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PubMed1990

Development of tolerance to the CNS effects of aminoglutethimide in mice.

Initially, there is a high incidence of CNS-depressant side-effects when the aromatase inhibitor, aminoglutethimide, is used in the treatment of patients with advanced breast cancer. Tolerance to these effects develops with continued dosing. This study examines the development of tolerance to various indices of CNS depression with the drug in mice. Single doses of aminoglutethimide induced a dose-dependent depression of spontaneous locomotor activity, rotarod performance, righting reflex and body temperature and a dose-related antileptazol activity. On repeated dosing with the drug, tolerance to these various activities occurred. The tolerance was found to be dose-dependent in the rotarod and righting reflex tests and time-dependent in the locomotor and body temperature tests. Although the results do not allow a determination of whether this clearly demonstrated phenomenon in the mouse is primarily functional or dispositional, the slow onset (14 days) for complete tolerance may be indicative of a functional mechanism.

Aminoglutethimide↗
PubMed1991

A revised rotarod procedure for measuring the effect of antinociceptive drugs on motor function in the rat.

Tests of putative antinociceptive agents that rely on a motor response of an experimental animal to a noxious stimulus will give false positive results, and may be unethical, if the agent compromises motor function. We report a procedure for measuring potential effects of antinociceptive agents on motor function in the trained rat, using an 80 mm diameter rotarod. Rats were selected for ability to exercise on the rotarod and trained to increasing speeds. In test trials, we measured the time that trained rats could stay on the rod, rotating at 25 rpm, with a cut off at 60 min. Morphine administration decreased rotarod performance significantly at doses of 5.0 mg/kg (P less than 0.05, n = 10) and 7.5 mg/kg (P less than 0.005, n = 10). We also assessed the response to a noxious thermal stimulus by measuring tail flick latency following tail immersion in water at 49 degrees C. A significant dose-dependent increase in tail flick latency was found for dosages of morphine between 2.5 mg/kg and 7.5 mg/kg (P less than 0.005, n = 10). Our rotarod procedure, which incorporates selection, training, and a 60 min trial, provides a sensitive and consistent means of assessing motor function. Our results, implying that morphine indeed compromises motor function in rats at doses at which it is antinociceptive, confirm the necessity for investigating the motor effects of any putative antinociceptive agent.

Analgesics↗
PubMed2004

Spatial learning/memory and social and nonsocial behaviors in the spontaneously hypertensive, Wistar-Kyoto and Sprague-Dawley rat strains.

The Spontaneously Hypertensive rat (SHR) is often described as less behaviorally reactive than its normotensive strain, the Wistar-Kyoto (WKY), although results are somewhat inconsistent across studies. In part, this may be due to the lack of a definitive characterization of "reactivity." Still, results from identical behavioral tests of SHR and WKY across studies are sometimes conflicting. Further, few comparisons with other rodent strains are available and these might provide guidance in outlining the meaning of reactivity. Here, social and nonsocial behaviors and spatial learning and memory were measured in male and female SHR, WKY, and Sprague-Dawley (SD) rats. Systolic blood pressure measurements at adulthood confirmed hypertension in the SHR. Juvenile play behavior indicated that SHRs were more sensitive to the strain of their play partner than were the WKY or SD, playing less with different strain partners than with same strain partners. However, adult dominance behavior (restricted access in a water competition test) indicated no strain differences. The SHR appeared to exhibit attenuated acoustic startle relative to the WKY and SD and their prepulse inhibition was substantially less at higher prepulse decibel intensities; however, this decreased prepulse inhibition was not the result of decreased startle during the test. Anxiety-related behavior in the elevated plus maze was most prominent in the SD strain, possibly as a result of poorer motor coordination as measured by rotarod performance. Elevated plus maze behavior as well as motor coordination did not differ between the SHR and WKY strains. Performance in the NCTR complex maze and the Morris water maze was significantly better in the SHR. These results do not support hypotheses of decreased behavioral reactivity in the SHR strain. Rather, they suggest complex interactions between social and nonsocial environments and the behavioral capabilities and requirements of the rat strain.

Animals↗
PubMed2001

Evaluation of R6/2 HD transgenic mice for therapeutic studies in Huntington's disease: behavioral testing and impact of diabetes mellitus.

