or low (LAB) anxiety-related behavior on the elevated plus-maze, were described as a novel psychopathologic animal model. The behavioral and neuroendocrine responses to exposure to an emotional stressor were markedly enhanced in HAB rats compared with LAB rats, thus resembling patients suffering from psychiatric diseases. The present study focused on the developmental and genetic basis of the line-specific differences by using cross-fostering and cross-breeding approaches. For the cross-fostering paradigm, neonate HAB offspring were nursed by a LAB foster mother, and vice versa, until weaning. In the cross-breeding approach, HAB females were mated with LAB males, and vice versa, to create an intermediate F1 generation. Thereafter, the F1 animals were strictly sibling-mated to produce a segregating F2 generation. At 10 weeks of age, anxiety-related behavior of all animals was tested on the elevated plus-maze. The robustness of emotionality was assessed in rats of both lines throughout their entire lifetime. Serving this purpose, the frequency of ultrasound isolation calls, indicative of the emotionality of newborn rats, was monitored in regularly-fostered HAB and LAB pups on postnatal day 11. In addition, the timecourse of anxiety-related behavior was studied by repeated testing on the elevated plus-maze at the ages of 10 weeks, 6 months, 16 months, and 19 months. The cross-fostering approach failed to reveal behavioral differences between regularly and cross-fostered HAB and LAB rats, indicating no line-specific differences in maternal care or maternally-influenced development, at least after postnatal day 1. In contrast, cross-breeding resulted in F1 and F2 offspring displaying intermediate behavioral patterns on the elevated plus-maze which were exactly in between those shown in HAB and LAB control rats, thus confirming a genetic basis of the differences in anxiety. Cross-breeding revealed no differences related to the gender of the offspring or to the line-derivation of sire or dam, indicating an autosomal, rather than heterosomal, heredity of the divergent emotionality in HABs and LABs. Further, we were able to show stable and robust emotional differences in rats of both lines during their entire lifetime. HAB rats showed an enhanced frequency of ultrasound isolation calls on postnatal day 11 (p < 0.05) and a lower open arm exploration of the elevated plus-maze throughout adulthood (p < 0.01) compared with the same-aged LABs. In conclusion, the extremely divergent anxiety levels of HAB and LAB rats are maintained during their whole lives and are determined genetically, rather than being learned. These findings may be important for further studies on the genetic basis of emotionality.

Dimensions of emotionality in a rat model of innate anxiety.

Emotionality is thought to be multidimensional, with "anxiety" representing one dimension. Dissecting emotional dimensions in animal models is an essential prerequisite for investigating the neurobiological mechanisms that underlie anxiety. The authors used factor analysis to investigate emotional dimensions in normal rats and rats bred for either high or low anxiety-related behavior. Hyperanxious rats were reduced in emotional dimensions in the elevated plus-maze by selection pressure, and a modified hole board test revealed a dissection of their emotionality with precisely defined dimensions. This enabled clear differentiation of "anxiety" from other emotional dimensions including risk assessment behavior and exploration. Factors extracted by analyzing data from a multiple-test battery corresponded to particular test characteristics rather than to emotional dimensions. The approach used might help to develop specific treatment strategies for anxiety disorders.

Neuroendocrine and behavioral effects of repetitive transcranial magnetic stimulation in a psychopathological animal model are suggestive of antidepressant-like effects.

The neuroendocrine and behavioral effects of repetitive transcranial magnetic stimulation (rTMS) were investigated in two rat lines selectively bred for high and low anxiety-related behavior. The stimulation parameters were adjusted according to the results of accurate computer-assisted and magnetic resonance imaging-based reconstructions of the current density distributions induced by rTMS in the rat and human brain, ensuring comparable stimulation patterns in both cases. Adult male rats were treated in two 3-day series under halothane anesthesia. In the forced swim test, rTMS-treatment induced a more active coping strategy in the high anxiety-related behavior rats only (time spent struggling; 332% vs. controls), allowing these animals to reach the performance of low anxiety-related behavior rats. In contrast, rTMS-treated low anxiety-related behavior rats did not change their swimming behavior. The development of active coping strategies in high anxiety-related behavior rats was accompanied by a significantly attenuated stress-induced elevation of plasma corticotropin and corticosterone concentrations. In summary, the behavioral and neuroendocrine effects of rTMS of frontal brain regions in high anxiety-related behavior rats are comparable to the effects of antidepressant drug treatment. Interestingly, in the psychopathological animal model repetitive transcranial magnetic stimulation induced changes in stress coping abilities in the high-anxiety line only.

The anxiolytic effect of the CRH(1) receptor antagonist R121919 depends on innate emotionality in rats.

