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PubMed2003

Effects of the novel analgesic, cizolirtine, in a rat model of neuropathic pain.

Cizolirtine (5-9[(N,N-dimethylaminoethoxy)phenyl]methyl0-1-methyl-1H-pyrazol citrate) is a centrally acting analgesic with a currently unknown mechanism of action, whose efficacy has been demonstrated in various models of acute and inflammatory pain in rodents. Further studies were performed in order to assess its potential antinociceptive action in a well-validated model of neuropathic pain, i.e. that produced by unilateral sciatic nerve constriction in rats. Animals were subjected to relevant behavioural tests based on mechanical (vocalization threshold to paw pressure) and thermal (struggle latency to paw immersion in a cold (10 degrees C) water bath) stimuli, 2 weeks after sciatic nerve constriction, when pain-related behaviour was fully developed. Acute pretreatment with 2.5-10 mg/kg p.o. of cizolirtine reversed both mechanical and thermal allodynia. These effects were antagonized by prior injection of the alpha(2)-adrenoceptor antagonist idazoxan (0.5 mg/kg i.v.), but not the opioid receptor antagonist naloxone (0.1 mg/kg i.v.). On the other hand, cizolirtine (10 mg/kg p.o.) produced no motor deficits in animals using the rotarod test. Our study showed that cizolirtine suppressed pain-related behavioural responses to mechanical and cold stimuli in neuropathic rats, probably via an alpha(2)-adrenoceptor-dependent mechanism. These results suggest that cizolirtine may be useful for alleviating some neuropathic somatosensory disorders, in particular cold allodynia, with a reduced risk of undesirable side effects.

Analgesics↗
PubMed2002

Genetic determinants of adult hippocampal neurogenesis correlate with acquisition, but not probe trial performance, in the water maze task.

A number of reports have indicated that adult neurogenesis might be involved in hippocampal function. While increases in adult neurogenesis are paralleled by improvements on learning tasks and learning itself can promote the survival of newly generated neurons in the hippocampus, a causal link between learning processes and adult hippocampal neurogenesis is difficult to prove. Here, we addressed the related question of whether the baseline level of adult neurogenesis is predictive of performance on the water maze task as a test of hippocampal function. We used ten strains of recombinant inbred mice, based on C57BL/6, which are good learners and show high baseline levels of neurogenesis, and DBA/2, which are known to be poor learners and which exhibit low levels of adult neurogenesis. Two of these strains, BXD-2 and BXD-8, showed a 26-fold difference in the number of newly generated neurons per hippocampus. Over all strains, including the parental strains, there was a significant correlation between the number of new neurons generated in the dentate gyrus and parameters describing the acquisition of the water maze task (slope of the learning curves). Similar results were seen when the parental strains were not included in the analysis. There was no correlation between adult hippocampal neurogenesis and probe trial performance, performance on the rotarod, overall locomotor activity, and baseline serum corticosterone levels. This result supports the hypothesis that adult neurogenesis is involved in specific aspects of hippocampal function, particularly the acquisition of new information.

Animals↗
PubMed2005

Optimal methods to characterize the G93A mouse model of ALS.

In the present study, we used the SOD1 (G93A) mutant transgenic mice as a model of amyotrophic lateral sclerosis (ALS). This model is widely used as a laboratory tool to study experimental treatments in vivo for ALS to investigate new therapeutic strategies for this neurodegenerative disease. Such studies require the objective quantification of different parameters while mice develop the disease. We have applied a battery of different and specific tests: scoring of motor deficits by a trained observer, weighing, survival measure, hanging wire test, rotarod task and electromyography, most of them commonly used to evaluate G93A animals. We have critically compared these methods, showing the significant influence of gender on the onset of symptoms, and the optimal moment to apply each test. These results should be taken into account in future therapeutic assays on this ALS model.

Age Factors↗
PubMedDate not supplied

Long-term effects of diazepam treatment of epileptic GABAA receptor beta3 subunit knockout mouse in early life.

