Nonopiate effects of alpha-neo-endorphin on mouse behavior using multi-dimensional behavioral analyses

The effects of alpha-neo-endorphin on mouse behavior were investigated by using a multi-dimensional behavioral analyser (Animex II) which classifies animal's movements into nine degrees. The intracerebral injection of alpha-neo-endorphin (30 micrograms) significantly decreased the 1/1, 1/2 and 1/4 sizes of movement (linear locomotion and rearing) within 15 min after injection. None of the effects were significantly affected by naloxone even at high doses. The results suggest that a behaviorally active site within the alpha-neo-endorphin sequence is capable of quite potent but nonopiate effects.     

A comparison of the antinociceptive and behavioral effects of D-Arg substituted dipeptides and tetrapeptides in mice

Intracerebroventricular administration of D-Arg substituted dipeptides, H-Tyr-D-Arg-OMe and H-Tyr(Et)-D-Arg-OMe, and D-Arg2 substituted N-terminal tetrapeptides of dermorphin, H-Tyr-D-Arg-Phe-Gly-OEt and H-Tyr(Et)-D-Arg-Phe-Gly-OEt resulted in dose-related and naloxone-reversible antinociceptive effects. Among them, tetrapeptides not only exhibited much more potent and prolonged activities than dipeptides but also were significantly antagonized even by a low dose of naloxone. Spontaneous motor activity was lowered by dipeptides throughout the observation period, which was scarcely antagonized by naloxone. Tetrapeptides elicited locomotor hyperactivity following an initial locomotor suppression. Only the locomotor hyperactivity was significantly antagonized by naloxone. These results suggest that tetrapeptides induce the effects via opioid receptors, whereas the effects of dipeptides are involved in various systems non-specifically.     

Effects of semi-purified diet on depressive behaviors in aged mice

Diet is a key modifiable factor influencing the composition of gut microbiota. There are two types of commercially available diets for experimental animals: non-purified and semi-purified diets. Non-purified diets are composed of complex ingredients from multiple sources, while semi-purified diets are formulated with refined ingredients. Accumulating evidence has demonstrated a link between the gut microbiota and depression, and feed ingredients may influence depressive physiology and behaviors. To test this hypothesis, we examined how chronic non-purified (CRF-1) and semi-purified (AIN-93G) diets affected phenotypes, including depressive behaviors, plasma corticosterone levels, and small-intestine microbiota in young (2 months old) and aged (22 months old) inbred C57BL/JJcl mice. In young mice, similar phenotypes were associated with non-purified and semi-purified diets. However, in aged mice, semi-purified diets increased depressive behaviors in the tail suspension (P < 0.05) and forced swimming tests (P < 0.01). The corticosterone levels were similar between the two diets under normal rearing conditions. However, immediately after exposure to the stressful conditions of the forced swimming test, the corticosterone levels in the aged mice fed the semi-purified diet were higher than those of mice fed the non-purified diet (P < 0.05). There were fewer Lactobacillales in the small intestines of aged mice fed the semi-purified diet compared to those fed the non-purified diet (P < 0.01). Further, α-diversity was lower in aged mice fed the semi-purified versus non-purified diet (P < 0.01). Our results indicate that host physiology and gut microbiota differed according to whether the aged mice were fed a non-purified or semi-purified diet. Specifically, those fed the semi-purified diet were more vulnerable to stress than age-matched mice fed the non-purified diet. Our findings indicate that researchers should consider the effects of feed ingredients on depressive physiology and behaviors, and select diets that are appropriate for their particular research design. Further, identification of the ingredients in non-purified diets could facilitate examination of the mechanisms by which gut microbiota composition might increase resistance to stress and depression.     