Hyperactivity of central corticotropin-releasing hormone (CRH) circuits appears to contribute to the symptomatology of affective and anxiety disorders and therefore CRH receptor antagonists have attracted attention as potential therapeutic agents. R121919, a novel high-affinity nonpeptide CRH(1) receptor antagonist, displaced (125)I-oCRH in rat pituitary, cortex and amygdala, but not in choroid plexus or cerebral blood vessels in vitro and in vivo, which is consistent with CRH(1) receptor antagonism. In vivo, R121919 significantly inhibited stress-induced corticotropin release in rats selectively bred for high- and low-anxiety-related behaviour but displayed anxiolytic effects in high-anxiety rats only. These data, corroborated by ex vivo receptor occupancy studies, suggest that this animal model is appropriate for the evaluation of CRH(1) receptor antagonists and that compounds such as R121919 will be beneficial whenever the central stress hormone system is hyperactive.

Attenuation of hypothalamic-pituitary-adrenal axis stress responses in late pregnancy: changes in feedforward and feedback mechanisms.

The hypothalamic-pituitary-adrenal axis is hyporesponsive to stress in late pregnancy, exemplified as reduced adrenocorticotropic hormone (ACTH) and corticosterone responses to restraint, but the mechanisms are unknown. We investigated forward drive and negative feedback upon the hypothalamic-pituitary-adrenal axis in pregnant rats. Corticotropin-releasing hormone (CRH) and vasopressin mRNA expression in the parvocellular paraventricular nucleus and mineralocorticoid and glucocorticoid receptor expression in the paraventricular nucleus and hippocampus were quantified with in situ hybridization. Because it can enhance the corticosterone negative feedback signal, 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) bioactivity in these brain regions and anterior pituitary was measured in vitro, and ACTH and corticosterone stress responses were measured after intracerebroventricular glycyrrhetinic acid, an 11beta-HSD inhibitor. Changes in corticosterone feedback on ACTH secretion were examined after pharmacological adrenalectomy by metyrapone and aminoglutethimide. Parvocellular paraventricular nucleus CRH mRNA content was reduced on day 21 and the CRH mRNA : vasopressin mRNA ratio was unaltered, indicating decreased production of both CRH and vasopressin. An increase in glucocorticoid receptor mRNA expression in the dentate gyrus (mineralocorticoid receptor mRNA expression was unaltered) and increased 11beta-HSD1 activity in the paraventricular nucleus and anterior pituitary suggest an increase in slow negative feedback mechanisms in pregnancy, but glycyrrhetinic acid did not modify the stress response. After metyrapone/aminoglutethimide treatment, corticosterone decreased ACTH secretion more slowly in pregnancy, indicating a decrease in rapid feedback sensitivity. Thus, reduced forward drive rather than increased effectiveness of glucocorticoid negative feedback may underlie stress hyporesponsiveness of the hypothalamic-pituitary-adrenal axis in pregnancy.

Unconditioned anxiety and social behaviour in two rat lines selectively bred for high and low anxiety-related behaviour.

Individuals of high anxiety-related behaviour (HAB) and low anxiety-related behaviour (LAB) rat lines were selectively bred for differences in anxiety-related behaviour on the elevated plus-maze. The goal of this study was to investigate whether this behavioural difference is restricted to the test used as the selection criterion or whether it is a stable and robust trait also in other conflict or non-conflict situations. Therefore, behaviour of male and female HAB and LAB rats was examined in two further tests of unconditioned anxiety: the black-white box and the social interaction test. Furthermore, behaviour of group-housed male HAB and LAB rats was studied in their home cages. In addition to standard statistics, discriminant analyses were performed. The difference in anxiety-related behaviour between the two lines was highly consistent in all tests of unconditioned anxiety. There were also differences in home cage behaviour, LAB rats being more active than HAB rats; this is likely to be a consequence of the LAB rats displaying a higher aggressiveness in social behaviour, compared to HAB rats. In all tests used HAB and LAB rats were clearly distinguished by discriminant analysis. However, while in the elevated plus-maze and the black-white box test the most important parameters for discrimination between the two lines were mainly those generally seen as closely related to anxiety, the discrimination in the social interaction paradigm was primarily due to differences in locomotor activity.

Brain oxytocin inhibits basal and stress-induced activity of the hypothalamo-pituitary-adrenal axis in male and female rats: partial action within the paraventricular nucleus.

Oxytocin is a classic reproductive neuropeptide in the female mammal, but its functions in the brain of the male have been less well studied. As stress induces intracerebral oxytocin release independently of gender, we postulated that central oxytocin may play a role in the control of stress responses. In both male and virgin female rats, oxytocin receptor blockade in the brain by intracerebral infusion of a selective oxytocin antagonist (des Gly-NH2 d(CH2)5 [Tyr(Me)2, Thr4] OVT; 0.75 microgram/5 microliter increased the activity of the hypothalamo-pituitary-adrenal (HPA) axis as indicated by a significantly enhanced basal and stress-induced (exposure to the elevated plus-maze, forced swimming) secretion of corticotropin (ACTH) and corticosterone into blood. The anxiety-related behaviour on the plus-maze was not altered by the antagonist in either males or females. Infusion of the oxytocin antagonist into the hypothalamic paraventricular nucleus by reversed microdialysis resulted in a significant increase in basal release of ACTH in both male and virgin female rats. These results demonstrate a novel, gender-independent physiological function of endogenous brain oxytocin in the regulation of neuroendocrine stress responses. Under basal conditions, the inhibition of the HPA axis occurs, at least in part, within the paraventricular nucleus.

