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PubMed1981

Effect of prenatal phenytoin administration on postnatal development of the rat: a behavioral teratology study.

Adult pregnant Wistar rats were treated with phenytoin (100 Mg/kg) orally from day 7 to 19 of pregnancy, and a control group was pair-fed during the whole treatment period. Within 24 hours after parturition , the offspring were culled to six to eight per litter and reared by fostering or cross-fostering. The physical and behavioral development of the offspring was observe up to 90 days of age. There was a reduced survival of the offspring and a reduction in body weight which persisted to the end of the experiment, though both of these effects could be reduced by cross-fostering. Certain neurological defects were also seen in the prenatal phenytoin group. For example, there was a delay of up to 15 days in the development of the dynamic righting reflex, a decrease in ability of offspring to stay on a rotating rod, and a decrease in ability to walk along elevated parallel rods. There seemed also to be some loss of cliff avoidance. However, there was no change in the development of crawling and walking activities at 9-21 days of age, and no important changes were observed in a head dipping test or in a conditioned avoidance test at 26-34 days. There was a significant decrease in brain weight of the treated group at age 3 days which remained significantly lower than the controls even at 90 days, but no change in the brain/body weight ratio. There was no difference in cerebellar DNA content.

Animals↗

PubMed1988

Methodological proposal in behavioural teratogenicity testing: assessment of propoxyphene, chlorpromazine, and vitamin A as positive controls.

Pregnant Sprague-Dawley rats received either 80 mg/kg d-propoxyphene HCl or 20 mg/kg chlorpromazine HCl or 80,000 and 160,000 IU/kg vitamin A palmitate daily between the 6th and 20th days of gestation. Vehicle control groups were similarly treated with saline or corn oil and considered as negative controls. Offspring were examined for physical landmarks, neuromotor development, and behaviour using righting reflex, swimming, negative geotaxis, open field, rotarod, water maze, and nocturnal activity. This test battery included biochemical measurements. No reduction in parental weight and physical offspring development was observed. All these treatments produced long-term changes in more than one test. Vitamin A palmitate (160,000 IU/kg) was judged as the best positive control with this test battery for future investigation of the behavioural teratology of drugs.

Animals↗

PubMed1997

Haloperidol decreases hyperkinetic paw treading induced by globus pallidus lesions in the rat.

Systemic haloperidol injections decrease the severity of several hyperkinetic syndromes caused by damage to the basal ganglia in humans. A model of hyperkinesia in the rat, exaggerated paw treading triggered by oral sensory stimulation, has been reported previously to result from lesions of the globus pallidus or ventral pallidum/substantia innominata. This hyperkinesia appears as forepaw and forelimb extension and retraction, which can be emitted vigorously and repeatedly for up to minutes at a time. The present study aimed to discover whether this experimental hyperkinesia is pharmacologically similar to human hyperkinetic syndromes: can it be suppressed by neuroleptic administration? Systemic injections of haloperidol (2 mg/kg), diazepam (5 mg/kg, as a sedative comparison), or vehicle were given to rats that expressed the paw treading syndrome after pallidal lesions. Effects on hyperkinetic treading and on tests of sensorimotor function were compared. Results indicated that haloperidol was effective in ameliorating the hyperkinesia in rats with bilateral globus pallidus lesions but not in rats with ventral pallidum/substantia innominata lesions. By contrast, diazepam, which produced sedation and sensorimotor impairment, did not decrease the hyperkinesia induced by either lesion. Although only haloperidol decreased hyperkinetic treading after globus pallidus lesions, haloperidol produced less of a sensorimotor impairment than diazepam on climbing, hanging, and righting reflex tests. These results implicate a specific role for dopamine neurotransmission in the expression of triggered hyperkinetic treading induced by globus pallidus lesions.

Animals↗

PubMed1998

Evaluation of the role of NMDA-mediated excitotoxicity in the selective neuronal loss in experimental Wernicke encephalopathy.