Expression of striatal adenosine and dopamine receptors in mice deficient in the p50 subunit of NF-kappaB

The striatal dopamine D2 receptor (D2R) and adenosine A2A receptor (A2AAR) exhibit mutually antagonistic effects through physical interactions and by differential modulation of post-receptor signaling pathways. The expression of the A2AAR and the D2R is differentially regulated by nuclear factor-kappaB (NF-kappaB). In this report, we determined the role of NF-kappaB in regulation of these receptors by comparing mice deficient in the NF-kappaB p50 subunit (p50 KO) with genetically intact B6129PF2/J (F2) mice. Quantification of adenosine receptor (AR) subtypes in mouse striatum by real time PCR, immunocytochemistry and radioligand binding assays showed more A2AAR but less A1AR in p50 KO mice as compared with F2 mice. Striata from p50 KO mice also had less D2R mRNA and [(3)H]-methylspiperone binding than did striata from F2 mice. G(alphaolf) and G(alphas) proteins, which are transducers of A2AAR signals, were also present at a higher level in striata from the p50 KO versus F2 mice. In contrast, the G(alphai1) protein, which transduces signals from the A1AR and D2R, was significantly reduced in striata from p50 KO mice. Behaviorally, p50 KO mice exhibited increased locomotor activity relative to that of F2 mice after caffeine ingestion. These data are consistent with a role for the NF-kappaB in the regulation of A1AR, A2AAR, D2R and possibly their coupling G proteins in the striatum. Dysregulation of these receptors in the striata of p50 KO mice might sensitize these animals to locomotor stimulatory action of caffeine.     

Effects of perinatal exposure to Zamzam water on the teratological studies of the mice offspring

Zamzam water is well documented for plenty of medicinal value for curing illness. In the present study, the effects of perinatal consumption of Zamzam and normal drinking water by the pregnant mice on their offspring’s physical parameters, early sensory motor reflexes, locomotor activities, acetylcholinesterase (AChE) activity in the homogenize brain tissue and blood parameters were compared. To achieve that; Zamzam water was given to female Swiss-Webster strain mice as the only source of drinking fluid and the control animals were administered plain tap water. Treatment started from the first day of pregnancy and continued until the postnatal day fifteen of delivery. All offspring were subjected to various tests. The rate of body weight gain remained relatively unaffected until the second week of weaning period, however; in the last week the offspring exposed to Zamzam water gained significant body weight as compared to their control offspring. Furthermore, the opening of eyes and appearance of body hairs in Zamzam exposed pups remained unaffected as compared to the controls. The sensory motor reflexes in Zamzam exposed pups after birth and during the first two weeks of weaning period were significantly increased. Locomotor Activity Test performed in the male and female offspring after weaning period showed a significant decrease in the male and increase in the female on most of the elements of this test due to Zamzam exposure. AChE activity in the homogenized brain tissue and blood parameters were unaffected as compared to the controls, the present Zamzam effects in the offspring are possibly via in utero action and/or via mother’s milk.     

Influence of different neural systems on the secretion of sex hormones in potassium deficient mice

The influence of different neural systems that modulate GnRH secretion by hypothalamic neurons was investigated in mice exposed to hypokalemic conditions, in which the pulsatile release of GnRH has been shown to be altered and associated with a significant decrease of plasma sex steroids. Our results demonstrate that the potentiation of the inhibitory pathways mediated by opiates and GABA may be implicated in the decrease of sex hormones secretion produced by hypokalemia since treatment with higher doses of naloxone or flumazenil are required to restore progesterone or testosterone levels in potassium deficient mice. The combination treatment of prazoxin and naloxone suggests that the inhibitory action of opiates take place through its action on noradrenergic neurons. It is also possible that the inhibition of GnRH release could be due to a decrease in the tonic stimulatory action of noradrenergic pathway implicated in the control of GnRH release. Our results also reveal that it is unlikely that the glutamatergic system may play any relevant direct role in the decrease of sex steroid secretion observed in potassium deficient mice. Finally, these results together with the normal pattern of estradiol levels found along the estrus cycle in potassium deficient mice indicate that factors different from estradiol and acting on neural systems implicated in the regulation of GnRH-secreting neurons participate in the generation of the preovulatory surge of GnRH.     