Brain oxytocin: differential inhibition of neuroendocrine stress responses and anxiety-related behaviour in virgin, pregnant and lactating rats.

The involvement of brain oxytocin in the attenuated responsiveness of the hypothalamo-pituitary-adrenal axis and the oxytocin systems to external stressors found in pregnant and lactating rats has been studied, including both neuroendocrine and behavioural aspects. Intracerebroventricular infusion of an oxytocin receptor antagonist (0.75 microg/5 microl), but not of vehicle, elevated basal corticotropin and corticosterone secretion into blood of virgin female, but not of late pregnant or lactating rats. Oxytocin antagonist treatment further elevated the stress-induced (exposure to the elevated plus-maze or forced swimming) secretion of both corticotropin and corticosterone, but only in virgin and not in pregnant or lactating rats. Thus, corticotropin and corticosterone plasma concentrations remained attenuated in antagonist-treated pregnant and lactating animals. In contrast, infusion of the oxytocin antagonist significantly elevated the stress-induced secretion of oxytocin into blood in pregnant and lactating, but not in virgin, animals, indicating an autoinhibitory influence of intracerebral oxytocin on neurohypophysial oxytocin secretion induced by non-reproduction-related stimuli. Treatment with oxytocin antagonist 10 min prior to behavioural testing on the elevated plus-maze significantly reduced the anxiety-related behaviour in both pregnant and lactating rats, without exerting similar effects in virgin female rats. The results demonstrate a tonic inhibitory effect of endogenous oxytocin on corticotropin and, consequently, corticosterone secretion in virgin female rats, an effect which is absent in the peripartum period. In contrast, an anxiolytic action of endogenous oxytocin was detectable exclusively in pregnant and lactating rats. Therefore, we conclude that the actions of intracerebral oxytocin include independent effects on the responses of the hypothalamo-pituitary-adrenal axis and oxytocin systems to stressors and the anxiety-related behaviour which are modulated by the reproductive state of the animals.

Pharmacological characterisation of cortical gamma-aminobutyric acid type A (GABAA) receptors in two Wistar rat lines selectively bred for high and low anxiety-related behaviour.

Two Wistar rat lines that have been selectively bred for high-anxiety-related behaviour (HAB) and low-anxiety-related behaviour (LAB) in the elevated plusmaze test may be considered as a genetically prone animal model to study the neurochemical correlates of anxiety-related behaviour. Because there are pronounced differences between the two lines both in baseline levels of open-arm exploration in the elevated plus-maze test and in sensitivity to the anxiolytic effects of 1 mg/kg diazepam, we used these lines to investigate the pharmacology of the benzodiazepine binding site and the GABA binding site of cortical GABAA receptors. No difference in characteristics of flunitrazepam, zolpidem or muscimol binding to cortical GABAA receptors could be detected between the two lines. Although there was an increase in the brain concentration of the anxiolytic neuroactive steroid allopregnanolone, a potent positive allosteric modulator of GABAA receptors, both in HAB and LAB animals after a forced swim stress, allopregnanolone concentrations did not differ between the two lines. Moreover, plasma dehydroepiandrosterone (DHEA) concentrations were similar in HAB and LAB animals. We conclude that anxiety-related behaviour and benzodiazepine sensitivity in these rat lines are likely to be independent of the pharmacology of cortical GABAA receptors.

Nonresponsiveness of the rat hypothalamo-pituitary-adrenocortical axis to parturition-related events: inhibitory action of endogenous opioids.

During the last 2 days of pregnancy in rats, basal corticosterone secretion is enhanced, although the response of the hypothalamo-pituitary-adrenocortical (HPA) axis to emotional and physical stressors is blunted, independent of the action of endogenous opioids. In this study, alterations in the reactivity of the HPA axis, which may accompany parturition-related stimuli, and the involvement of endogenous opioids were examined in chronically catheterized rats. In vehicle-treated controls (n = 9), ACTH and corticosterone secretion decreased in preparation for birth (P < 0.01) and further declined immediately after delivery of the second pup (P < 0.01), remaining low for 150 min. In contrast, in animals injected with the opiate antagonist naloxone (5 mg ml(-1) kg(-1), i.v., n = 6) after delivery of the second pup, ACTH and corticosterone release were enhanced within 20 min (ACTH, 5.0-fold; corticosterone, 2.3-fold; P < 0.01 vs. controls) and returned to control levels after 90 min. In confirmation of previous reports, oxytocin secretion into blood was elevated in control rats after the onset of parturition (P < 0.01) and was further enhanced in the naloxone group (1.4-fold, P < 0.01 vs. control). Plasma lactate concentration was increased, 30 min after the onset of delivery (1.9-fold, P < 0.01), independent of the treatment. The data indicate that parturition-related events do not trigger HPA axis hormone release because of an effective inhibition by endogenous opioids. This nonresponsiveness of the HPA axis is likely to protect the pups' well-being during birth.