The knockout mouse for the beta3 subunit of the GABAA receptor exhibits spontaneous epilepsy and hyperactivity, and has been proposed as a model for the severe developmental disorder, Angelman's syndrome, which is known to be of genetic origin. We have used this mutant to test an approach of therapeutic intervention prior to seizure onset by daily injection with diazepam during either the first or second postnatal week. Results showed differences between postnatal week 1 and week 2 injections both acutely, with respect to sedative effects, and in long-term outcome, with respect to EEG and behavioral tests measured at 12-14 weeks of age. The EEG of control mice remained unaffected under all conditions, but the EEG of beta3 (-/-) injected with diazepam in week 1 was worsened, showing increased oscillatory activity at 5-6Hz, and more myoclonic jerks, particularly among males. For beta3 (-/-) injected with diazepam in week 2, the EEG was normalized in half the mice but worsened similarly to week 1 in the other half. Neonatal diazepam injection had a long-term normalizing effect on behavior of beta3 (-/-) mice injected in week 1, but diazepam treatment in week 2 did not affect the hyperactive and circling behavior characteristic of the beta3 knockout mouse. Diazepam treatment in postnatal week 2 significantly decreased anxiety in the adult beta3 group. Diazepam treatment in both postnatal weeks 1 and 2 improved the motor coordination of beta3 (-/-) on the rotarod, although performance of control mice injected with diazepam in postnatal week 2 was significantly impaired. The observed long-term outcome of neonatal diazepam injections may result from interference with developmental processes, and shows that enhancing GABAergic activity with diazepam during the period where GABA can be excitatory can produce narrow stage-related effects on brain development.

Age Factors↗
PubMed1998

Psychomotor and spatial memory performance in aging male Fischer 344 rats.

Psychomotor and spatial memory performance were examined in male Fischer 344 rats that were 6, 12, 15, 18, and 22 months of age, to assess these parameters as a function of age and to determine at what age these behaviors begin to deteriorate. Complex motor behaviors, as measured by rod walk, wire suspension, plank walk, inclined screen, and accelerating rotarod performance, declined steadily with age, with most measures being adversely affected as early as 12 to 15 months of age. Spatial learning and memory performance, as measured by the working memory version of the Morris water maze (MWM), showed decrements at 18 and 22 months of age (higher latencies on the working memory trial), with some change noticeable as early as 12-15 months of age (no improvement on the second trial following a 10-min retention interval); these differences were not due to swim speed. Therefore, complex motor and spatial memory behaviors show noticeable declines early in the lifespan of the male Fisher 344 rat. This cross-sectional age analysis study using the latest behavioral techniques determines the minimal age at which psychomotor and spatial learning and memory behaviors deteriorate; this information is important when planning for longitudinal studies where interventions are tested for their efficacy in preventing or restoring age-related behavioral deficits.

Aging↗
PubMed2003

Saiko-ka-ryukotsu-borei-to, a herbal medicine, ameliorates chronic stress-induced depressive state in rotarod performance.

Exposure to chronic stress is thought to play an important role in the etiology of depression. This disorder has been shown to involve disruption of the hypothalamo-pituitary-adrenal (HPA) system and dysfunction of the prefrontal cortex (PFC). We have demonstrated that chronic stress in rats induces similar HPA disruption or a depressive state caused by a reduction of dopaminergic and serotonergic transmission in the PFC. We have also shown that saiko-ka-ryukotsu-borei-to, a herbal medicine, prevents such chronic stress-induced HPA disruption. However, the behavioral and neurochemical bases of this drug remain unclear. Here we examined the effects of saiko-ka-ryukotsu-borei-to on the depressive behavioral state and the reduction of transmission resulting from chronic stress. The chronic stress was induced by water immersion and restraint (2 h/day) for 4 weeks followed by recovery for 10 days. The treatment with saiko-ka-ryukotsu-borei-to (100, 300, or 1000 mg/kg p.o.) ameliorated the stress-induced depressive state in a dose-dependent manner, evaluated by a rotarod test. A microdialysis study indicated that the drug treatment significantly prevented the chronic stress-induced decreases in extracellular concentrations of dopamine and serotonin in the PFC. These results suggest that saiko-ka-ryukotsu-borei-to ameliorates the chronic stress-induced depressive state based on the prevention of PFC dysfunction. These findings provide important information for treatment of depression.

Animals↗
PubMed1991

The development of tolerance to ataxia and to diuresis induced by ethanol in rats is not simultaneous.

