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At least 487 records · Page 27Linked to original sources
PubMed1998

GTS-21, a nicotinic agonist, attenuates multiple infarctions and cognitive deficit caused by permanent occlusion of bilateral common carotid arteries in rats.

We examined the effects of GTS-21 [3-(2,4-dimethoxybenzylidene)-anabaseine dihydrochloride], a nicotinic agonist, on histopathological changes of the brain and radial maze learning performance in rats with permanent occlusion of the bilateral common carotid arteries (2VO) and elucidated whether this compound has a protective effect against the neuronal degeneration and spatial cognitive deficit caused by chronic ischemia. Rats were administered GTS-21 (1 and 10 mg/kg, p.o.) or vehicle 24 hr and 30 min before the 2VO operation and then once daily for 2 months after the operation. The 2VO rats given vehicle had multiple infarctions in the cerebral cortex, hippocampus and striatum and rarefaction in the white matter at 2 months after the operation, although the number and distribution of infarctions varied among individual animals. In addition, the 2VO rats given vehicle showed a higher rate of errors in the acquisition trials of the 8-arm radial maze task than sham-operated controls. However, 2VO rats treated with GTS-21 (1 and 10 mg/kg, p.o.) showed significantly decreased neuropathological changes and less errors in the acquisition trials compared to the vehicle-treated 2VO rats. These results indicate that GTS-21 attenuates impairment of spatial cognitive deficit and progressive neuronal degeneration induced by 2VO and suggest that this compound is beneficial for the treatment of neurodegenerative diseases following chronic cerebral hypoperfusion.

Animals↗
PubMed2006

A carboxyfullerene SOD mimetic improves cognition and extends the lifespan of mice.

In lower organisms, such as Caenorhabditis elegans and Drosophila, many genes identified as key regulators of aging are involved in either detoxification of reactive oxygen species or the cellular response to oxidatively-damaged macromolecules. Transgenic mice have been generated to study these genes in mammalian aging, but have not in general exhibited the expected lifespan extension or beneficial behavioral effects, possibly reflecting compensatory changes during development. We administered a small-molecule synthetic enzyme superoxide dismutase (SOD) mimetic to wild-type (i.e. non-transgenic, non-senescence accelerated) mice starting at middle age. Chronic treatment not only reduced age-associated oxidative stress and mitochondrial radical production, but significantly extended lifespan. Treated mice also exhibited improved performance on the Morris water maze learning and memory task. This is to our knowledge the first demonstration that an administered antioxidant with mitochondrial activity and nervous system penetration not only increases lifespan, but rescues age-related cognitive impairment in mammals. SOD mimetics with such characteristics may provide unique complements to genetic strategies to study the contribution of oxidative processes to nervous system aging.

Age Factors↗
PubMed1996

Behavioral effects of prenatal exposure to pulsed-wave ultrasound in unanesthetized rats.

The present experiment examined the developmental neurotoxicity of pulsed-wave (pw) ultrasound in rats, using an exposure system designed to eliminate restraint or anesthesia from the exposure conditions. Pregnant Sprague-Dawley CD rats trained to remain immobile in a water-filled ultrasound exposure tank were scanned with 3-MHz pw ultrasound at spatial peak temporal average intensities (ISPTA) of 0, 2, 20, or 30 W/cm2 on embryonic days 4-20 for approximately 10 min/day. The data showed that such insonation produced no adverse effects on maternal weight gain or reproductive outcome, nor on the postnatal growth or survival of the offspring. No exposure-related alterations in behavioral development were observed in the offspring of rats scanned with pw ultrasound during gestation. In addition, there was no consistent evidence of an ultrasound-associated change in the adult offspring behaviors tested; i.e., no treatment effects were found on measures of locomotor activity, water maze learning, and acoustic startle reactivity. An effect on tactile startle was observed on some trials in the low exposure group male offspring, but this effect was neither dose dependent nor consistent with any other finding. Overall, these results indicate that the neurobehavioral development of rats was not altered by prenatal exposure to pw ultrasound at ISPTA levels of up to 30 W/cm2.

Animals↗
PubMed2006

Reproductive and neurobehavioural toxicity study of Ponceau 4R administered to mice in the diet.

