Twenty-three generations of mice bidirectionally selected for open-field thigmotaxis: selection response and repeated exposure to the open field

We examined: (a) the response to bidirectional selection for open-field (OF) thigmotaxis in mice for 23 generations and (b) the effects of repeated exposure (during 5 days) on different OF behaviors in the selectively bred high OF thigmotaxis (HOFT) and low OF thigmotaxis (LOFT) mice. A total of 2049 mice were used in the study. Prior to the testing in the selection experiment, the mice were exposed to the OF apparatus for approximately 2 min on each of 4 consecutive days. Thus, the selection was based on the scores registered on the 5th day after the four habituation periods. The HOFT mice were more thigmotactic than the LOFT mice in almost each generation. The HOFT mice also tended to rear less than the LOFT mice, which was explained by the inverse relationship between emotionality and exploratory tendencies. The lines did not generally differ in ambulation. Sex differences were found in thigmotaxis, ambulation, and rearing. In the repeated exposure experiment, the development of nine different OF behaviors across the 5 days of testing was addressed. Both lines ambulated, explored, and reared most on the 1st, 4th, and 5th days. Grooming and radial latency decreased and thigmotaxis increased linearly across the testing days. Line differences were found in ambulation, exploration, grooming, and rearing, while sex differences were manifested in ambulation and exploration. The line difference in thigmotaxis was evident only on the 5th day. Temporal changes were partially at variance with the general assumptions. OF thigmotaxis was found to be a powerful characteristic for producing two diverging lines of mice.     

Magnetic shielding induces early developmental abnormalities in the newt, Cynops pyrrhogaster

Developing larvae of the Japanese newt, Cynops pyrrhogaster, were subjected for 5 days to a shielded environment in which the static magnetic field was about 10,000 times weaker (5 nT) than the geomagnetic norm, which ranges between 30 and 60 microT at the earth's surface. Larvae from non-cleavage to neurula stages were exposed under shielded or normal (control) conditions and then examined for evidence of developmental abnormalities either 1 day or 20 days after treatment. The magnetic shielding was associated with an increased incidence of somatic defects, especially in larvae that were examined 20 days after shielding. Bi-headedness and intestinal protrusion were observed in magnetically shielded larvae but not in controls. Other abnormalities more frequently observed in shielded larvae were spinal curvature, malformed eyes, and retarded or blocked development. These data are among the first to illustrate the effects of magnetic-field deprivation on a developing animal.     

The detection threshold for extremely low frequency magnetic fields may be below 1000 nT-Hz in mice

Previous experiments with mice have shown that a repeated 1 h daily exposure to an ambient magnetic field shielded environment induces analgesia (anti-nociception). This shielding reduces ambient static and extremely low frequency magnetic fields (ELF-MF) by approximately 100 times for frequencies below 120 Hz. To determine the threshold of ELF-MF amplitude that would attenuate or abolish this effect, 30 and 120 Hz magnetic fields were introduced into the shielded environment at peak amplitudes of 25, 50, 100 and 500 nT. At 30 Hz, peak amplitudes of 50, 100, and 500 nT attenuated this effect in proportion to the amplitude magnitude. At 120 Hz, significant attenuation was observed at all amplitudes. Exposures at 10, 60, 100, and 240 Hz with peak amplitudes of 500, 300, 500, and 300 nT, respectively, also attenuated the induced analgesia. No exposure abolished this effect except perhaps at 120 Hz, 500 nT. If the peak amplitude frequency product was kept constant at 6000 nT-Hz for frequencies of 12.5, 25, 50, and 100 Hz, the extent of attenuation was constant, indicating that the detection mechanism is dependent on the nT-Hz product. A plot of effect versus the induced current metric nT-Hz suggests a threshold of ELF-MF detection in mice at or below 1000 nT-Hz.     