The present study was conducted to determine whether behaviorally accelerated development of tolerance to the disruptive effects of ethanol on rotarod performance paralleled the development of tolerance to ethanol-induced diuresis and to determine the effect of pre- and post-training ethanol administration on the development of tolerance to both of these effects. Male Wistar rats were treated with ethanol (2 g kg-1 day-1, ip) over a period of 5 weeks under one of the following schemes: ethanol injections before training (pre-training ethanol group) or after training (post-training ethanol group). Control animals received 0.9% NaCl, ip, after training. The effect of ethanol on diuresis was assessed once a week. Data are reported as means +/- SEM of 6 animals. Significant tolerance to the uncoordinating effect of ethanol was detected from the 17th day of treatment onwards in animals of the pre-training ethanol group (2nd day = 1.7 +/- 0.6 s vs 17th day = 39.0 +/- 8.1 s, Student t-test for related samples) but was not observed in animals of the post-training ethanol group until 34 days of treatment (pre-training ethanol group = 56.1 +/- 8.5 s; post-training ethanol group = 29.8 +/- 9.6 s vs control group = 12.6 +/- 7.6 s, Newman-Keuls test).(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Variance↗
PubMed2003

Involvement of NMDA receptors in alcohol-mediated behavior: mice with reduced affinity of the NMDA R1 glycine binding site display an attenuated sensitivity to ethanol.

BACKGROUND: Ethanol antagonizes central effects of glutamate by inhibition of the N-methyl-D-aspartate (NMDA) receptor function. The co-agonist glycine has been shown to reverse alcohol-mediated effects. The aim of this study was to evaluate the influence of the glycine binding site of the NMDA receptor on the behavioral effects of alcohol by investigating mice with an 80% reduced affinity of the NMDA R1 subunit for glycine (Grin1(D481N)). METHODS: Free-choice and forced alcohol intake was studied over a period of 52 days. Anxiolytic activity (elevated plus maze, open field) and motor coordination (rotarod) was tested after 3 days of forced alcohol intake and during ethanol withdrawal. RESULTS: In contrast to wild-type mice, alcohol-associated anxiolysis and motor impairment was attenuated in Grin1(D481N) mice during intoxication. Free-choice alcohol intake did not differ between wild-type and Grin1(D481N) mice. CONCLUSIONS: Our results give first evidence in vivo for a possible role of an altered NMDA-receptor complex with a hyposensitive glycine binding site for behavioral effects mediated by ethanol.

Alcohol Drinking↗
PubMedDate not supplied

Impaired learning and motor behavior in heterozygous Pafah1b1 (Lis1) mutant mice.

Heterozygous mutation or deletion of Pafab1b1 (LIS1) in humans is associated with syndromes with type 1 lissencephaly, a severe brain developmental disorder resulting from abnormal neuronal migration. We have created Lis1 heterozygous mutant mice by gene targeting. Heterozygous mutant mice are viable and fertile, but display global organizational brain defects as a result of impaired neuronal migration. To assess the functional impact of the mutation, Lis1 heterozygous mice and their wild-type littermates were evaluated on a wide variety of behavioral tests. Lis1 mutant mice displayed abnormal hindpaw clutching responses and were impaired on a rotarod test. Lis1 heterozygous mice were also impaired in the spatial learning version of the Morris water task. Impaired motor behavior and spatial learning and memory in Lis1 mutant mice indicates that impaired neuronal migration can have functional effects on complex behavioral responses. The behavioral findings also support the use of the Lis1 mutant mice as a model from human type 1 lissencephaly.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗
PubMed2005

Talampanel improves the functional deficit after transient focal cerebral ischemia in rats. A 30-day follow up study.