The goal of the studies described was to evaluate the role of NMDA receptor-mediated glutamate excitotoxicity in the pathogenesis of selective neuronal loss due to thiamine deficiency. Administration of the central thiamine antagonist pyrithiamine to adult male rats resulted in a sequence of neurological symptoms including ataxia and loss of righting reflex followed by convulsions. Prior to the onset of convulsions, neuropathologic evaluation revealed significant neuronal loss in the ventral posterior medial thalamic nucleus. However, in vivo cerebral microdialysis at preconvulsive stages did not demonstrate significant increases of extracellular glutamate in this region and pretreatment with the NMDA receptor antagonist MK801 (1 mg/ kg/12 h, i.p.) did not afford significant neuroprotection. Following the onset of convulsions, microdialysate glutamate concentrations were increased fivefold (P > 0.05) and MK801 treatment resulted in significant attenuation of neuronal loss in some thalamic nuclei. A comparable degree of neuroprotection was afforded by pretreatment with an anticonvulsant dose of diazepam (10 mg/kg/12 h, i.p.) a compound whose action is not NMDA receptor mediated. These findings suggest that NMDA receptor-mediated excitotoxicity is not responsible for early selective neuronal loss in this model of thiamine deficiency encephalopathy and that the neuroprotective effect of MK801 at later stages are at least in part a consequence of its anticonvulsant properties.

Animals↗

PubMed1994

A comparison of the acute behavioral effects of alkylbenzenes using a functional observational battery in mice.

The acute neurobehavioral effects of six alkylbenzenes (benzene, toluene, ethylbenzene, propylbenzene, m-xylene, and cumene) were evaluated after 20-min inhalation exposures using a functional observational battery (FOB) in mice. In order to do this, an explicit protocol for the FOB developed for rats by Moser was adapted for use in mice with inhalation exposures. All six alkylbenzenes, in the concentration range of 2000 to 8000 ppm, produced a nearly identical profile of effects, a profile that was also produced by ip administration of the central nervous system depressant drug pentobarbital. These effects included changes in posture, decreased arousal and rearing, increased ease of handling, disturbances of gait, mobility, and righting reflex, decreased forelimb grip strength, increased landing foot splay, and impaired psychomotor coordination. The response to various sensory stimuli was also decreased by the alkylbenzenes and pentobarbital. These acute effects of alkylbenzenes were short-lived, with recovery beginning within minutes of removal from the exposure chamber. The finding that the alkylbenzenes produce a profile of neurobehavioral effects similar to that of pentobarbital is consistent with a growing body of other evidence that many solvents produce a profile of acute effects similar to that of central nervous system depressant drugs and ethanol.

Administration, Inhalation↗

PubMed1997

A comparison of the acute behavioral effects of inhaled amyl, ethyl, and butyl acetate in mice.

The acute neurobehavioral effects of three acetates (amyl, ethyl, and n-butyl acetate) were investigated after 20-min inhalation exposures in mice using locomotor activity and a functional observational battery (FOB). Ethyl and n-butyl acetate produced significant decreases in locomotor activity at the highest concentrations examined, while amyl acetate was without effect. Minimally effective concentrations for activity-decreasing effects were 2000 ppm for ethyl acetate and 8000 ppm for n-butyl acetate. The potency order was similar in the FOB where ethyl acetate was more potent in disrupting the neurobehavioral measures. The FOB profile of effects for all three acetates included changes in posture, decreased arousal, increased tonic/clonic movements, disturbances in gait, delayed righting reflexes, and increased sensorimotor reactivity. Furthermore, handling-induced convulsions were produced in some mice acutely exposed to each of these acetates. Recovery from the acute effects of these acetates was rapid and began within minutes of removal from the exposure chamber. The acetates produced a profile of neurobehavioral effects that were different from those reported for depressant solvents (i.e., toluene, 1,1,1-trichloroethane) that are subject to abuse. Evidence is emerging for qualitative differences in the acute neurobehavioral effects of various volatile chemicals.