R6/2 transgenic mice express exon 1 of the human Huntington's disease (HD) gene with an increased CAG repeat length. They develop a progressive neurological phenotype, die within 12-14 weeks of age and were also found to develop diabetes mellitus. Since R6/2 mice are broadly used to screen for potential therapies in HD, the aim of this study was (a) to search for behavioral tests that are best applicable to monitor the behavioral abnormalities in therapy studies and (b) to investigate the extent to which diabetes influences the disease phenotype. We found that the rotarod test for motor coordination and the open field test for spontaneous explorative behavior were useful to monitor the progressive behavioral deterioration of R6/2 mice. An accelerating rotarod paradigm was superior over testing with a rotarod at various fixed speeds since it leads to similar results with less repetitive daily trials so that exhaustion cannot contribute substantially to their decline in performance. With the Morris water maze, however, it was only possible to monitor cognitive decline in visuo-spatial learning in the first weeks of disease since, at later stages, mice were not able to learn the task adequately. A latent diabetes mellitus was found in all transgenic mice demonstrated by a pathological glucose tolerance. Only 26% of the mice, however, were found to develop a manifest diabetes with increasing blood glucose levels on normal diet over the disease period. R6/2 mice with manifest and latent diabetes showed no significant differences in survival, weight loss, motor coordination, or spontaneous explorative behavior. These results suggest that diabetes mellitus is not a major contributing factor to the disease phenotype.

Animals↗
PubMed1997

AWD 140-190: a new anticonvulsant with a very good margin of safety.

The anticonvulsant activity of the novel drug AWD 140-190 (4-(p-bromophenyl)-3-morpholino-1H-pyrrole-2-carboxylic acid methyl ester) was evaluated in animal models of epileptic seizures. AWD 140-190 was active at nontoxic doses after oral and intraperitoneal administration in rats and mice in a range of anticonvulsant tests. The compound was active against electrically-induced seizures (MES, ED50 rat p.o. = 2.47 mg/kg), in a genetic animal model the DBA/2 mouse, and in corneally kindled rats. It was not active against seizures induced chemically by pentylenetetrazole, bicuculline and strychnine. Effective doses in mice following both oral and intraperitoneal administration are similar indicating good oral absorption. During 14 days chronic oral treatment of mice with 10 mg/kg, no development of tolerance was observed. The protective indices (TD50/MES ED50) in rats and mice following oral administration are favorable when compared to phenytoin, carbamazepine and valproate. No motor impairment, evaluated with the rotarod test and by observation in the open field test, was observable following oral administration of doses up to 500 mg/kg. There was no influence on spontaneous motility and learning performance in rats and no interaction with ethanol in mice after administration of doses which are above anticonvulsant effective doses indicating the absence of central side effects. AWD 140-190 thus presents an orally active and safe anticonvulsant agent, which is structurally unrelated to anticonvulsants currently used.

Animals↗
PubMed1991

Behavioral and neurochemical studies in diazepam-sensitive and -resistant mice.

Benzodiazepine (BZ) effects include anxiolyis, sedation, seizure protection, and muscle relaxation; the mechanisms underlying these various effects are not understood. We have recently used the rotarod test in conjunction with selective breeding techniques to develop lines of mice which are diazepam-sensitive (DS) and diazepam-resistant (DR). We review the general methods of selective breeding, along with a description of the DS/DR selection study, and then describe a variety of behavioral and neurochemical studies which have been conducted in an attempt to characterize these mice. We have investigated the effects of other sedative drugs believed to interact with the BZ receptor, including ethanol, pentobarbital, and phenobarbital. We have also tested these mice for seizure threshold and open-field activity. DS and DR mice do not differ in diazepam-induced seizure protection, suggesting that different mechanisms underlie rotarod performance and the anti-convulsant effect. These results provide evidence to support the search for nonsedating anti-convulsants. To determine the neurochemical basis for observed differences, BZ receptor density and chloride flux have been measured. We discuss the interaction between behavioral and neurochemical approaches, and describe a conceptual framework to guide future studies with these unique new animals.

Animals↗
PubMed1990

Abecarnil, a metabolically stable, anxioselective beta-carboline acting at benzodiazepine receptors.

Abecarnil (isopropyl 6-benzyloxy-4-methoxymethyl-beta-carboline-3-carboxylate) is a novel ligand for central benzodiazepine (BZ) receptors, possessing anxiolytic and anticonvulsant properties, but with considerably reduced muscle relaxant effects in comparison to diazepam (DZP). In vitro, abecarnil inhibited the binding of the BZ [3H]lormetazepam to rat cerebral cortex membranes with an IC50 value of 0.82 nM in comparison to 56 nM for DZP. The ability of abecarnil to displace [3H]lormetazepam was enhanced 1.24-fold in the presence of 30 microM gamma-aminobutyric acid; the corresponding value for DZP was 2.8-fold. DZP and abecarnil were equally effective in enhancing the binding of t-[35S]butylbicyclophosphorothionate to rat cortical membranes. In vivo, abecarnil exhibited a 3- to 6-fold higher affinity to forebrain BZ receptors than DZP. Abecarnil was from 2 to 10 times more potent than DZP in most rodent tests of anxiolytic activity, and in reducing locomotor activity in mice and rats thoroughly habituated to the test chamber. However, in rats newly exposed to a novel cage, abecarnil was less potent than DZP in reducing locomotor activity. In tests of motor coordination, abecarnil, in contrast to DZP, showed no or only weak activity, and in potentiating the effects of ethanol and hexobarbital on motor performance abecarnil was 4 to 25 times less potent than DZP. Abecarnil antagonized the effects of BZs in the chimney and loss of righting reflex tests, but not in the rotarod test.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1997

