Effects of Single Cage Housing on Stress, Cognitive, and Seizure Parameters in the Rat and Mouse Pilocarpine Models of Epilepsy.

Many experimental approaches require housing rodents in individual cages, including in epilepsy research. However, rats and mice are social animals; and individual housing constitutes a stressful situation. The goal of the present study was to determine the effects of individual housing as compared to conditions maintaining social contact on stress markers and epilepsy. Control male mice socially housed during pretest and then transferred to individual cages for six weeks displayed anhedonia, increased anxiety and biological markers of stress as compared to pretest values or mice kept socially housed during six weeks. Pilocarpine (pilo)-treated mice housed together showed increased levels of anhedonia, anxiety and stress markers as well as decreased cognitive performance as compared to the control group. The differences were more significant in pilo-treated mice housed individually. Anxiety correlated linearly with cognitive performance and stress markers independently of the experimental conditions. In the male rat pilo model, seizures were sixteen times more frequent in singly housed animals as compared to animals kept in pairs. Daily interactions with an experimenter in otherwise singly housed animals was sufficient to produce results identical to those found in animals kept in pairs. We propose that social isolation produces a severe phenotype in terms of stress and seizure frequency as compared to animals maintaining social contact (at least in these two models), a factor that needs to be taken into account for data interpretation, in particular for preclinical studies.

Nrf2-dependent persistent oxidative stress results in stress-induced vulnerability to depression.

Stressful life events produce a state of vulnerability to depression in some individuals. The mechanisms that contribute to vulnerability to depression remain poorly understood. A rat model of intense stress (social defeat (SD), first hit) produced vulnerability to depression in 40% of animals. Only vulnerable animals developed a depression-like phenotype after a second stressful hit (chronic mild stress). We found that this vulnerability to depression resulted from a persistent state of oxidative stress, which was reversed by treatment with antioxidants. This persistent state of oxidative stress was due to low brain-derived neurotrophic factor (BDNF) levels, which characterized the vulnerable animals. We found that BDNF constitutively controlled the nuclear translocation of the master redox-sensitive transcription factor Nrf2, which activates antioxidant defenses. Low BDNF levels in vulnerable animals prevented Nrf2 translocation and consequently prevented the activation of detoxifying/antioxidant enzymes, ultimately resulting in the generation of sustained oxidative stress. Activating Nrf2 translocation restored redox homeostasis and reversed vulnerability to depression. This mechanism was confirmed in Nrf2-null mice. The mice displayed high levels of oxidative stress and were inherently vulnerable to depression, but this phenotype was reversed by treatment with antioxidants. Our data reveal a novel role for BDNF in controlling redox homeostasis and provide a mechanistic explanation for post-stress vulnerability to depression while suggesting ways to reverse it. Because numerous enzymatic reactions produce reactive oxygen species that must then be cleared, the finding that BDNF controls endogenous redox homeostasis opens new avenues for investigation.

Nrf2-dependent persistent oxidative stress results in stress-induced vulnerability to depression.

This corrects the article DOI: 10.1038/mp.2016.144.

Repeated social defeat-induced depression-like behavioral and biological alterations in rats: involvement of cholecystokinin.