Acetates↗

PubMed1993

Genetic mapping and evaluation of candidate genes for spasmodic, a neurological mouse mutation with abnormal startle response.

Spasmodic (spd) is a recessive mouse mutation characterized by a prolonged righting reflex, fine motor tremor, leg clasping, and stiffness. Using an intersubspecific backcross that segregates spd, we placed spd on Chr 11 with the following gene order: Adra-1-3.8 +/- 2.1 cM-Pad-1-6.3 +/- 2.7-(spd, Anx-6, Csfgm, Glr-1, Il-3, Il-4, Il-5, Sparc)-9.1 +/- 2.4-D11 Mit5-2.2 +/- 1.5-Asgr-1. This localization eliminated the alpha 1-adrenergic receptor (Adra-1) and the alpha 1 and gamma 2 subunits of the GABAA receptor as candidate genes. Two other promising candidate genes, annexin VI (Anx-6) and a glutamate receptor (Glr-1), were mapped to within 2.1 cM of the spd locus. Although no recombination was observed between spd and Anx-6 or Glr-1, no evidence was obtained for a lesion in either gene. The presence of normal Anx-6 and Glr-1 mRNA transcripts was confirmed by Northern blot analysis, in situ hybridization, and DNA sequence analysis. The localization of Anx-6 and Glr-1 extends the known synteny homology between human chromosome 5q21-q31 and mouse Chr 11 and reveals the probable chromosomal location of the human counterpart to spd. Synteny homology and phenotypic similarities suggest that spasmodic mice may be a genetic model for the inherited human startle disease, hyperekplexia (STHE).

Alternative Splicing↗

PubMed1997

Intracerebroventricular infusion of the NMDA receptor-associated glycine site antagonist 7-chlorokynurenate impairs water maze performance but fails to block hippocampal long-term potentiation in vivo.

Most previous studies investigating the relationship between N-methyl-D-aspartate receptor-dependent synaptic plasticity and learning have employed drugs that either compete with glutamate for access to the primary agonist binding site (e.g., D-2-amino-5-phosphopentanoic acid) or block the associated ion channel (e.g., dizocilpine). This study targeted the glycine receptor site located on the NMDA receptor complex. Chronic intracerebroventricular infusion of the glycine site antagonist 7-chlorokynurenate (7CK; 75 mM, 0.5 microliter/h, icv, for up to 14 days) impaired performance of male Lister hooded rats during acquisition of a spatial reference memory task in the water maze. In addition, however, these animals showed sensorimotor deficits, including a prolonged righting reflex, ataxia, and difficulty in staying on the escape platform. On completion of behavioral testing, the rats were anesthetized with urethane and an attempt was made to induce LTP in the hippocampus ipsilateral to the infusion cannula. Both control and 7CK-infused animals displayed equivalent long-term potentiation (LTP) 60 min posttetanus. A novel analytical technique for assaying drug tissue levels involving high-performance liquid chromotography with fluorescence detection revealed that tissue levels of 7CK in hippocampus were extremely low and unlikely to be sufficient to affect LTP, as observed. These findings neither support nor compromise the LTP/learning hypothesis, but they illustrate some of the problems of using drugs to elucidate the neurobiological mechanisms of learning and memory and the importance of a within-subjects design incorporating behavioral, physiological, and biochemical measures.

Animals↗

PubMed1996

Neurotoxicity of misonidazole in rats following intravenous administration.