Genetic differences in behavioral sensitivity to a neuroactive steroid.

Recent work found that lower endogenous levels of the gamma-aminobutyric acid-agonist, neuroactive steroid 3alpha-hydroxy-5alpha-pregnan-20-one (3alpha,5alpha-THP) may be correlated with increased ethanol withdrawal severity in the selectively bred Withdrawal Seizure-Prone and -Resistant mice. The present studies were conducted to determine whether decreased sensitivity to 3alpha,5alpha-THP was correlated with ethanol withdrawal hyperexcitability in another genetic mouse model, namely the C57BL/6 (B6) and DBA/2 (D2) inbred strains. These strains also differ in ethanol withdrawal severity (D2 >> B6). B6 and D2 male mice were injected with 3alpha,5alpha-THP (0-10 mg/kg i.p.) 15 min before the timed tail vein infusion of pentylenetetrazol. B6 mice were more sensitive than D2 animals to the anticonvulsant effect of 3alpha,5alpha-THP. Subsequent studies measured sensitivity to several of the pharmacological effects of 3alpha,5alpha-THP. B6 and D2 male mice were injected with 3alpha,5alpha-THP (0-32 mg/kg) before testing for locomotor activation (total number of entries) and anxiolysis (percent open arm entries) on the elevated plus maze, muscle relaxation (impairment of forelimb grip strength), ataxia (impairment of Rotarod performance) and seizure susceptibility to pentylenetetrazol. B6 mice were more sensitive than D2 animals to the anxiolytic, locomotor stimulant and anticonvulsant effects of 3alpha,5alpha-THP. In contrast, D2 mice were more sensitive than B6 mice to 3alpha,5alpha-THP-induced muscle relaxation and ataxia. Plasma 3alpha,5alpha-THP levels did not differ in the B6 and D2 mice injected with this steroid, suggesting that the strain differences were not pharmacokinetic. Collectively, the results in selectively bred Withdrawal Seizure-Prone and -Resistant mice and B6 and D2 inbred strains suggest that genetic differences in neuroactive steroid sensitivity and biosynthesis may contribute to ethanol withdrawal severity.

Animals↗
PubMed2005

Neurexophilin 3 is highly localized in cortical and cerebellar regions and is functionally important for sensorimotor gating and motor coordination.

Neurexophilin 3 (Nxph3) is a specific ligand of synaptic alpha-neurexins that are essential for efficient neurotransmitter release. Previous biochemical work demonstrated that Nxph3 interacts with an extracellular domain of alpha-neurexins in a tight complex; however, no information is available on the localization or functional role of Nxph3 in the brain. Here, we generated lacZ reporter gene knock-in mice to investigate the distribution of Nxph3 at the single-cell level and Nxph3 knockout mice to examine its functional importance. Nxph3 expression was restricted mostly to subplate-derived neurons in cortical layer 6b, granule cells in the vestibulocerebellum, and Cajal-Retzius cells during development. Colabeling experiments demonstrated that neurons expressing Nxph3 do not belong to a uniform cell type. Morphological analyses and systematic behavioral testing of knockout mice revealed no anatomical defects but uncovered remarkable functional abnormalities in sensory information processing and motor coordination, evident by increased startle response, reduced prepulse inhibition, and poor rotarod performance. Since Nxph3-deficient mice behaved normally while performing a number of other tasks, our data suggest an important role for Nxph3 as a locally and temporally regulated neuropeptide-like molecule, presumably acting in a complex with alpha-neurexins in select neuronal circuits.

Alleles↗
PubMed1976

Influence of phosphoserine on the performance of rats on the rotarod.

The anti-fatigue effect of phosphoserine, L-serine and a mixture of sodium phosphate and L-serine has been studied in rats. Phosphoserine orally administered induced a statistically significant anti-fatigue effect in rats of both sexes submitted to a training test by rotarod, with 14 sessions in 3 days. Furthermore, phosphoserine was utilized better than the mixture of sodium phosphate and L-serine, whereas L-serine alone induced no effect. Therefore the effect of phosphoserine seems to be due to the phosphoryl bond.