Cholecystokinin (CCK) involvement in depression-like disorders is poorly documented. Here, we investigated whether CCKergic neurotransmission is relevant to depressive-like symptoms and antidepressant therapy using a novel preclinical model based on repeated social defeat over 4 weeks in rats. Repeated social defeat triggers changes that could be considered as behavioral and biological correlates of depressive symptoms in humans, such as a hyperactivity of hypothalamic-pituitary-adrenal (HPA) axis (increase of serum corticosterone levels and of adrenal gland weight), increased immobility time in the forced swimming test (FST), decrease of body weight and of sweet water consumption and reduction of hippocampal volume associated with a decreased cell proliferation in the dentate gyrus. In addition, in vivo microdialysis showed that cortical CCK release was tonically increased in defeated rats. Chronic imipramine treatment (16 mg kg(-1) per day for 25 days) prevented both the repeated social defeat-induced alterations of biological and behavioral parameters and the associated increase of cortical CCK release. Chronic blockade of CCK2 receptors by the specific antagonist CI-988 (1 mg kg(-1) per day for 25 days) also normalized immobility time in the FST and prevented HPA axis hyperactivity, reduction of hippocampal volume and cell proliferation and decreased sweet water intake normally evoked by repeated social defeat. These data showed that the repeated social-defeat paradigm can be considered as a suitable model of 'depression' in rats. The causal link between social defeat-evoked (1) increase in cortical CCKergic neurotransmission and (2) depression-like symptoms that we highlighted here strongly suggests that CCKergic systems may be a relevant target for novel antidepressant therapy.

Subcutaneous formalin enhances outflow of met-enkephalin- and cholecystokinin-like materials in the rat nucleus accumbens.

Using the microdialysis technique, the present study investigated the effects of a noxious stimulation on the extracellular levels of met-enkephalin and (sulfated octapeptide) cholecystokinin-like materials in the nucleus accumbens of freely moving rats. Injection of 50 microl of 5% formalin into the forepaw produced pain-related behaviours associated with an immediate and sustained (for approximately 2 h) increase (+27%) in the outflow of met-enkephalin-like material within the nucleus accumbens. This treatment also progressively enhanced the local outflow of cholecystokinin-like material that reached 200%-250% of the basal level at the end of the experiment, i.e. 4.5 h after formalin administration. Because naloxone (1.5 mg/kg i.p., 10 min prior to formalin injection) prevented the latter effect, it can be inferred that noxious stimulation-induced activation of cholecystokininergic neurotransmission in the nucleus accumbens probably resulted from the preceding activation of opioidergic systems. These data suggest that the nucleus accumbens may be another structure where interactions between opioids and cholecystokinin play a key role in the control of pain-processing mechanisms.

Enhanced cortical extracellular levels of cholecystokinin-like material in a model of anticipation of social defeat in the rat.

The involvement of cholecystokinin (CCK) in the mechanisms of stress and/or anxiety was assessed by in vivo microdialysis in rats subjected to a social stress paradigm. During the initial 30 min period of each conditioning session, a male Sprague Dawley rat (intruder) was placed in a protective cage inside the cage of a male Tryon Maze Dull rat (resident), allowing unrestricted visual, olfactory, and auditory contacts but precluding close physical contact between them. During the following 15 min period, both the protective cage and the resident were removed (nondefeated intruders) or only the protective cage was removed allowing the resident to attack the intruder (defeated rats). This procedure was repeated once daily for 4 d. On the fifth day, a guide cannula was implanted into the prefrontal cortex of intruders. During a single 30 min test session, performed 4 d later, intruders were subjected to only the 30 min protected confrontation to the resident. Anxiety-like behavior (immobility, ultrasonic vocalizations, and defensive postures), associated with an increase (approximately +100% above baseline) in cortical outflow of CCK-like material (CCKLM), were observed in defeated intruders. Pretreatment with diazepam (5 mg/kg, i.p.), but not buspirone (0.5-2 mg/kg, i.p.), prevented both the anxiety-related behavior and CCKLM overflow. The selective CCK-B receptor antagonist CI-988 (2 mg/kg, i.p.) reduced the anxiety-like behavior without affecting the increase in CCKLM outflow. These data indicate that anticipation of social defeat induces a marked activation of cortical CCKergic neurons associated with anxiety-related behaviors in rats.

Domains of nursing intervention after sudden cardiac arrest and automatic internal cardioverter defibrillator implantation.