Ponceau 4R was given to mice in the diet at levels of 0 (control), 0.12%, 0.24%, and 0.48% from 5 weeks of age of the F(0) generation to 9 weeks of age of the F(1) generation, and selected reproductive and neurobehavioural parameters were measured. There was no adverse effect of Ponceau 4R on litter size, litter weight or sex ratio at birth. The average body weight of male and female offspring was increased significantly in the high-dose group at postnatal days (PNDs) 0, 4 and 21. In behavioural developmental parameters, surface righting at PND 4 was affected significantly in the high-dose group in male offspring. Other variables measured showed no consistently significant adverse effect on either sex in the lactation period. In multiple water T-maze performance in the F(1) generation, the time taken was significantly longer than the control in the middle-dose and high-dose groups in males, and those effects were significantly dose-related (P<0.01). The dose level of Ponceau 4R in the present study produced no adverse effect on reproduction, and a few adverse effects on neurobehavioural parameters in mice. The non-observed adverse effect level (NOAEL) was presumed to be 0.12% in the diet (approximately 205mg/kg per day) for maze learning by males in the F(1) generation. Nevertheless, the middle-dose and high-dose levels were in excess of the acceptable daily intake (ADI) of Ponceau 4R (0-4.0mg/kg body weight), and the actual dietary intake of Ponceau 4R in humans is presumed to be much lower. It would appear, therefore, that the level of dietary intake of Ponceau 4R is unlikely to produce any adverse reproductive or neurobehavioural effect in humans.

Animals↗
PubMed2005

Gestational and lactational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin affects social behaviors between developing rhesus monkeys (Macaca mulatta).

Pregnant rhesus monkeys (Macaca mulatta) were exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) at 30 and 300 ng/kg by subcutaneous injection at gestational day 20, followed by additional injections of TCDD (1.5 and 15 ng/kg, respectively) every 30 days till 90 days after parturition. The offspring delivered from these experimentally TCDD-exposed mothers were subjected to a series of behavioral tests after the weaning at 12-14 months old (MO): a finger maze learning task (12-15 MO), encounter tests between two monkeys (at 12-15 and 24-27 MO), and an eye-contact test (23-26 MO) to estimate learning ability, social interaction with a peer subject, and interest or hostility to a human observer, respectively. TCDD exposure had no significant effect on learning ability or interest/hostility to an observer. It did, however, significantly affect behavioral characteristics in the encounter tests. In the first encounter test, monkeys exposed to TCDD showed more visual exploration and mutual proximity but less stereotypy behavior compared to control monkeys. In the second encounter test, these differences seemed to disappear, suggesting that the behavioral effects of TCDD exposure in the encounter tests might disappear as the monkey develops. This study produced evidence of the behavioral toxicity of TCDD in social interactions using non-human primates.

Animals↗
PubMed2007

Aluminum adjuvant linked to Gulf War illness induces motor neuron death in mice.

Gulf War illness (GWI) affects a significant percentage of veterans of the 1991 conflict, but its origin remains unknown. Associated with some cases of GWI are increased incidences of amyotrophic lateral sclerosis and other neurological disorders. Whereas many environmental factors have been linked to GWI, the role of the anthrax vaccine has come under increasing scrutiny. Among the vaccine's potentially toxic components are the adjuvants aluminum hydroxide and squalene. To examine whether these compounds might contribute to neuronal deficits associated with GWI, an animal model for examining the potential neurological impact of aluminum hydroxide, squalene, or aluminum hydroxide combined with squalene was developed. Young, male colony CD-1 mice were injected with the adjuvants at doses equivalent to those given to US military service personnel. All mice were subjected to a battery of motor and cognitive-behavioral tests over a 6-mo period postinjections. Following sacrifice, central nervous system tissues were examined using immunohistochemistry for evidence of inflammation and cell death. Behavioral testing showed motor deficits in the aluminum treatment group that expressed as a progressive decrease in strength measured by the wire-mesh hang test (final deficit at 24 wk; about 50%). Significant cognitive deficits in water-maze learning were observed in the combined aluminum and squalene group (4.3 errors per trial) compared with the controls (0.2 errors per trial) after 20 wk. Apoptotic neurons were identified in aluminum-injected animals that showed significantly increased activated caspase-3 labeling in lumbar spinal cord (255%) and primary motor cortex (192%) compared with the controls. Aluminum-treated groups also showed significant motor neuron loss (35%) and increased numbers of astrocytes (350%) in the lumbar spinal cord. The findings suggest a possible role for the aluminum adjuvant in some neurological features associated with GWI and possibly an additional role for the combination of adjuvants.

Adjuvants, Pharmaceutic↗
PubMed2006

Deletion of the triplet repeat encoding polyglutamine within the mouse Huntington's disease gene results in subtle behavioral/motor phenotypes in vivo and elevated levels of ATP with cellular senescence in vitro.