Misonidazole is a hypoxic cell radiosensitizer that induces a peripheral neuropathy in humans after exceeding a schedule-dependent cumulative threshold dose. Clinical studies of misonidazole have been conducted using oral administration, whereas most other radiosensitizers have been administered intravenously. Since route of exposure can potentially influence the toxicity of xenobiotics, the objective of this study was to assess the neurotoxicity of misonidazole in rats following intravenous dosing using a battery of routine clinical, neurofunctional, biochemical, and histopathologic screening methods. Male Sprague-Dawley rats were administered intravenous doses of misonidazole at 0 (vehicle control), 100, 200, 300, or 400 mg kg-1 once per day, 5 days per week, for 2 weeks. Animals were evaluated for neurofunctional and pathological changes following termination of treatment (Days 15-17) and at the end of a 4 week observation period (Days 43-45). During the dosing phase, hypoactivity, salivation, rhinorrhea, chromodacryorrhea, rough pelage and ataxia were observed at 400 mg kg-1, and body weight gain of the 300 and 400 mg kg-1 groups was significantly decreased relative to the vehicle controls by 24% and 49%, respectively. Corresponding reductions in food consumption were 8% and 23%, respectively. Although most 400 mg kg-1 animals appeared normal on Day 15 prior to the neurofunctional evaluations, rotorod testing precipitated a number of clinical signs including: ataxia, impaired righting reflex, excessive rearing, tremors, vocalization, circling, head jerking, excessive sniffing and hyperactivity. All of these animals recovered and appeared normal from Day 17 through study termination. There were no treatment-related effects on motor activity, acoustic startle response, rotorod performance, forelimb group strength, toe and tail pinch reflexes, tibial nerve beta-glucuronidase activity or tail nerve conduction velocity. Although hindlimb grip strength of the 400 mg kg-1 group was significantly decreased by 17% relative to the vehicle controls on Day 15, this finding appeared related to the reduced food consumption and body weight gain in these animals. No microscopic changes were detected in peripheral nerves. Necrosis and proliferation of fibrillary astrocytes (gliosis) were seen in the cerebellum and medulla of the 400 mg kg-1 animals on Day 16. Gliosis in these same brain regions was observed in the 300 and 400 mg kg-1 groups on Day 44. The results show that intravenous administration of misonidazole to rats causes dose-limiting central nervous system toxicity without effects on peripheral nervous tissue. The lack of peripheral neurotoxicity was most likely due to a combination of several interrelated factors including route of administration, duration and intensity of the dosing regimen, and total cumulative dose.

Animals↗

PubMed1997

The effect of 7-nitro indazole on pentobarbital-induced sleep in mice.

The sleep-wakefulness continuity is sensitive to a wide range of agents with pharmacological activity. There is some strong evidence about the role of nitric oxide (NO) as an intercellular messenger in the central physiological mechanisms. The effects of 7-nitro indazole (7-NI 15, 30, 60 mg kg-1; intraperitoneal, i.p.), a selective inhibitor of neuronal nitric oxide synthase (NOS) and L-arginine (500, 1000 mg kg-1, i.p.), a NO precursor, on pentobarbital (35 mg kg-1, i.p.) sleep were examined in mice. Loss of the righting reflex was used to determine the start of sleep. Sleep latency and sleeping time were evaluated in each experiment. 7-Nitro indazole (7-NI 30 mg kg-1; i.p.), had no apparent effect on sleep latency but significantly increased sleeping time (P < 0.02) on pentobarbital sleep in mice. L-Arginine had no effect on both parameters. These findings suggest that NO might be an important modulator of sleep regulation and implicate that inhibition of release and/or synthesis of NO might lead to changes in the maintenance of sleep.

Animals↗

PubMed2000

N-Methyl-D-aspartic acid- and metaphit-induced audiogenic seizures in rat model of seizures.