PURPOSE: The purpose of the study was to explore individual and family experiences after sudden cardiac arrest and automatic internal cardioverter defibrillator implantation during the first year of recovery. This report specifically addresses the domains of concern expressed and helpful strategies used by participants that are relevant to the development of future intervention programs. DESIGN: A grounded theory approach was used to gain an understanding of areas of concern of sudden cardiac arrest survivors and families that could be used when designing future nursing interventions. Semistructured interviews were conducted with both sudden cardiac arrest survivors and 1 family member each at 5 points during the first year of recovery (hospitalization; 1, 3, 6, and 12 months after hospitalization). Participants were asked to identify those specific areas that most concerned them and that they would like assistance with during the first year. A total of 150 interviews were conducted with 176 hours of data generated. SETTING: The study focused on 10 northwest urban community medical centers and participants' homes within a 50-mile driving distance from the medical centers. SAMPLE: The sample included 15 first-time sudden cardiac arrest survivors (13 men and 2 women) and 1 family member each between the ages of 31 and 72 years. RESULTS: Domains of concern identified by participants that can be used to design future nursing intervention programs included preventive care, dealing with automatic internal cardioverter defibrillator shocks, emotional challenges, physical changes, activities of daily living, partner relationships, and dealing with health care providers. Suggestions of helpful strategies used by participants during the first year are outlined. IMPLICATIONS: Domains of concern and helpful strategies identified by participants provide a framework for the development and testing of nursing intervention programs to enhance recovery following sudden cardiac arrest for survivors and their families.

Delta-opioid receptor-mediated increase in cortical extracellular levels of cholecystokinin-like material by subchronic morphine in rats.

Numerous pharmacological data indirectly support the idea that interactions between cholecystokinin (CCK) and opioids participate in the development of tolerance to morphine. Biochemical investigations were performed with the aim of directly assessing the status of such interactions in morphine treated rats. Tolerance to the alkaloid after s.c. implantation of morphine pellets for three days was not associated with any change in the levels of both CCK like-material (CCKLM) and proCCK mRNA in the frontal cortex. However, microdialysis in the freely moving rat showed that this morphine treatment produced a significant increase (+40%) of the cortical spontaneous CCKLM outflow, which could be completely prevented by intracortical infusion of naloxone (10 microM). The opioid receptors responsible for morphine-induced cortical CCKLM overflow appeared to be of the delta type because intracortical infusion of selective delta-opioid receptor antagonists such as naltriben (10 microM) and 7-benzylidenenaltrexone (10 microM) also prevented the effect of morphine, whereas CTOP (10 microM), a selective mu-opioid receptor antagonist, and nor-binaltorphimine (10 microM), a selective K-opioid receptor antagonist, were inactive. These data indicate that morphine tolerance is associated with delta-opioid receptor mediated activation of cortical CCKergic systems in rats.

Behavioral and psychological symptoms in Alzheimer's disease. Relation between apathy and regional cerebral perfusion.

Fundamental and therapeutic research in Alzheimer's disease (AD) focused for a long time exclusively on cognitive aspects. However, AD also frequently involves complex disorders of affect and behavior, which are currently grouped under the heading 'behavioral and psychological signs and symptoms of dementia' (BPSSD). Several rating tools have been developed over the years on the basis of a variety of source data. Some are derived from psychiatric practise or have specifically been developed for dementia, such as the Neuropsychiatric Inventory (NPI). In this study we prospectively used the NPI to examine BPSSD. Sixty-three French patients (mean age 74.7 years, SD 7.9) with a Mini-Mental State Examination (MMSE) score higher than 10 were examined. BPPSD were detected by NPI in 95. 2% of the patients. Anxiety was the most common abnormality (65.1%), followed by apathy and dysphoria (58.7%). The highest frequency x severity NPI score was observed for apathy. In order to identify the relationship between regional cerebral perfusion and apathy, 20 of these AD patients underwent a technetium-99m-bicisate SPECT protocol within the same week as the NPI evaluation. The mean age of this population was 74.4 years (SD 5.3) and the mean MMSE score was 21 (SD 4.1). The apathy NPI score was correlated with right cingulate deficit whereas the highest correlation for the MMSE was with the left temporoparietal area. This stresses the interest to focus on SPECT imaging of AD patients not only in the posterior areas. CopyrightCopyright 1999S.KargerAG,Basel

Delta(2)-opioid receptor mediation of morphine-induced CCK release in the frontal cortex of the freely moving rat.