Immobility response elicited by clamping the neck induces antinociception in a "tonic pain" test in mice

Clamping the neck followed by body inversion to a supine position in mice elicits an immobility response called immobility by clamping the neck (ICN). The noxious pinch to the scruff of the neck produces antinociception in "phasic pain" models (e.g. tail-flick test). Here, a "tonic pain" model was used to test the antinociception associated with the ICN, and naloxone was used to determine the role of opioids in such antinociception. Mice were injected intraperitoneally with 0.3 mL of 0.4% acetic acid to produce writhing responses that were measured for one hour. ICN was induced every five minutes for one hour. Naloxone (5 mg/kg ip) was injected 10 min before acetic acid administration. There was a control group, sham clamping (SCLA). These mice were handled and restricted every five minutes as in the ICN but without real clamping. The repetitive inductions of ICN were able to reduce the writhing behavior; this antinociception was blocked by the naloxone pretreatment. In the SCLA group antinociception was not observed. These findings indicate that as in the "phasic pain" model, ICN also was able to elicit antinociception in this "tonic pain" model, and such antinociception seems to be mediated by opioids.     

Gamma-decanolactone effect on behavioral and genotoxic parameters

Gamma-decanolactone is a monoterpene compound, which is shown to be active in some animal models. The psychopharmacological evaluation of this compound in mice has revealed that it has a dose-dependent effect on the central nervous system, including hypnotic, anticonvulsant and hypothermic activities. The aim of the present study was to evaluate the effect of gamma-decanolactone at 0.1 and 0.3 g/kg on behavior parameters related to plus-maze, open field and forced swim tests. In addition, we investigated its genotoxic activity. Gamma-decanolactone at the dose of 0.3 g/kg, but not 0.1 g/kg, decreased the number of crossings and rearings and there were no significant differences among groups regarding the latency to start locomotion in open field. A single i.p. administration of gamma-decanolactone, at the higher, but not at lower dose used, was able to increase the exploratory activity in the test session (24 h after training), as assessed by the number of rearings performed in open field, and induced DNA damage on brain tissue as measured in comet assay, suggesting an impairment of nonassociative, nonaversive learning and a genotoxic effect on CNS. Gamma-decanolactone did not change the behavior of animals in plus-maze and forced swim tests, suggesting this compound shows no anxiolytic or antidepressant activity.     

不同时间睡眠干扰所致小鼠的类抑郁样行为

目的研究不同时间睡眠干扰后所致的小鼠类抑郁样行为学表现。方法使用滚筒睡眠干扰仪对小鼠进行不同时间(5、10、15 d)睡眠干扰后,分别对各组动物进行自主活动测试实验、强迫游泳实验和悬尾实验。结果干扰5 d组与对照组比,自主活动总路程、平均速度、运动总时间减少(P<0.05),干扰10 d组与对照组比,自主活动总路程、平均速度、运动总时间减少(P<0.05)。干扰5 d后,小鼠强迫游泳、悬尾实验中各指标与对照组比无差异,干扰10 d组小鼠的游泳不动时间[(143.92±9.48)s]和悬尾不动时间[(127.89±6.33)s]均较对照组小鼠游泳不动时间[(128.50±6.63)s]和悬尾不动时间[(102.64±9.57)s]长(P<0.05),干扰15 d组小鼠的游泳不动时间[(143.08±8.13)s]和悬尾不动时间[(119.10±10.43)s]均较对照组小鼠游泳不动时间[(113.00±7.28)s]和悬尾不动时间[(89.55±9.07)s]长(P<0.05)。干扰5 d组、10 d组、15 d组与对照组比,体重均降低(P<0.05)。结论滚筒法睡眠干扰10、15 d可引起小鼠的类抑郁样行为学表现。     

Possible nitric oxide modulation in protective effect of (Curcuma longa, Zingiberaceae) against sleep deprivation-induced behavioral alterations and oxidative damage in mice