The neuroprotective effect of talampanel, a negative allosteric modulator of alpha-amino-3-hydroxy-methyl-4-isoxazolyl-propionic acid (AMPA) receptors has been described previously. However, in these studies the histological changes and not the functional consequences of the brain damage were evaluated. The aim of present investigation was to analyze the sensorimotor function after stroke and to test the influence of talampanel (GYKI-53773, LY-300164) by 30-day monitoring in rats. After 1h middle cerebral artery occlusion (MCAO) general 'well-being', neurological status, spontaneous motor activity, rotation, motor coordination, balancing, muscle strength and reaction time were followed for 1 month. Talampanel (6 x 10 mg/kg i.p. given on the day of stroke) improved the motor coordination in rotarod (p < 0.01) and beam walking (p < 0.01) tests, reduced the number of stroke-induced rotations (p < 0.05), shortened the reflex time on the forelimb contralateral to brain ischemia and improved the survival rate comparing with vehicle treated control. After stroke, serious sensorimotor deficits appeared in rats but they showed partial spontaneous recovery after 30 days. Talampanel treatment enhanced the rate of functional improvement without changing the morphology at the end of the experiment. Our results indicate that modulation of AMPA receptors by talampanel can be a promising therapeutic approach to the treatment of stroke.

Animals↗
PubMedDate not supplied

Effects of delta 9-THC on pregnancy and offspring in rats.

Pregnant rats were intubated with increasing doses of delta 9-THC (5-50 mg/kg/day) up to gestation day 5. On gestation day 5, these animals continued to receive either 50 or 150 mg/kg/day of delta 9-THC. Animals receiving the 50 mg/kg/day dose and a control group of vehicle (olive oil) treated animals were pair-fed and pair- watered to animals given the 150 mg/kg/day dose. A second control group served as nontreated, ad lib control animals. Animals were tested postnatally for spontaneous alteration, avoidance learning and rotarod behavior to determine if delta 9-THC was behaviorally teratogenic. Drug treatments produced a dose-related decrease in pregnancies carried to term, weight gain during pregnancy, and birth weight. However, since no viable litters were born to animals in the high dose-group, their data was not included in statistical analyses. Nevertheless, the effects of drug treatment (50 mg/kg/day) were still statistically significant for weight gain during pregnancy and birth weight. Drug treatment (50 mg/kg/day) did not affect litter size or weight at 21 days of age, nor did it affect any of the behavioral tests.

Animals↗
PubMedDate not supplied

Neurobehavioral changes in mice treated with methylmercury at two different stages of fetal development.

Pregnant C57BL/6 mice were orally given daily doses of 4 or 6 mg/kg of methylmercury chloride (MeHg) or vehicle during either gestational days 7-9 (GD7-9) or days 12-14 (GD12-14). Their female offspring were tested between 6 and 16 weeks of age on a variety of behavioral tasks. Motor coordination on the rotarod and visual discrimination learning in the Y maze were not affected by administration of MeHg either at GD7-9 or at GD12-14. In the open field, the total number of square crossings was lower in mice treated with 4 and 6 mg/kg of MeHg at GD12-14 than in control mice whether the environment was new or familiar, but prenatal administration of MeHg at GD7-9 had no effect on this measure. Administration of MeHg either at GD7-9 or at GD12-14 had no effect on the percentage of central square crossings or on the frequency of rearings in the open field. On spatial alternation training in the T maze, both treated groups in Condition GD7-9 and the group treated with 6 mg/kg at GD12-14 required more sessions to reach the learning criterion than their respective vehicle groups. When spatial alternation was tested with delays, treated groups did not differ from their respective control groups. In the radial arm maze, the performance of mice treated at GD7-9 was normal, but reference memory and working memory were impaired by administration of MeHg at GD12-14. In mice treated with 4 mg/kg of MeHg, reference memory was impaired only on the first block of trials, whereas in mice treated with 6 mg/kg, the deficit persisted on all blocks of trials. Overall, these results indicate that prenatal administration of MeHg at GD12-14 had more detrimental effects on behavioral performance than administration at GD7-9. It reduced locomotor activity and impaired reference memory for egocentric and allocentric spatial information as well as working memory for places.

Aging↗
PubMed2006

Prostaglandin H synthase-catalyzed bioactivation of amphetamines to free radical intermediates that cause CNS regional DNA oxidation and nerve terminal degeneration.