Numerous pharmacological data have been accumulated in support of the existence of physiological interactions between cholecystokinin (CCK) and opioids in the central nervous system. With the aim of further characterizing these interactions, an in vivo microdialysis approach was used to directly assess the possible influence of opioids on the extracellular levels of CCK-like material (CCKLM) in the frontal cortex of the awake, freely moving rat. Systemic administration of a high dose of morphine (10 mg/kg i.p.) produced a marked increase (up to +200%) of cortical CCKLM outflow, and this effect could be completely prevented by systemic (1.5 mg/kg i.p.) as well as intracortical (10 microM) administration of the opioid receptor antagonist naloxone. The opioid receptors activated by morphine appeared to be of the delta type because the intracortical infusion of naltrindole (10 microM) also prevented the effect of morphine, whereas CTOP (10 microM), a selective mu-opioid receptor antagonist, and nor-binaltorphimine (10 microM), a selective kappa-opioid receptor antagonist, were inactive. In addition, naltriben (10 microM), which acts selectively at the delta(2) subtype, also abolished the stimulatory effect of morphine on cortical CCKLM outflow, whereas 7-benzylidenenaltrexone (10 microM), a selective delta(1)-opioid receptor antagonist (10 microM), did not alter the morphine effect. Conversely, the direct stimulation of cortical delta(2)-opioid receptors by local infusion of [D-Ala(2)] deltorphin II mimicked the stimulatory effect of systemic morphine on CCKLM outflow. These data indicate that delta(2)-opioid receptors play a key role in opioid-CCK interactions in the rat frontal cortex.

Prevention by 5-HT1A receptor agonists of restraint stress- and yohimbine-induced release of cholecystokinin in the frontal cortex of the freely moving rat.

In line with the idea that cholecystokinin (CCK) is involved in anxiety-related behaviours, previous investigations showed that stressful conditions and an 'anxiogenic' drug, yohimbine, increased the cortical release of CCK like-material (CCKLM) in awake rats, and that this effect could be prevented by diazepam. Here, we investigated whether other anxiolytic drugs such as 5-HT1A receptor agonists could also affect cortical CCKLM release. Indeed, neither buspirone (1 mg/kg i.p.), alnespirone (1 mg/kg i.p.) nor lesopitron (3 mg/kg i.p.) affected, on their own, CCKLM release. However, pretreatment with the latter drugs completely abolished the stimulatory effect of restraint stress on the peptide outflow. As expected of the involvement of 5-HT1A receptors, tertatolol (10 mg/kg i.p) markedly reduced the inhibitory effect of buspirone on restraint stress-evoked CCKLM overflow. On the other hand, pretreatment with buspirone, alnespirone or lesopitron also inhibited the stimulatory effect of yohimbine (5 mg/kg i.p.) on cortical CCKLM outflow. These data support the idea that the anxiolytic action of 5-HT1A receptor agonists could be mediated, at least partly, through their inhibitory influence on cortical CCK-ergic systems.

Inhibition of calcium influx during hypoxia/reoxygenation in primary cultured rat hepatocytes.

Calcium has been demonstrated to play an important role in hepatocyte damage during ischemia/reperfusion phases. Calcium influx was determined in primary cultured rat hepatocytes submitted to a succession of warm hypoxia and reoxygenation phases in the presence of diltiazem, gallopamil and a Na+/H+ antiport inhibitor, HOE-694. Only diltiazem significantly inhibited calcium influx with higher potency after reoxygenation than after hypoxia only, suggesting a complex mechanism of action of diltiazem which could act on different physiological functions involved in Ca2+ invasion of hepatocytes after hypoxic insult.