Sleep is essential for the physical and mental health of a human being. Problems of sleep deprivation are increasing in modern society nowadays. Recently, various antioxidants have been implicated as neuroprotectants in the treatment of stress and stress related problems. The present study was designed to explore the possible role of nitric oxide in the protective effect of Curcumin (Curcuma longa, Zingiberaceae) against 72-h sleep deprivation-induced behavioral alterations and oxidative damage in mice. 72-h sleep deprivation significantly caused weight loss, anxiety like behavior, impaired locomotor activity and oxidative damage (increased lipid peroxidation, nitrite level and deplete glutathione and catalase activity) in animals. Treatment with Curcumin extract (10 and 20 mg/kg, ip) for 5 days significantly prevented weight loss, impairment in locomotor activity, anxiety like effects in all behavioral paradigms tasks (mirror chamber, plus maze, zero maze) as compared to control (72-h sleep-deprived) (P<0.05). Biochemically, Curcumin extract treatment significantly restored depleted reduced glutathione, catalase activity, attenuated raised lipid peroxidation and nitrite level as compared to control (72-h sleep-deprived) animals. Further, pretreatment of l-arginine (50 mg/kg, ip), nitric oxide precursor reversed the protective effect of Curcumin (10 mg/kg, ip) (P<0.05). However, pretreatment of l-NAME (5 mg/kg, ip), nitric oxide synthase inhibitor caused a potentiation in the protective effect of Curcumin (P<0.05). The present study suggests that nitric oxide modulation is involved in the protective effect of Curcumin in ameliorating sleep deprivation-induced behavioral alterations and oxidative damage.     

Mechanism of fasting heterothermia and re-feeding normothermia in mice

Mice subjected to caloric restriction (CR) typically display heterothermia characterized by hypothermia in the daytime and normothermia at night. The possible thermoregulatory mechanisms that mediate the CR-induced daytime hypothermia or the recovery of core temperature upon re-feeding are not well understood. In the present study drugs that inhibit three different pathways of thermogenesis were applied before, during and after CR in mice, while core temperature was monitored by biotelemetry. The time course of core temperature during complete CR and re-feeding was not modified by administration of the postganglionic adrenergic blocker guanethidine (10 mg/kg/day). Administration of the centrally acting muscle relaxant mephenesin (42 mg/kg/day) exacerbated the CR-induced hypothermia. Administration of the nonspecific opioid antagonist naloxone (20 mg/kg/day) also exacerbated the CR-induced hypothermia. None of the drugs had any effect on the rate of the rise in core temperature during re-feeding after a fast. It is concluded that mice may rely on the heat from motor activity to remain normothermic during the first night of complete fasting. Shivering thermogenesis appears to be critical in thermoregulation during fasting. Furthermore, opiate-dependent thermogenesis may also contribute to the regulation of body temperature during the second night of fasting.     

Effects of beta-endorphin on body temperature in mice at different ambient temperatures

The effect of intracerebroventricular injection of beta-endorphin (beta-END) on body temperature of mice was studied at ambient temperatures (Ta) of 10 degrees, 20 degrees and 31 degrees C. Doses between 0.1 and 10.0 microgram/mouse were studied. The lower (less than 1 microgram) doses of beta-END produced a hyperthermia at all Ta's studied. The higher doses of beta-END produced hyper- or hypothermia depending on the Ta. The subcutaneous injection of naloxone (1 mg/kg) antagonized the high dose hypothermic effects, but not the hyperthermic effect of beta-END. These data suggest that there may be different receptors and/or sites of action for high and low doses of beta-END.     