Aversive Responses of Female Mice to the Odors of Parasitized Males: Neuromodulatory Mechanisms and Implications for Mate Choice

The detection and avoidance of parasitized conspecifics is proposed to have important consequences for the behavior of animals, especially as related to mate choice. A reduction in pain sensitivity (i.e. analgesia) is a major correlate of exposure to real or potential danger and threatening stimuli, facilitating the expression of various active (e.g. fleeing) and passive (e.g. immobilization) defense responses. The present study examined pain sensitivity (latency of a foot-lifting response to 50 ° C thermal surface) of female mice, Mus musculus, that were exposed to the urine and other odor secretions of male mice subclinically infected with the naturally occurring, enteric, sporozoan parasite, Eimeria vermiformis. A 30-min exposure to the odors of a parasitized male induced an analgesia in the female mice that was found to be mediated by the increased activity of endogenous opioid peptide systems. A brief 1-min exposure to the male odors induced a shorter duration and lower amplitude analgesia of a non-opioid (serotonergic) nature. Maximum analgesic responses were induced by the odors of pre-infective [5 days post-infection (PI)] and infective (day 10 PI) males, with significantly lower responses elicited by the odors of post-infective (day 17 PI) male mice. Exposure to the odors of unparasitized males had no significant effects on the pain sensitivity of female mice. These results indicate that female mice can distinguish between the odors of parasitized and non-parasitized male mice, and find the odors of parasitized males threatening and/or stressful. These odor-induced analgesic responses and their neurohormonal correlates may be part of an adaptive preparatory defense mechanism that facilitates the detection and avoidance of parasitized males by female mice and contributes to female mate choice.     

Modulation of human neuroblastoma transplanted into nude mice by endogenous opioid systems

The role of endogenous opioid systems (endogenous opioids and opioid receptors) in human cancer was explored using an opioid antagonist paradigm and neuroblastoma cells (SK-N-MC) transplanted into nude mice. Mice inoculated with 2.5 X 10(6) neuroblastoma cells received daily injections of either 0.1 or 10 mg/kg naltrexone (=0.1 and 10 NTX groups) which blocked the opioid receptor for 6-8 hr/day or the entire 24 hr/day, respectively, or sterile water. The latency for appearance of a measurable tumor (5 mm diameter) in the 0.1 NTX group was 27% longer than controls (11 days), and the first death in this group occurred 33% later than controls (day 27). Mice inoculated with tumor cells in the 10 NTX group had an acceleration (18%) in the latency of tumor appearance and, 2 weeks after cell inoculation, 70% of the mice in this group had tumors, in contrast to 10% of the controls. At the termination of the experiment (day 45), only 33% of the 10 NTX group were alive, in contrast to 90% of the controls. Receptor binding assays using DAGO, DADLE, or EKC revealed specific saturable binding only for DADLE and EKC. NTX administration resulted in a 148-186% increase in density for both binding sites, but no changes in binding affinity. Measures of opioid levels showed that tumor tissue levels of both beta-endorphin and methionine-enkephalin were elevated 2.5 to 6.5 fold from control values in both NTX groups, whereas plasma beta-endorphin was subnormal by 4 to 6 fold. These results indicate that endogenous opioid systems regulate human neuro-oncogenesis, with opioids being active inhibitors of growth. Opioid antagonists up-regulate receptors and increase tissue levels of endogenous opioids and, under conditions in which the opioid antagonist is short-acting (e.g., 0.1 NTX), can have an exaggerated antitumor effect during the interval when the antagonist is no longer present.     

Survival of Toxoplasma gondii oocysts in Eastern oysters (Crassostrea virginica)

Toxoplasma gondii has recently been recognized to be widely prevalent in the marine environment. It has previously been determined that Eastern oysters (Crassostrea virginica) can remove sporulated T. gondii oocysts from seawater and that oocysts retain their infectivity for mice. This study examined the long-term survival of T. gondii oocysts in oysters and examined how efficient oysters were at removing oocysts from seawater. Oysters in 76-L aquaria (15 oysters per aquarium) were exposed to 1 x 10(6) oocysts for 24 hr and examined at intervals up to 85 days postexposure (PE). Ninety percent (9 of 10) of these oysters were positive on day 1 PE using mouse bioassay. Tissue cysts were observed in 1 of 2 mice fed tissue from oysters exposed 21 days previously. Toxoplasma gondii antibodies were found in 2 of 3 mice fed oysters that had been exposed 85 days previously. In another study, groups of 10 oysters in 76-L aquaria were exposed to 1 x 10(5), 5 x 10(4), or 1 x 10(4) sporulated T. gondii oocysts for 24 hr and then processed for bioassay in mice. All oysters exposed to 1 x 10(5) oocysts were infected, and 60% of oysters exposed to 5 x 10(4) oocysts were positive when fed to mice. The studies with exposure to 1 x 10(4) oocysts were repeated twice, and 10 and 25% of oysters were positive when fed to mice. These studies indicate that T. gondii can survive for several months in oysters and that oysters can readily remove T. gondii oocysts from seawater. Infected filter feeders may serve as a source of T. gondii for marine mammals and possibly humans.     