Huntingtin (htt), the protein encoded by the Huntington's disease (HD) gene, contains a polymorphic stretch of glutamines (polyQ) near its N-terminus. When the polyQ stretch is expanded beyond 37Q, HD results. However, the role of the normal polyQ stretch in the function of htt is still unknown. To determine the contribution of the polyQ stretch to normal htt function, we have generated mice with a precise deletion of the short CAG triplet repeat encoding 7Q in the mouse HD gene (Hdh(DeltaQ)). Hdh(DeltaQ/DeltaQ) mice are born with normal Mendelian frequency and exhibit no gross phenotypic differences in comparison to control littermates, suggesting that the polyQ stretch is not essential for htt's functions during embryonic development. Adult mice, however, commit more errors initially in the Barnes circular maze learning and memory test and perform slightly better than wild-type controls in the accelerating rotarod test for motor coordination. To determine whether these phenotypes may reflect an altered cellular physiology in the Hdh(DeltaQ) mice, we characterized the growth and energy status of primary embryonic and adult Hdh(DeltaQ/DeltaQ) fibroblasts in culture. The Hdh(DeltaQ) fibroblasts exhibited elevated levels of ATP, but senesced prematurely in comparison with wild-type fibroblasts. Taken altogether, these results suggest that htt's polyQ stretch is required for modulating longevity in culture and support the hypothesis that the polyQ stretch may also modulate a htt function involved in regulating energy homeostasis.

Adenosine Triphosphate↗
PubMed1995

Complementary memory storage sites in mice: their development as affected by the competitive NMDA receptor antagonist, CPP.

Bitemporal injections of puromycin consistently induce amnesia of aversive maze learning in mice when administered within 3 days of training. These bitemporal puromycin injections lose their amnestic effectiveness if the latency between training and injection is extended beyond 6 days. Consistent with other evidence, we conclude that in our experimental paradigm, complementary memory storage sites normally develop in additional cerebral areas within 6 days following training. Previous experiments have indicated that the central adrenergic and cholinergic systems are critically involved in this process. We now present evidence that administration of the NMDA receptor antagonist, CPP, blocks the development of these complementary memory storage sites. As suggested by studies of long-term potentiation, NMDA receptor-dependent postsynaptic calcium appears to be essential for the development of these storage sites and indeed to trigger their development.

Amnesia↗
PubMed2005

Developmental exposure of rats to chlorpyrifos leads to behavioral alterations in adulthood, involving serotonergic mechanisms and resembling animal models of depression.

Developmental exposure to chlorpyrifos (CPF) causes persistent changes in serotonergic (5HT) systems. We administered 1 mg/kg/day CPF to rats on postnatal days 1-4, a regimen below the threshold for systemic toxicity. When tested in adulthood, CPF-exposed animals showed abnormalities in behavioral tests that involve 5HT mechanisms. In the elevated plus maze, males treated with CPF spent more time in the open arms, an effect seen with 5HT deficiencies in animal models of depression. Similarly, in an anhedonia test, the CPF-exposed group showed a decreased preference for chocolate milk versus water. Developmental CPF exposure also has lasting effects on cognitive function. We replicated our earlier finding that developmental CPF exposure ablates the normal sex differences in 16-arm radial maze learning and memory: during acquisition training, control male rats typically perform more accurately than do control females, but CPF treatment eliminated this normal sex difference. Females exposed to CPF showed a reduction in working and reference memory errors down to the rate of control males. Conversely, CPF-exposed males exhibited an increase in working and reference memory errors. After radial-arm acquisition training, we assessed the role of 5HT by challenging the animals with the 5HT2 receptor antagonist ketanserin. Ketanserin did not affect performance in controls but elicited dose-dependent increases in working and reference memory errors in the CPF group, indicating an abnormal dependence on 5HT systems. Our results indicate that neonatal CPF exposures, classically thought to be subtoxic, produce lasting changes in 5HT-related behaviors that resemble animal models of depression.

Animals↗
PubMed2003

Functional recovery after simultaneous transplantation with neuro-epithelial stem cells and adjacent mesenchymal tissues into infarcted rat brain.