Reactive oxygen species (ROS) are implicated in amphetamine-initiated neurodegeneration, but the mechanism is unclear. Here, we show that amphetamines are bioactivated by CNS prostaglandin H synthase (PHS) to free radical intermediates that cause ROS formation and neurodegenerative oxidative DNA damage. In vitro incubations of purified PHS-1 with 3,4-methylenedioxyamphetamine (MDA) and methamphetamine (METH) demonstrated PHS-catalyzed time- and concentration-dependent formation of an amphetamine carbon- and/or nitrogen-centered free radical intermediate, and stereoselective oxidative DNA damage, evidenced by 8-oxo-2'-deoxyguanosine (8-oxo-dG) formation. Similarly in vivo, MDA and METH caused dose- and time-dependent DNA oxidation in multiple brain regions, remarkably dependent on the regional PHS levels, including the striatum and substantia nigra, wherein neurodegeneration of dopaminergic nerve terminals was evidenced by decreased immunohistochemical staining of tyrosine hydroxylase. Motor impairment using the rotarod test was evident within 3 wk after the last drug dose, and persisted for at least 6 months. Pretreatment with the PHS inhibitor acetylsalicylic acid blocked MDA-initiated DNA oxidation and protected against functional motor impairment for at least 1.5 months after drug treatment. This is the first direct evidence for PHS-catalyzed bioactivation of amphetamines causing temporal and regional differences in CNS oxidative DNA damage directly related to structural and functional neurodegenerative consequences.

3,4-Methylenedioxyamphetamine↗
PubMed2005

Behavioural phenotypes of hypomorphic KCC2-deficient mice.

Hyperpolarizing fast inhibitory neurotransmission by gamma-aminobutyric acid and glycine requires an efficient chloride extrusion mechanism in postsynaptic neurons. A major effector of this task in adult animals is the potassium-chloride co-transporter KCC2 that is selectively and abundantly expressed postsynaptically in most CNS neurons. Yet, the role of KCC2 in adult brain at the systems level is poorly known. Here, we characterize the behaviour of mice doubly heterozygous for KCC2 null and hypomorphic alleles that retain 15-20% of normal KCC2 protein levels in the brain. These hypomorphic KCC2-deficient mice were viable and fertile but weighed 15-20% less than wild-type littermates at 2 weeks old and thereafter. The mice displayed increased anxiety-like behaviour in several tests including elevated plus-maze and were more susceptible to pentylenetetrazole-induced seizures. Moreover, the mice were impaired in water maze learning and showed reduced sensitivity to tactile and noxious thermal stimuli in von Frey hairs, hot plate and tail flick tests. In contrast, the mice showed normal spontaneous locomotor activity in open field and Y-maze tests, and intact motor coordination in rotarod and beam tests. The results suggest that requirements for KCC2-dependent fast hyperpolarizing inhibition may differ among various functional systems of the CNS. As shunting inhibition is expected to be intact in KCC2-deficient neurons, these mice may provide a useful tool to study the specific functions and relative importance of hyperpolarizing fast synaptic inhibition in adult CNS that may have implications for human neuropsychiatric disorders, such as epilepsy, pain and anxiety.

Analysis of Variance↗
PubMedDate not supplied

Developmental lead exposure: behavioral alterations in the short and long term.

Wistar dams were exposed to 500 ppm of Pb, as Pb acetate, or 660 ppm Na acetate in drinking water during pregnancy and lactation. Male pups at 23 (weaned) or 70 days (adult) of age were submitted to behavioral evaluation and Pb determination. The behaviors evaluated were: locomotor activity (open-field test), motor coordination (rotarod test), exploratory behavior (holeboard test), anxiety (elevated plus maze and social interaction tests), and learning and memory (shuttle box). Pb levels were measured in the blood and cerebral regions (hippocampus and striatum) of dams and pups. The results of the present report demonstrated that exposure to Pb during pregnancy and lactation induces in weaned pups hyperactivity, decreased exploratory behavior, and impairment of learning and memory. These alterations were observed at blood Pb levels in the range that may be attained in children chronically exposed to low levels of Pb (21+/-3 microg/dl). Regarding adults, the results demonstrated that the regimen of exposure adopted induces anxiety in these animals at nondetectable blood Pb levels.

Aging↗
PubMed2006

Pain sensitivity in mice lacking the Ca(v)2.1alpha1 subunit of P/Q-type Ca2+ channels.