Chronic morphine treatment induces oxidant and apoptotic damage in the mice liver

Recently many researchers have proposed a protective role for morphine against tumor growth and metastasis, especially through induction of apoptosis in tumoral cells. These findings may lead to underestimation of cytotoxic effects of opioid drugs which are usually expected only at high doses. The present study was conducted to clarify whether repeated morphine administration, which is commonly used for relief from chronic pain, would interfere with liver antioxidant defence and hepatocytes vitality. Morphine was injected repeatedly at doses that have been reported to relieve cancer pain and reduce tumor spread in mice (5 and 10 mg/kg/day for nine consecutive days). The changes in hepatic glutathione concentration, its synthesis pathway and enzymatic antioxidant defense revealed the pro-oxidant effects of chronic morphine treatment on the liver. None of these changes were observed in those mice that were co-treated with naltrexone (opioid antagonist) and same doses of morphine. However induction of liver conjugating enzymes following morphine treatment was not receptor mediated. Moreover, chronic morphine treatment induced hepatocytes apoptosis. Interestingly, the apoptotic changes were antagonized by co-administration of either naltrexone or thiol antioxidant. In conclusion, although hepatotoxic effects of morphine at high doses have been reported previously, our findings propose that repeated morphine administration even at lower doses would induce oxidative stress in the liver, which may contribute to induction of apoptosis in hepatocytes. Since many of the observed adverse effects were mediated by opioid receptors, our results suggest that other opioid analgesics should also be used more cautiously.     

Dissociation of morphine withdrawal diarrhea and jumping in mice by the peripherally selective opioid antagonist SR 58002 C

Mice were rendered physically dependent by repeated administration of morphine, 25 mg/kg s.c., 5 times daily for 4 days, and on the 5th day, 2 h after the last morphine dose, they were challenged with a s.c. injection of either naloxone, 25 mg/kg, or the peripherally selective opioid antagonist SR 58002 C (N-methyl levallorphan mesilate), 75 mg/kg. Naloxone provoked jumping and diarrhea in all the animals; mice challenged with SR 58002 C presented no significant jumping but a high frequency of withdrawal diarrhea. When naloxone, 12 mg/kg, or SR 58002 C, 50 mg/kg, were given s.c. in combination with repeated morphine as above, mice which had received naloxone with morphine presented virtually no diarrhea or jumping upon naloxone challenge; those repeatedly treated with morphine plus SR 58002 C were substantially protected from naloxone-precipitated diarrhea, but not jumping. These results further support the remarkable selectivity for peripheral opioid receptors of SR 58002 C, even after repeated high-dose treatment, and are strongly consistent with the primary role of a local intestinal mechanism in the development and expression of opioid withdrawal diarrhea in mice. The in vivo dissociation of central and peripheral components of dependence on morphine is illustrated, apparently for the first time.     

Influence of Clonidine and Ketamine on m-RNA Expression in a Model of Opioid-Induced Hyperalgesia in Mice

Background

We investigated the influence of morphine and ketamine or clonidine in mice on the expression of genes that may mediate pronociceptive opioid effects.

Material and Methods

C57BL/6 mice received morphine injections thrice daily using increasing doses (5-20mg∙kg^-1) for 3 days (sub-acute, n=6) or 14 days (chronic, n=6) and additionally either s-ketamine (5mg∙kg^-1, n=6) or clonidine (0.1mg∙kg^-1, n=6). Tail flick test and the assessment of the mechanical withdrawal threshold of the hindpaw was performed during and 4 days after cessation of opioid treatment. Upon completion of the behavioural testing the mRNA-concentration of the NMDA receptor (NMDAR1) and β-arrestin 2 (Arrb2) were measured by PCR.