Expression pattern of Drosophila translin and behavioral analyses of the mutant

Translin is an evolutionarily conserved approximately 27-kDa protein that binds to specific DNA and RNA sequences and has diverse cellular functions. Here, we report the cloning and characterization of the translin orthologue from the fruit fly Drosophila melanogaster. Under protein-denaturing conditions, purified Drosophila translin exists as a mixture of dimers and monomers just like human translin. In contrast to human translin, the Drosophila translin dimers do not appear to be stabilized by disulfide interactions. Drosophila translin shows a ubiquitous cytoplasmic localization in early embryonal syncytial stage, with an enhanced staining in ventral neuroblasts at later stages (8-9), which are probably at metaphase. An elevated expression was seen in several other cell types, such as cells around the tracheal pits in the embryo and oenocytes in the third instar larva. RNA in situ hybridization showed an increased expression in the ventral midline cells of the larval brain, suggesting a neuronal expression, which was corroborated by protein immunostaining. In adult flies, Drosophila translin is localized in the brain neuronal cell bodies and in early spermatocytes. Interestingly, Drosophila translin mutants exhibit an impaired motor response which is sex specific. Taken together, the multiple cellular localizations, the high neuronal expression and the attendant locomotor defect of the Drosophila translin mutant suggest that Drosophila translin may have roles in neuronal development and behavior analogous to that of mouse translin.     

Neuropharmacological screening of two 1,5-benzodiazepine compounds in mice

This work investigates whether the two 1,5-benzodiazepine compounds: 4-(2-hydroxyphenyl)-1,5-benzodiazepin-2-one (RG0501) and Benzopyrano [4,3-c] 1,5-benzodiazepine (RG0502) have any neuropharmacological activities. Diazepam and Flunitrazepam were used as drug references. The investigational 1,5-BDZ were tested in vivo for potentiating hexobarbital-induced sleep and pentylenetetrazole (PTZ)-induced seizures. Our study demonstrated that the increase of sleep duration was significantly higher with RG0501 as compared to RG0502. However, RG0502 anticonvulsant effect was more pronounced than that of RG0501 in the range dose of 6.25-37.5 mg.kg^-1. From the 50 mg.kg^-1 dose, RG0502 offered a protection against clonic-tonic seizures as well as lethality (p ≤ 0.05). The results showed that the required doses to obtain a pharmacological activity were more than those of the references. This difference could be related to the lack of specific substituants responsible for the pharmacological activity in the tested compounds.     

Pair-housing of male and female rats during chronic stress exposure results in gender-specific behavioral responses

Social support has a positive influence on the course of a depression and social housing of rats could provide an animal model for studying the neurobiological mechanisms of social support. Male and female rats were subjected to chronic footshock stress for 3 weeks and pair-housing of rats was used to mimic social support. Rats were isolated or housed with a partner of the opposite sex. A plastic tube was placed in each cage and subsequently used as a 'safe' area in an open field test. Time spent in the tube was used as a measurement of anxiety levels. Chronic stress increased adrenal weights in all groups, except for isolated females who showed adrenal hypertrophy in control conditions. In isolated males, chronic stress resulted in an increase in the time the animals spent in the tube. While stress did not affect this parameter in socially housed males, males with a stressed partner showed a similar response as isolated stressed males. Even though adrenal weights showed that isolated females were more affected by stress, after chronic stress exposure, they spent less time in the tube than socially housed females. Socially housed stressed females spent less time in the 'safe' tube compared to control counterparts, indicating that stress has a gender-specific behavioral effect. In conclusion: pair-housing had a stress-reducing effect on behavior in males. Isolation of females was stressful by itself. Pair housing of females was not able to prevent stress-induced behavioral changes completely, but appeared to reduce the effects of chronic stress.     

Pharmacological effects of vinorelbine on body temperature and locomotor activity circadian rhythms in mice