BACKGROUND: Cerebral infarction results in impairment of motor and cognitive functions. We performed intracranial transplantation of multipotential neuro-epithelial stem cells with mesenchyme into experimentally large ischemic lesions to study their potential to relieve deficits. METHODS: Wistar albino rats were subjected to transient middle cerebral artery occlusion for 60 minutes, producing an extensive ischemic lesion in the ipsilateral striatum and adjacent cerebral cortex. The rat mesencephalic neural plate at the early somite stage (embryonic day 10.5) together with adjacent ventral mesenchyme was used as donor material. We performed histological and immunohistochemical studies, with antibodies against tyrosine hydroxylase, and dopamine- and adenosine 3': 5'-monophosphate-regulated phosphoprotein 32 (DARPP-32; a striatal marker). Micro-angiograms were made by using Microfil silicone rubber. Morris Water-maze learning and treadmill task were employed to evaluate motor and cognitive functions. FINDINGS: A viable non-tumoral mass was recognized in the rat striatum, up to as long as 156 days after transplantation. There were many cells positive for tyrosine hydroxylase or DARPP-32 in the graft. Some of the DARPP-32 positive cells within the graft had extended their dendrites into host tissues. In the micro-angiograms, many fine vessels were observed within the graft and dilated vessels meandered around the graft. Transplanted animals recovered significantly better in motor and cognitive functions than animals injected with only culture medium. INTERPRETATION: Neuro-epithelial stem cells may follow several lines of differentiation; along the naturally genetically programmed line of differentiation, or along other cell lines depending on different environments. Grafting of neuro-epithelial stem cells with mesenchyme may merit a further study as a treatment for cerebral infarction.

Animals↗
PubMed1992

Differential ethanol intake in Tryon maze-bright and Tryon maze-dull rats: implications for the validity of the animal model of selectively bred rats for high ethanol consumption.

The search for a genetically based "animal model of alcoholism" has led to the creation of extensive research programs using various combinations of initial ethanol preference screening techniques and breeding methods to yield rodents with primary genetic differences that contribute to high or low ethanol preference. The present experiment examined the ethanol intake of the Tryon rat strain, which were bred for high and low maze learning scores. It was observed that the Tryon Maze Bright rats displayed an unprecedented affinity for ethanol with stable intakes between 12.7 and 13.7 g/kg per day and preference ratios exceeding 0.75 for ethanol concentrations ranging between 15 and 29%. The pattern of ethanol intake of the Tryon Maze Dull rats resembled the ethanol intake pattern of other, non-selectively bred strains of rats, approximately 2-3 g/kg of absolute ethanol at preference ratios between 0.11 and 0.28. The affinity for ethanol observed for the Tryon Maze Bright rats seems to exceed the reported consumption patterns of rat strains specifically bred for high ethanol consumption although the Tryon rats were selectively bred for variables that were seemingly unrelated to ethanol intake.

Alcohol Drinking↗
PubMed2000

Diazepam modifies the effect of pedunculopontine lesions on morphine but not on amphetamine conditioned place preference.

We have previously shown that T-maze learning impairments caused by lesions to the pedunculopontine tegmental nucleus (PPTg) can be reversed by the anxiolytic diazepam. We now report that diazepam also reverses the effect of PPTg lesions on conditioned place preference (CPP) to morphine but not to amphetamine. Rats with bilateral sham or N-methyl-D-aspartate lesions (0.1 or 0.05 M) to the PPTg were trained in a unbiased CPP paradigm with 2 mg/kg morphine or 2 mg/kg D-amphetamine associated with one compartment of the apparatus and vehicle injections in the alternative compartment. After three drug/saline-compartment pairings, the preference of the animals was assessed by allowing them to explore the entire apparatus for 20 min. In contrast to sham-lesioned subjects, the rats with PPTg lesions did not show a preference for the compartment paired with morphine or amphetamine. In two experiments the expression of a morphine CPP was restored by injecting the lesioned animals with 1 mg/kg of diazepam 30 min before the test session. Diazepam pre-treatment did not restore the expression of amphetamine CPP.

Amphetamine↗
PubMed2000

Neural and behavioral teratological evaluation of rats exposed to ultra-wideband electromagnetic fields.