Results

Chronic opioid treatment resulted in a delay of the tail flick latency with a rapid on- and offset. Simultaneously the mice developed a static mechanical hyperalgesia with a delayed onset that that outlasted the morphine treatment. Sub-acute morphine administration resulted in a decrease of NMDAR1 and Arrb2 whereas during longer opioid treatment the expression NMDAR1 and Arrb2 mRNA increased again to baseline values. Coadministration of s-ketamine or clonidine resulted in a reversal of the mechanical hyperalgesia and inhibited the normalization of NMDAR1 mRNA expression but had no effect on the expression of Arrb2 mRNA.

Conclusion

In the model of chronic morphine therapy the antinociceptive effects of morphine are represented by the thermal analgesia while the proniceptive effects are represented by the mechanical hyperalgesia. The results indicate that the regulation of the expression of NMDAR1 and Arrb2 may be associated to the development of OIH in mice.

Perspective

The results indicate that co-administration of clonidine or ketamine may influence the underlying mechanisms of OIH.     

100Hz电针刺受时大鼠脑和脊髓k受体结构特性的改变

西方采用放射配体结合实验研究了１００ＨＺ电针耐受发生发展过程中大鼠脑和脊髓Ｋ受体结构特性的变化。大鼠每天给予１００ＨＺ电针１次,连续７ｄ。分别在电针的第１、３、５、７天取不同脑区进行观察。     

Yokukansan,a traditional Japanese herbal medicine,alleviates the emotional abnormality induced by maladaptation to stress in mice

The aim of the present study was to examine the effect of yokukansan, a traditional Japanese herbal medicine that is composed of Atractylodis lanceae Rhizoma, Poria, Cnidii Rhizoma, Uncariae Uncis cum Ramulus, Angelicae Radix, Bupleuri Radix and Glycyrrhizae Radix, on the emotional abnormality induced by maladaptation to stress in mice. Mice were exposed to repeated restraint stress for 60 or 240 min/day for 14 days. From the 3rd day of stress exposure, mice were given yokukansan orally (p.o.) or the 5-HT_1A receptor agonist flesinoxan intraperitoneally (i.p.) immediately after the daily exposure to restraint stress. After the final exposure to restraint stress, the emotionality of mice was evaluated using an automatic hole-board apparatus. A single exposure to restraint stress for 60 min induced a decrease in head-dipping behavior in the hole-board test. This emotional stress response disappeared in mice that had been exposed to repeated restraint stress for 60 min/day for 14 days, which confirmed the development of stress adaptation. In contrast, mice that were exposed to restraint stress for 240 min/day for 14 days did not develop this stress adaptation, and still showed a decrease in head-dipping behavior. The decreased emotionality observed in stress-maladaptive mice was significantly recovered by chronic treatment with yokukansan (1000 mg/kg, p.o.) as well as flesinoxan (0.25 and 0.5 mg/kg, i.p.) immediately after daily exposure to stress. These findings suggest that yokukansan may have a beneficial effect on stress adaptation and alleviate the emotional abnormality under conditions of excessive stress.     

A quantitative trait locus on chromosome 1 modulates intermale aggression in mice

Aggression between male conspecifics is a complex social behavior that is likely modulated by multiple gene variants. In this study, the BXD recombinant inbred mouse strains (RIS) were used to map quantitative trait loci (QTLs) underlying behaviors associated with intermale aggression. Four hundred and fifty‐seven males from 55 strains (including the parentals) were observed at an age of 13 ± 1 week in a resident‐intruder test following 10 days of isolation. Attack latency was measured directly within a 10‐minute time period and the test was repeated 24 hours later. The variables we analyzed were the proportion of attacking males in a given strain as well as the attack latency (on days 1 and 2, and both days combined). On day 1, 29% of males attacked, and this increased to 37% on day 2. Large strain differences were obtained for all measures of aggression, indicating substantial heritability (intraclass correlations 0.10‐0.18). We identified a significant QTL on chromosome (Chr) 1 and suggestive QTLs on mouse Chrs 1 and 12 for both attack and latency variables. The significant Chr 1 locus maps to a gene‐sparse region between 82 and 88.5 Mb with the C57BL/6J allele increasing aggression and explaining about 18% of the variance. The most likely candidate gene modulating this trait is Htr2b which encodes the serotonin 2B receptor and has been implicated in aggressive and impulsive behavior in mice, humans and other species.     