The effects of vinorelbine (VRL) on the circadian rhythms in body temperature and locomotor activity were investigated in unrestrained B6D2F₁ mice implanted with radio-telemetry transmitters. A single intravenous VRL dose (24 or 12 mg/kg) was given at 7 h after light onset (HALO), a time of high VRL toxicity, and resulted in transient suppression of temperature and activity circadian rhythms in mice kept in light-dark (LD) 12h:12h. Such suppression was dose-dependent. It occurred within 1-5 d after VRL dosing. Recovery of both rhythms was partially complete within 5 d following the high dose and within 2 or 3 d after the low dose and was not influenced by suppression of photoperiodic synchronization by housing in continuous darkness. Moreover, VRL induced a dose-dependent relative decrease in amplitude and phase shift of the temperature circadian rhythm. The mesor and amplitude of the activity rhythm were markedly reduced following the VRL administration. The relevance of VRL dosing time was studied in mice housed in LD 12h:12h. Vinorelbine was injected weekly (20 mg/kg/injection) for 3 wk at 6 or 18 HALO. Vinorelbine treatment ablated the rest-activity and temperature rhythms 3-6 d after each dose, with fewer alterations after VRL dosing at 18 HALO compared to 6 HALO, especially for the body temperature rhythm. There was at least partial recovery 1 wk after dosing, suggesting the weekly schedule of drug treatment is acceptable for therapeutic purposes. Our findings demonstrate that VRL can transiently, yet profoundly, alter circadian clock function. Vinorelbine-induced circadian dysfunction may contribute to the toxicokinetics of this and possibly other anticancer drugs.     

Comparison of psychic emergence reactions after (+/-)-ketamine and (+)-ketamine in mice

Ketamine is a racemic mixture containing equal parts of (+)-ketamine and (-)-ketamine. The ketamine enantiomorphs are different in anesthesia and psychic emergence reactions after anesthesia. Therefore, (+)-ketamine was compared with racemic ketamine in a number of randomized studies in volunteers and patients. However, their relations remain controversial. In the present studies, the psychic emergence reactions after injection of (+/-)-ketamine and (+)-ketamine were compared in mice. At equimolar doses, the (+)-isomers elicited episodes of hypnosis nearly 1.4-fold more potent than those of the racemic ketamine. After the administration of equihypnotic doses of (+)-ketamine and (+/-)-ketamine, the posthypnotic stimulation of locomotor activity, stereotype behavior and 5-HT-induced head-twitch response by the (+)-enantiomorph was significantly less intense than that of racemic ketamine. In receptor binding test, (+)-ketamine showed a higher affinity for NMDA receptor than that of (+/-)-ketamine, while (+)-ketamine and (+/-)-ketamine showed no affinity for dopamine D2 and serotonin 5-HT2 receptor. These results suggest that the (+)-ketamine has fewer posthypnotic side effects than (+/-)-ketamine when (+)-ketamine and (+/-)-ketamine were administered at equihypnotic dosages and that dopamine D2 and serotonin 5-HT2 receptor were not involved in the effects of (+)-ketamine and (+/-)-ketamine.     

Thresholds for masking responses to light in three strains of retinally degenerate mice

Mutant mice with retinal degeneration (rd/rd) were given 1-h pulses of light of varying brightness at times of the night when they would normally be active. The mutant mice showed a significantly greater inhibition of locomotor activity to light (negative masking) than wildtype controls. Lack of impairment, or even enhancement of negative masking suggests that this response may depend on sparing in retinally degenerate mice of the same receptor type that mediates clock resetting, because synchronization of the circadian system is known to be unimpaired in these mutants. With very dim light pulses, mutants did not change their activity, but wildtypes actually became more active (positive masking). Positive and negative masking appear to depend on different sensory and central processes. Accepted: 11 May 1998     

Sex differences in morphine-induced behavioral sensitization and social behaviors in ICR mice

Gender and genetic strain are two prominent variants that influence drug abuse. Although certain sexrelated behavioral responses have been previously characterized in ICR mice, little is known about the effects of sex on morphine-induced behavioral responses in this outbred strain. Therefore, in this study, we investigated the sex differences of morphine-induced locomotion, anxiety-like and social behaviors in ICR mice. After morphine or saline exposure for four consecutive days(twice daily), increased locomotion, more time spent in the central area, as well as attenuated rearing and self-grooming behaviors were found in morphine-treated females in an open field; no differences were found in locomotion and the time spent in the central area between male and female controls. When interacting with the samesex individuals, female controls were engaged in more social investigation, following, body contacting and self-grooming behaviors than controls; morphine exposure reduced contacting and self-grooming behaviors in females; in contrast, these effects were not found in males. These results indicate that female ICR mice are more prosocial and are more susceptible to morphine exposure than males.