The effects of NMDA (N-methyl-D-aspartic acid) on metaphit (1-[1(3-isothiocyanatophenyl)-cyclohexyl]piperidine)-induced audiogenic seizures in adult male Wistar albino rats were studied with the aim of developing a suitable animal model of seizures. The animals were divided into four experimental groups: 1, saline control; 2, metaphit-injected; 3, metaphit + NMDA administered and 4, NMDA-treated. Upon the treatment, the rats were exposed to sound stimulation (100 +/- 3 dB, for 60 s) at hourly intervals and the incidence and severity (running, clonus and tonus) of seizures were analysed. In group 3, only the animals which did not exhibit any metaphit-induced audiogenic seizures over 8 h were given a subconvulsive NMDA dose after the eighth audiogenic testing. For EEG recordings, three gold-plated screws were implanted into the rat skull. In most animals, metaphit led to EEG abnormalities and elicited epileptiform activity recorded as spikes, polyspikes and spike-wave complexes. Maximum incidence and severity of metaphit-induced convulsions occurred 8 h after injection (incidence 9/12), abating gradually until disappearing 30 h later. NMDA alone provoked no seizure response but the initial signs characterized by isolated spike activity evolving into sporadic slow-wave complexes, thus representing a proconvulsive brain state, were observed. This compound led to stereotyped behaviour seen as asymmetric posture, loss of righting reflex and tonic hind limb extension lasting for 60-90 min. It also potentiated metaphit-induced audiogenic seizures. Potentiation of metaphit-related audiogenic seizures by NMDA was recorded in three out of 17 rats that had never displayed seizures in eight previous testings, with a maximum incidence of eight out of 17 animals, 13-14 h after metaphit administration and seizures lasted for 10 h.

Animals↗

PubMed1997

Longitudinal studies on the interaction of perfluorochemicals with liver cytochromes P-450 by means of testing the rate of detoxification of pentobarbital.

Four perfluorochemicals, Bis-[F-butyl]ethene, perfluorocyclohexylmorpholine, perfluorodecalin and perfluorooctylbromide were compared by their influence on the liver cytochrome P-450 system, measuring the pentobarbital sleeping time as defined by the time of loss of the righting reflex in rats. In all experiments first a prolongation of barbital detoxification was observed, which lasted at least 2-4 days. Thereafter a very long extended period of abbreviated sleeping time followed which was only missed after perfluoroctylbromide. Thus substrate competition, uncoupling of monooxygenation and enzyme induction determine the detoxifying processes in the liver that follow the administration of perfluorochemicals.

Animals↗

PubMed1980

Reversal of tolerance to ethanol associated with the induction of physical dependence on ethanol in the rat.

Three experimental paradigms were employed to investigate the possible relationship between tolerance to and dependence on ethanol in the rat. Groups of rats were exposed to ethanol vapor at various concentrations for different periods of time (e.g., 10 mg/l ethanol vapor for 10 days; 15 mg/l for 0.5 to 10 days; 20 mg/l for up to 12 hours). Tolerance was tested by measuring the concentration of ethanol in the breath at loss of righting reflex of the animal and the withdrawal syndrome was assessed behaviorally. Tolerance developed rapidly and was observed to reverse in association with the development of physical dependence.

Alcoholism↗

PubMed1980

Behavioural tests in peri- and post-natal toxicity study in rats of trithiozine (Tresanil) [4-(3,4,5-trimethoxythiobenzoyl)-tetrahydro-1,4-oxazine].

During the biological research on trithiozine [4-(3,4,5-trimethoxythiobenzoyl)-tetrahydro-1,4-oxazine], a substance with gastric antisecretory action, a study on peri- and post-natal toxicity was conducted in rats, during which an attempt was made to set up a series of tests which would consist of the study of the behaviour of offspring in their first 21 days of life. To confirm the validity of these tests, a parallel peri- and post-natal toxicity study was carried out with two compounds phenobarbital and diazepam, known to be active on the CNS and likewise known to pass from plasma into milk. The three compounds in question were administered by the oral route to pregnant rats from the 15th day of pregnancy to the 20th day after delivery in the following dosages; trithiozine: 100-200-500 mg/kg/day, phenobarbital: 60-100 mg/kg/day, diazepam: 30-60 mg/kg/day. The offspring were submitted, between their 14th and 20th day of life to the cheminée test, traction test, righting reflex test and avoidance test. The cheminée and avoidance tests proved to be the most suitable for studying neonatal behaviour. The percentage of success in these two tests decreased in a statistically significant manner for the groups treated with phenobarbital and diazepam, while trithiozine did not produce any variations in neonatal behaviour.