Effects of low‐level 50 Hz magnetic fields on the level of host defense and on spleen colony formation

The results of 3 sets of experiments on the effects of 22 μT sinusoidal 50 Hz magnetic fields (MF), applied for 1 h on 5 successive days (1 h/5 days), on the level of host defense and on spleen colony formation are reported. The first set of experiments shows the effects on the number of colony‐forming units (CFUs) on the spleen and on the cellularity of the thymus in mice. The MF exposures resulted in an increase in CFUs which was statistically significant with respect to the controls, but not with respect to the shams. Statistically significant changes in the thymic weight and thymic index with respect to both the controls and the shams were measured 1 h after the last MF exposure. In the second set of experiments, the mice were given a sublethal dose of X‐rays (6 Gy), which was followed by exposure 2 h later to the MF. The MF exposure was repeated at the same time of day for 5 days. The number of colonies per spleen showed a consistent, statistically significant increase with MF exposure and the number of CFUs per femur was decreased. In the third set of experiments, bone marrow was taken from mice which had been exposed to 22 μT fields and injected into mice which had been exposed to a lethal dose of X‐rays (9 Gy). The number of CFUs per femur in the recipient mice was shown to be reduced by a statistically significant amount at 1 and 4 days after injection. Bioelectromagnetics 20:57–63, 1999. © 1999 Wiley‐Liss, Inc.     

Phenotypic induction in Pieris napi L.: role of temperature and photoperiod in a coastal California population

Abstract. 1. Californian Pieris napi have previously been reported as producing dark-veined and light-veined adults from diapausing and. non-diapausing pupae respectively; the converse has not been reported.
2. A population of the coastal subspecies venosa from Monterey County was examined to determine whether pupal temperature exposure was involved in proximate control of seasonal phenotypes.
3. When reared under continuous light at 25°C this stock produced seventeen diapause pupae, thirteen of which have eclosed yielding typical dark-veined adults, and thirty-eight non-diapause pupae.
4. Of fifteen non-diapause pupae held in a dark box at 25°C, fourteen produced typical light-veined adults and one produced a dark-veined individual of intermediate phenotype.
5. Of twenty-three non-diapause pupae held in a dark box at 10°C for 24 days, twenty-two produced dark-veined butterflies of intermediate phenotype and one produced a light-veined adult.
6. When the experiment was repeated with an inland, population of subspecies microstriata , which is normally univoltine and monophenic, the temperature effect on phenotype was still present but less pronounced.
7. The nature of phenotypic determination is reviewed with particular regard for the developmental environment of butterflies from diapaused pupae. The thermal environment of reactivating diapausers, rather than the diapause state itself, may determine adult phenotype.     

Response of mice to continuous 5-day passive hyperthermia resembles human heat acclimation

Chronic repeated exposure to hyperthermia in humans results in heat acclimation (HA), an adaptive process that is attained in humans by repeated exposure to hyperthermia and is characterized by improved heat elimination and increased exercise capacity, and acquired thermal tolerance (ATT), a cellular response characterized by increased baseline heat shock protein (HSP) expression and blunting of the acute increase in HSP expression stimulated by re-exposure to thermal stress. Epidemiologic studies in military personnel operating in hot environments and elite athletes suggest that repeated exposure to hyperthermia may also exert long-term health effects. Animal models demonstrate that coincident exposure to mild hyperthermia or prior exposure to severe hyperthermia can profoundly affect the course of experimental infection and injury, but these models do not represent HA. In this study, we demonstrate that CD-1 mice continuously exposed to mild hyperthermia (ambient temperature ~37°C causing ~2°C increase in core temperature) for 5 days and then exposed to a thermal stress (42°C ambient temperature for 40 min) exhibited some of the salient features of human HA, including (1) slower warming during thermal stress and more rapid cooling during recovery and (2) increased activity during thermal stress, as well as some of the features of ATT, including (1) increased baseline expression of HSP72 and HSP90 in lung, heart, spleen, liver, and brain; and (2) blunted incremental increase in HSP72 expression following acute thermal stress. This study suggests that continuous 5-day exposure of CD-1 mice to mild hyperthermia induces a state that resembles the physiologic and cellular responses of human HA. This model may be useful for analyzing the molecular mechanisms of HA and its consequences on host responsiveness to subsequent stresses.     