The role of voltage-gated Ca(2+) (Ca(V)) channels in pain mechanisms has been the object of intense investigation using pharmacological approaches and, more recently, using mutant mouse models lacking the Ca(V)alpha(l) pore-forming subunit of N-, R- and T-type channels. The role of P/Q-type channels in nociception and pain transmission has been investigated by pharmacological approaches but remains to be fully elucidated. To address this issue, we have analyzed pain-related behavioral responses of null mutant mice for the Ca(V)2.1alpha(1) subunit of P/Q-type channels. Homozygous null mutant Ca(V)2.1alpha(1)-/- mice developed dystonia at 10-12 days after birth and did not survive past weaning. Tested at ages where motor deficit was either absent or very mild, Ca(V)2.1alpha(1)-/- mice showed reduced tail withdrawal latencies in the tail-flick test and reduced abdominal writhes in the acetic acid writhing test. Adult heterozygous Ca(V)2.1alpha(1)+/- mice did not show motor deficits in the rotarod and activity cage tests and did not show alterations in pain responses in the tail-flick test and the acetic acid writhing test. Strikingly, they showed a reduced licking response during the second phase of formalin-induced inflammatory pain and a reduced mechanical allodynia in the chronic constriction injury model of neuropathic pain. Our findings show that P/Q-type channels play an antinociceptive role in sensitivity to non-injurious noxious thermal stimuli and a pronociceptive role in inflammatory and neuropathic pain states, pointing to an important role of Ca(V)2.1 channels in central sensitization.

Analysis of Variance↗
PubMed1990

Metabolites of methohexitone do not contribute to its prolonged action on the central nervous system.

Methohexitone has been reported to have a prolonged action on the central nervous system (CNS) despite its relatively short elimination half-life. A hydroxy metabolite of methohexitone was identified, purified and isolated from the urine collected from eight surgical patients and five mongrel dogs anaesthetized with methohexitone. Using a rotarod device, the CNS-activity of the human and canine metabolites was tested in mice and compared to that of methohexitone. In this test, the metabolites showed CNS-depressant activity, but the ED50 (dose needed to affect 50% of the animals) of the metabolites was ten times higher than the ED50 of the parent drug. Because in patients, no traces of the hydroxy metabolite could be found in blood, and in dogs the plasma concentration of the metabolite was about two-thirds of that of the parent compound, it is unlikely that the residual CNS-effects of methohexitone are due to its major metabolite, hydroxymethohexitone.

Animals↗
PubMed1990

General pharmacology of recombinant human tumor necrosis factor. 2nd communication: effects on central nervous system functions.

Effects of recombinant human Tumor Necrosis Factor (rHu-TNF, PT-050) administered s.c. and i.v. on the central nervous system were investigated behaviorally and physiologically in different animal species. With i.v. administration at doses of 10(4) U/kg and less, PT-050 produced no significant changes in most of behavioral and physiological tests, except that a transient increase in rectal temperature in dogs occurred with 0.765 x 10(4) U/kg and acetic acid-induced writhing syndrome in mice was inhibited with 10(4) U/kg. Locomotor activity in mice was inhibited after 3 x 10(4) U/kg. With 10(5) U/kg and more, in addition to the above effects, diverse effects were observed as follows: various symptoms were induced in general behavior in mice such as piloerection, catalepsy, lowering of body position, ptosis and pupil dilatation; rectal temperature was increased in rats and decreased in mice; cortical EEG was synchronized in hippocampal theta waves were disturbed in gallamine-immobilized cats. On the other hand, with s.c. administration, the effect on rectal temperature was seen at 10(4) U/kg in dogs and at 10(5) U/kg in rats. Cortical EEG in conscious rabbits was affected with 10(6) U/kg. At higher dose of 10(7) U/kg. PT-050 (s.c.) further influenced locomotor activity, rectal temperature and acetic acid-induced writhing syndrome in mice. However, even with 10(7) U/kg (s.c.), no effect was found in general behavior, rotarod performance and hexobarbital narcosis in mice. Thus, it is concluded that PT-050 has weaker effects on the central nervous system by s.c. route than by i.v. route. From the present findings and the efficacy of PT-050 as TNF, it is suggested that PT-050, when administered intratumorally, may be useful for cancer therapy without severe side effects.

Analgesics↗