Several investigators have reported teratologic effects of electromagnetic field exposure. The majority of these studies have been performed at levels of exposure that could produce substantial heating of the animals. New and unique sources of ultra-wideband (UWB) electromagnetic fields are currently being developed and tested that are capable of generating nonthermalizing, high-peak-power, microwave (MW) pulses with nanosecond (ns) pulse widths, picosecond (ps) rise times, and an UWB of frequencies. Our study was performed to determine if teratological changes occur in rat pups as a result of (i) daily UWB exposures during gestation days 3-18, or (ii) as a result of both prenatal and postnatal (10 days) exposures. Dams were exposed either to (i) UWB irradiation from a Kentech system that emitted a 55 kV/m-peak E field, 300 ps rise time, and a 1.8 ns pulse width, average whole-body specific absorption rate 45 mW/kg; (ii) sham irradiation; or (iii) a positive control, lead (Pb) acetate solution (2000 microg/ml) continuously available in the drinking water. Offspring were examined for ontogeny (litter size, sex-ratios, weights, coat appearance, tooth-eruption, eye-opening, air-righting, and ultrasonic stress vocalizations). Male pups were tested on various performance measures (locomotor, water-maze learning, and fertilization capabilities). The pups postnatally exposed were examined for hippocampal morphology and operant behavior. Behavioral, functional, and morphological effects of UWB exposure were unremarkable with these exceptions: (i) The UWB-exposed pups emitted significantly more stress vocalizations than the sham-exposed pups; (ii) the medial-to-lateral length of the hippocampus was significantly longer in the UWB-exposed pups than in the sham-exposed animals; (iii) male offspring exposed in utero to UWB mated significantly less frequently than sham-exposed males, but when they did mate there was no difference in fertilization and offspring numbers from the sham group. There does not appear to be a unifying physiological or behavioral relationship among the significant differences observed, and our findings could be due to the expected spurious results derived when a large number of statistical comparisons are made. Significant effects found between our positive-controls and other groups on numerous measures indicates that the techniques used were sensitive enough to detect teratological effects. Bioelectromagnetics 21:524-537, 2000. Published 2000 Wiley-Liss, Inc.

Animals↗
PubMed2004

The effect of repeated isoflurane anesthesia on spatial and psychomotor performance in young and aged mice.

UNLABELLED: Exposure to general anesthesia may contribute to postoperative cognitive impairment in elderly patients, but the relationship remains poorly understood. We investigated whether aged mice, 18-19 mo, are more susceptible to postanesthetic cognitive impairment than young mice, 3-4 mo, using spatial memory (Barnes maze) and psychomotor (rotarod) tasks. Initially we studied the effect of a single anesthetic episode on asymptotic maze performance. We then tested whether repeated anesthesia would impair spatial memory and psychomotor performance to a greater extent in aged mice. Mice were anesthetized with isoflurane (1.4% atm) for 30 min; controls received 90% oxygen. Anesthesia, administered during the asymptotic period of maze learning, did not impair performance tested the following day (P > 0.05). Repeated anesthesia, 2-3 h after each session, did not impair overall maze or rotarod performance in young or aged mice (P > 0.05). Spatial learning appeared to be facilitated by anesthesia, F(1,204) = 7.97, P < 0.01 for pooled results. Asymptotic performance-when learning had stabilized-remained unimpaired in both the maze and rotarod tasks. These results suggest that an age-related risk of anesthetic-induced impairment appears to be limited to acquisition of a novel motor skill and that anesthesia alone does not lead to prolonged cognitive impairments in aged mice. IMPLICATIONS: This study demonstrates that repeated isoflurane general anesthesia impaired psychomotor performance in aged mice during the initial learning period; however, spatial learning improved and, overall, spatial memory and psychomotor performance were unimpaired. Thus, general anesthesia alone does not appear to result in prolonged cognitive deficits in aged mice.

Aging↗
PubMed2005

Influence of chronic treatment with olanzapine, clozapine and scopolamine on performance of a learned 8-arm radial maze task in rats.

Cognitive deficit is a significant symptom in schizophrenic patients. Use of atypical antipsychotics has been demonstrated to improve some cognitive functions in schizophrenics, as well as in patients with dementia. However, side effects like sedation and muscarinic antagonism induced by these drugs have detracted from this improvement. We are interested in determining the behavioural effect of acute and chronic treatments with olanzapine and clozapine, two atypical antipsychotics, in a paradigm of working memory, and the influence on behavioural response of possible motor effects during test performance. Unspecific muscarinic antagonist scopolamine has been used for comparison. Male Wistar rats were trained on the 8-arm radial maze up to an accuracy level in choice of 80%. Distance travelled in the maze was also measured during test performance. Acute olanzapine, clozapine and scopolamine caused significant impairment of correct performance. Rats treated with olanzapine and clozapine presented a decrease in motor activity level at the same time. After the test at acute dosage, rats were chronically treated for 14 days with olanzapine, clozapine or scopolamine and 24 h after the last dose were again tested in the 8-arm radial maze. Under this procedure, chronic treatment with olanzapine, clozapine and scopolamine did not impair correct task performance and did not modify distance travelled. We concluded that the sedative effect masked a possible effect on working memory after acute administration of olanzapine and clozapine, whereas chronic treatment with olanzapine, clozapine and scopolamine did not adversely affect working memory performance. In the case of scopolamine, it suggests that chronic muscarinic antagonism does not induce memory impairment and for atypical antipsychotics, it suggests that chronic treatment induced a tolerance to acute motor effects of these drugs.

Animals↗