Role of TNF-alpha in prenatal alterations in dams of mice under thermal stress

The possible involvement of cytokines such as tumour necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta) and interferon-gamma (IFN-gamma) that are suspected of causing pregnancy loss and miscarriage has been investigated in dams of mice subjected to hyperthermia. Thermal stress was induced by exposing mice dams at 40+/-2 degrees C for 4 h every day during the different phases of the gestation period whereas the normothermic animals were housed at 22+/-2 degrees C. The effect of maternal thermal stress was measured in pregnant mice at different phases of the gestation period namely, blastogenesis-implantation phase (days 0-5 postconceptionem [p.c.]), organogenesis or embryogenesis phase (days 6-15 p.c.) and fetogenesis phase (days 16-20 p.c.). Uterine examination of dams subjected to hyperthermia on days 6-15 p.c. showed maximum reduction in live fetus number, gestational index and maximum pre and postimplantation loss in comparison with dams housed in normothermic environment and dams exposed to thermal stress between days 0-5 and 16-20 p.c. Maximum resorption rate and number of non-viable fetuses were observed in dams exposed to hyperthermia during days 6-15 p.c. Elevated levels of TNF-alpha and IL-1 beta were observed in the amniotic fluid of dams subjected to hyperthermia during days 6-15 p.c. but IFN-gamma levels remained unaltered. Single intraperitoneal (i.p.) administration of recombinant mouse TNF-alpha at a dose of 1 and 0.5 ng/mice in dams on day 6 in normothermic condition resulted in a reduced number of live fetuses. Administration of anti-TNF-alpha antibody i.p. at a dose of 10 microg/dam on day 6 p.c. and subjected to thermal stress between days 6-15 p.c. increased marginally the number of fetuses but failed to attain statistical significance in comparison with days 6-15 p.c. thermally stressed dams without antibody treatment. It is concluded that the induction of TNF-alpha, in the amniotic fluid is associated with thermal stress during pregnancy and may be linked to the reproductive performances of dams. This study will help in understanding the mechanism of thermal injury in pregnant subjects.     

Radial arm maze performance of rats following repeated low level microwave radiation exposure

We examined the possibility of changes in "working" memory of rats following whole body exposure to microwave (MW) radiation. During each of 10 days, we exposed rats within circularly polarized waveguides for 45 min to 2450 MHz fields at whole body SARs of 0.6 W/kg (2 micros pulses, 500 pps), followed by testing in a 12 arm, radial arm maze (RAM). Rats received a preexposure injection of one of three psychoactive compounds or saline, to determine whether a compound would interact with MW exposure to affect performance in the maze. Error rate, i.e., reentry into arms already visited, and time to criterion data for 10 consecutive days of testing were analyzed by a three way analysis of variance (ANOVA) using main effects of "exposure" and "drug" and a repeated factor of "test day." Our alpha limit for significance was P <.05. Analyzes of error rates revealed no significant exposure effect, no significant drug effect and no significant interaction between the two main factors. There was a significant difference in test days, as expected, with repeated test-trial days, which indicates that learning was accomplished. There was no significant interaction of test day and the other two factors. The results of our analyzes of time to criterion data included no significant exposure effect, a significant drug effect, a significant test day effect, and a significant interaction between drug and test day factors. Post hoc analyzes of the drug factor revealed that rats treated with either physostigmine or nalrexone hydrochloride, took significantly longer to complete the maze task than rats pretreated with saline or with naloxone methodide. We conclude that there is no evidence from the current study that exposure to of MW radiation under parameters examined caused decrements in the ability of rats to learn the spatial memory task.     