Effects of peripheral axotomy on cholecystokinin neurotransmission in the rat spinal cord.

Because cholecystokinin (CCK) acts as a "functional" endogenous opioid antagonist, it has been proposed that changes in central CCKergic neurotransmission might account for the relative resistance of neuropathic pain to the analgesic action of morphine. This hypothesis was addressed by measuring CCK-related parameters 2 weeks after unilateral sciatic nerve section in rats. As expected, significant decreases (-25-38%) in the tissue concentrations and in vitro release of both substance P and calcitonin gene-related peptide were noted in the dorsal quadrant of the lumbar spinal cord on the lesioned side. In contrast, the tissue levels and in vitro release of CCK were unchanged in the same area in lesioned rats. Measurements in dorsal root ganglia at L4-L6 levels revealed no significant changes in proCCK mRNA after the lesion. However, sciatic nerve section was associated with a marked ipsilateral increase in both CCK-B receptor mRNA levels in these ganglia (+70%) and the autoradiographic labeling of CCK-B receptors by [3H]pBC 264 (+160%) in the superficial layers of the lumbar dorsal horn. Up-regulation of CCK-B receptors rather than CCK synthesis and release probably contributes to increased spinal CCKergic neurotransmission in neuropathic pain.

Polyarthritis-associated changes in the opioid control of spinal CGRP release in the rat.

As a model of chronic inflammatory pain, Freund's adjuvant-induced polyarthritis has been shown to be associated with marked alterations in the activity of opioid- and calcitonin gene-related peptide (CGRP)-containing neurons in the dorsal horn of the spinal cord in rats. Possible changes in the interactions between these two peptidergic systems in chronic inflammatory pain were investigated by comparing the effects of various opioid receptor ligands on the spinal outflow of CGRP-like material (CGRPLM) in polyarthritic and age-paired control rats. Intrathecal perfusion of an artificial cerebrospinal fluid in halothane-anaesthetized animals allowed the collection of CGRPLM released from the spinal cord and the application of opioid receptor ligands. The blockade of kappa-opioid receptors similarly increased CGRPLM release in both groups of rats as expected of a kappa-mediated tonic inhibitory control of CGRP-containing fibres in control, as well as in polyarthritic rats. In contrast, the higher increase in CGRPLM outflow due to the preferential blockade of mu opioid receptors by naloxone in polyarthritic rats as compared to non-suffering animals supports the idea of a reinforced mu opioid receptor-mediated tonic inhibitory control of CGRP-containing fibres in rats suffering from chronic pain. Even more strikingly, the differences observed in the effects of delta-opioid receptor ligands on CGRPLM outflow suggest that delta receptors are functionally shifted from a participation in a phasic excitatory control in non-suffering rats to a tonic inhibitory control in polyarthritic rats. These data indicate that agonists acting at the three types of opioid receptors all exert a tonic inhibitory influence on CGRP-containing nociceptive primary afferent fibres within the spinal cord of polyarthritic rats. Such a convergence probably explains why morphine and other opioids are especially potent to reduce pain in subjects suffering from chronic inflammatory diseases.

[Interactions between central opioidergic and cholecystokininergic systems in rats: possible significance for the development of of opioid tolerance]. / Interactions entre les systèmes opioïdergiques et cholécystokininergiques centraux chez le rat: implications dans le développement de la tolérance aux opioïdes.