Animals↗

PubMed1984

Behavioural and electrocortical spectrum power changes after intraventricular injection of patulin in rats.

The effects of patulin when given into the third cerebral ventricle of rats, on behaviour and electrocortical spectrum power have been investigated. Patulin (10 micrograms i.v.t.) produced behavioural sedation, hypoalgesia, tail rigidity, piloerection and postural changes. This symptomatology lasted approx. 3 h and was accompanied by slower frequency and larger amplitude potentials in the electrocorticogram (ECoG) and by an increase in total voltage power. A larger dose (50 micrograms) produced a more dramatic picture characterized by catatonic posture with kyphosis, loss of the righting reflex, tail rigidity and on a few occasions short-duration episodes of tonic-clonic convulsions. Such a symptomatology was accompanied by a flattening of ECoG activity with a significant fall in total voltage power, as well as in preselected bands (0-3, 3-6, 6-9, 9-12, and 12-16 Hz). A lower dose (1 microgram) of patulin, on the other hand, produced behavioural sedation without significant changes in ECoG spectrum power.

Animals↗

PubMed1986

Effects of diazepam, tofizopam or phenytoin during foetal development on subsequent behaviour and benzodiazepine receptor characteristics in rats.

The development of rats was studied for 3 postnatal weeks after prenatal medication with diazepam (10 mg/kg/day), phenytoin (50 mg/kg/day), or tofizopam (50 mg/kg twice daily) given by gastric intubation from day 7 to 21 of pregnancy. The treatments had no effect on the litter size. There were also no differences between the groups in a battery of tests for development (negative geotaxis, righting reflex, cliff avoidance, rotarod, passive avoidance), but the activity spurt seen at postnatal days 18-21 was missing in pups of diazepam-treated mothers. The number of benzodiazepine receptors and their affinity for tritiated flunitrazepam developed similarly in all of the rat groups. Thus, the transient changes in motor development seen 2-3 weeks after birth of rats whose mothers received diazepam during pregnancy do not seem to be related to changes in ontogenesis of benzodiazepine receptors.

Animals↗

PubMed1992

Multi-compartment model to study the effect of air-blood and blood-tissue partition coefficients on concentration-time-effect relationships.

The influence of the air-blood (lambda) and blood-tissue partition coefficients of substances on the concentration-time-effect relationship E = [aCnT]b was studied by model simulation of uptake and distribution of gases. The model consisted of a lung compartment and four tissue compartments. Rat and human model parameters were obtained from physiological data, and substance-dependent variables. The observable effect E (righting reflex, mortality, etc.) for directly acting systemic agents was supposed to be related to the (arbitrarily chosen) concentration of the substance in the arterial blood or in the liver compartment. We conclude that for a directly acting systemic agent n greater than or equal to 1. If n less than 1 other mechanisms such as metabolism must be incorporated in the model which, however, should not be excluded when n greater than or equal to 1. If the observable effect is related to arterial concentration of the substance, n increases with decreasing lambda. If the liver concentration is related to the observable effect, man and rat may behave quite differently. This has major consequences for the extrapolation of animal results to the human situation in risk assessment.

Air↗

PubMed1992

Pentylenetetrazol-induced seizures in rats: an ontogenetic study.

A quantitative description of motor seizures induced by pentylenetetrazol (PTZ, metrazol) was performed. Seizures were induced by PTZ in doses from 40 to 120 mg/kg s.c. in 477 male albino rats of the Wistar strain 7 to 90 days old. Two patterns of seizures were elicited: minimal, i.e. predominantly clonic seizures of facial and forelimb muscles with preserved righting ability, and major, i.e. generalized tonic-clonic seizures with a loss of righting reflex. Minimal seizures could be reliably elicited since the age of 18 days; the CD50 for these seizures did not significantly differ with age. Major seizures were elicited regularly at all developmental stages studied. Their CD50 did not significantly differ among 7-, 12- and 25-day-old rat pups but the value for 18-day-old rats was smaller and for adult animals larger than these three age groups.

Aging↗