Isoflurane Exposure during Mid-Adulthood Attenuates Age-Related Spatial Memory Impairment in APP/PS1 Transgenic Mice

Many in vitro findings suggest that isoflurane exposure might accelerate the process of Alzheimer Disease (AD); however, no behavioral evidence exists to support this theory. In the present study, we hypothesized that exposure of APP/PS1 transgenic mice to isoflurane during mid-adulthood, which is the pre-symptomatic phase of amyloid beta (Abeta) deposition, would alter the progression of AD. Seven-month-old Tg(APPswe,PSEN1dE9)85Dbo/J transgenic mice and their wild-type littermates were exposed to 1.1% isoflurane for 2 hours per day for 5 days. Learning and memory ability was tested 48 hours and 5 months following isoflurane exposure using the Morris Water Maze and Y maze, respectively. Abeta deposition and oligomers in the hippocampus were measured by immunohistochemistry or Elisa 5 months following isoflurane exposure. We found that the performance of both the transgenic and wild-type mice in the Morris Water Maze significantly improved 48 hours following isoflurane exposure. The transgenic mice made significantly fewer discrimination errors in the Y maze following isoflurane exposure, and no differences were found between wild-type littermates 5 months following isoflurane exposure. For the transgenic mice, the Abeta plaque and oligomers in the hippocampus was significantly decreased in the 5 months following isoflurane exposure. In summary, repeated isoflurane exposure during the pre-symptomatic phase not only improved spatial memory in both the APP/PS1 transgenic and wild-type mice shortly after the exposure but also prevented age-related decline in learning and memory and attenuated the Abeta plaque and oligomers in the hippocampus of transgenic mice.     

Altered behavioural adaptation in mice with neural corticotrophin-releasing factor overexpression

Overproduction of corticotrophin-releasing factor (CRF), the major mediator of the stress response, has been linked to anxiety, depression and addiction. CRF excess results in increased arousal, anxiety and altered cognition in rodents. The ability to adapt to a potentially threatening stimulus is crucial for survival, and impaired adaptation may underlie stress-related psychiatric disorders. Therefore, we examined the effects of chronic transgenic neural CRF overproduction on behavioural adaptation to repeated exposure to a non-home cage environment. We report that CRF transgenic mice show impaired adaptation in locomotor response to the novel open field. In contrast to wild-type (WT) mice, anxiety-related behaviour of CRF transgenic mice does not change during repeated exposure to the same environment over the period of 7 days or at retest 1 week later. We found that locomotor response to novelty correlates significantly with total locomotor activity and activity in the centre at the last day of testing and at retest in WT but not in CRF transgenic mice. Mice were divided into low responders and high responders on the basis of their initial locomotor response to novelty. We found that differences in habituation and re-exposure response are related to individual differences in locomotor response to novelty. In summary, these results show that CRF transgenic mice are fundamentally different from WT in their ability to adapt to an environmental stressor. This may be related to individual differences in stress reactivity. These findings have implications for our understanding of the role of CRF overproduction in behavioural maladaptation and stress-related psychiatric disorders.     

Sex differences in the effects of Tyr-MIF-1 on morphine- and stress-induced analgesia

There is evidence suggesting that the endogenous tetrapeptide, Tyr-MIF-1 (Tyr-Prol-Leu-Gly-amide), has antagonistic or modulatory effects on opioid-mediated analgesia. There is also substantial evidence for sex differences in opioid effects, whereby male rodents display greater levels of opioid-mediated analgesia than females. In the present study, determinations were made of the effects of Tyr-MIF-1 on morphine- and restraint stress-induced opioid analgesia in adult male and female deer mice, Peromyscus maniculatus. Intraperitoneal treatment with Tyr-MIF-1 (0.10–10 mg/kg) reduced morphine- and stress-induced analgesia in both male and female mice, with Tyr-MIF-1 having markedly greater antagonistic effects in male than female mice. These results indicate that there are sex differences in the modulatory (antiopiate) effects of Tyr-MIF-1 on opioid-mediated analgesia.