Numerous data suggest that cholecystokinin (CCK) acts as an opioid-modulating peptide. Because pharmacological and behavioural studies have shown that CCK reduces the analgesic effects of opioids, an opioid-mediated activation of CCK-containing neurones has been proposed to be responsible for the development of opioid tolerance. In an attempt to directly assess this hypothesis, we have examined, in naive or morphine-tolerant/dependent rats, the possible influence of opioid-receptor ligands on--1 the release of CCK from spinal cord slices and--2 the extracellular levels of CCK in the frontal cortex in awake, freely moving animals. Whereas the stimulation of mu or delta 1 receptors inhibited the release of the peptide, the stimulation of delta 2 receptors increased CCK release. Morphine also increased CCK release, via an action at delta 2 receptors. The blockade of delta 1 receptors resulted in an enhancement of the peptide release, suggesting that endogenous opioids probably exert inhibitory tonic influence on CCK release through the stimulation of delta 1 receptors. In rats rendered tolerant/dependent, the inhibitory effects of opioids on CCK release, due to the stimulation of mu or delta 1 receptors, and the enhancing effect of delta 1 receptor blockade, were no longer present. In contrast, the delta 2-mediated increase in CCK release persisted. Thus, in morphine-tolerant/dependent rats, opioids apparently retain only their excitatory effects on CCK-containing neurones. These data support the idea that morphine exerts an excitatory influence on central CCKergic neurones, which could tend to reduce the analgesic action of the alkaloid, and are in line with the hypothesis that morphine tolerance/dependence is associated with an activation of CCK-containing neurones.

The effects of home nursing care for patients during terminal illness on the bereaved's psychological distress.

BACKGROUND: Although some studies have examined the effects of terminal illness care models such as hospice care on survivor outcomes, no studies could be found that examined whether nursing care affected such outcomes. OBJECTIVE: To determine whether specialized oncology home care services provided to terminally ill patients with lung cancer positively influenced bereavement psychological distress among survivors, compared with other models of care. METHODS: A secondary analysis was performed to test the effects of home nursing care for terminally ill patients on spousal psychological distress during bereavement. Forty-six patient-spousal dyads were randomly assigned to either an oncology home care group (OHC), a standard home care group, or an office care control group. Patient-spousal dyads were entered into the study 2 months after the patient's diagnosis of lung cancer and received follow-up until the patient died. Bereaved spouses continued to receive follow-up for 25 months after the patient's death. RESULTS: Psychological distress was significantly lower initially among spouses of patients that received the OHC intervention compared with the other two groups. Significant mean group differences were found on the subscales of depression and paranoid ideation; marginal group differences were found on the subscales of hostility and psychoticism. There were no significant differences among the groups at 25 months. CONCLUSIONS: These results suggest that the bereaved's psychological distress can be positively influenced depending on how their loved one is cared for during the terminal phase of illness.

Enkephalinergic and dynorphinergic neurons in the spinal cord and dorsal root ganglia of the polyarthritic rat - in vivo release and cDNA hybridization studies.

Complex and contradictory data have been reported regarding the changes in spinal opioidergic systems associated with chronic inflammatory pain in the rat. In an attempt to solve these discrepancies, the in vivo release of met-enkephalin and dynorphin and the expression of the corresponding propeptide genes were investigated at the spinal level in arthritic rats and paired controls. A dramatic increase in the concentration of prodynorphin mRNA (+300-550%) and a less pronounced elevation of that of dynorphin-like material (+40-50%) were found in the dorsal part of cervical and lumbar segments of the spinal cord in rats rendered arthritic by an intradermal injection of Freund's adjuvant four weeks prior to these measurements. In addition, the spinal release of dynorphin-like material (assessed through an intrathecal perfusion procedure in halothane-anaesthetized animals) was approximately twice as high in arthritic rats as in controls. In spite of significant elevations in the levels of both met-enkephalin (+30-70%) and proenkephalin A mRNA (+40-50%) in the dorsal part of cervical and lumbar segments, the spinal release of met-enkephalin-like material was decreased (-50%) in arthritic rats as compared to paired controls. Proenkephalin A mRNA (but not prodynorphin mRNA) could be measured in dorsal root ganglia, and its levels were dramatically reduced in ganglia at the lumbar segments in arthritic rats. Such parallel reductions in the spinal release of met-enkephalin-like material and the levels of proenkephalin A mRNA in dorsal root ganglia of arthritic rats support the idea that the activity of primary afferent enkephalinergic fibres decreases markedly during chronic inflammatory pain.