Animals↗
PubMed2000

Effects of prenatal aflatoxin B1 exposure on behaviors of rat offspring.

The effects of prenatal aflatoxin B1 (AFB) exposure on eight behavioral parameters in Jcl:Wistar rat offspring were assessed. Pregnant rats were injected subcutaneously with 0.3 mg/kg/day of AFB dissolved in dimethylsulfoxide on days 11-14 (Group A) or 15-18 (Group B) of gestation. Controls received the vehicle similarly on days 11-18 of gestation. Before weaning, the offspring were examined using the cliff avoidance response (5 days of age), the negative geotaxis reflex (7 days), and swimming development (6, 8, and 10 days). After weaning, animals were examined using the rotarod test (5 weeks of age), the open field test (6 weeks), a conditioned avoidance learning test (14 weeks), an underwater T-maze test (15 weeks), and a reproduction test (16 weeks). The preweaning offspring in the AFB-A group showed significantly lower success rates than controls in cliff avoidance responses. In swimming development, the offspring in the AFB-A group had significantly lower scores than controls for swimming direction. In the rotarod test, the AFB-A group remained on the rod for a significantly shorter time than the controls at 15 rpm on both the first and second trial days. The avoidance performance of the rats in AFB-A and AFB -B groups was significantly poorer than that of controls. These results indicate that prenatal exposure to AFB produced a delay of early response development, impaired locomotor coordination, and impaired learning ability in the offspring of rats exposed to AFB during middle pregnancy, and the early gestational exposure appears to produce more effects than latter exposure.

Aflatoxin B1↗
PubMed1995

Behavioural analysis of changes in nociceptive thresholds produced by remoxipride in sheep and rats.

The antinociceptive potential of remoxipride was investigated in sheep and rats with concurrent motor function assessments. Previous studies of sheep given intravenous remoxipride have revealed increases in mechanical nociceptive thresholds. Here, further investigation in sheep demonstrated elevated thermal nociceptive thresholds with no effect on subjectively assessed sedation or motor impairment scores. However, in rats, the dose of remoxipride (100 mg/kg i.p.) required to produce nociceptive thresholds similar to those elicited by morphine (30 mg/kg i.p.), itself reduced rotarod performance. Medetomidine (200 micrograms/kg i.p.) evoked sedation without influencing rotarod performance or antinociception. The antinociceptive, motor deficit and cataleptogenic actions of remoxipride were similar to those induced by two other dopamine antagonists, haloperidol (5 mg/kg) and raclopride (16 mg/kg i.p). Tocainide (100 mg/kg i.p.) induced thermal antinociception with normal rotarod performance and no catalepsy suggesting that Na+ channel blockade by remoxipride is not responsible for the changes in nociceptive thresholds. This study emphasizes the importance of motor function assessment during acute antinociceptive testing.

Analgesia↗
PubMed2004

Transgenic mice ectopically expressing HOXA5 in the dorsal spinal cord show structural defects of the cervical spinal cord along with sensory and motor defects of the forelimb.

Mutation of murine Hoxa5 has shown that HOXA5 controls lung, gastrointestinal tract and vertebrae development. Hoxa5 is also expressed in the spinal cord, yet no central nervous system phenotype has been described in Hoxa5 knockouts. To identify the role of Hoxa5 in spinal cord development, we developed transgenic mice that express HOXA5 in the dorsal spinal cord in the brachial region. Using HOXA5-specific antibodies, we show this expression pattern is ectopic as the endogenous protein is expressed only in the ventral spinal cord at this anterio-posterior level. This transgenic line (Hoxa5SV2) also displays forelimb-specific motor and sensory defects. Hoxa5SV2 transgenic mice cannot support their body weight in a forelimb hang, and forelimb strength is decreased. However, Rotarod performance was not impaired in Hoxa5SV2 mice. Hoxa5SV2 mice also show a delayed forelimb response to noxious heat, although hindlimb response time was normal. Administration of an analgesic significantly reduced the hang test defect and decreased the transgene effect on forelimb strength, indicating that pain pathways may be affected. The morphology of transgenic cervical (but not lumbar) spinal cord is highly aberrant. Nissl staining indicates superficial laminae of the dorsal horn are severely disrupted. The distribution of cells and axons immunoreactive for substance P, neurokinin-B, and their primary receptors were aberrant only in transgenic cervical spinal cord. Further, we see increased levels of apoptosis in transgenic spinal cord at embryonic day 13.5. Our evidence suggests apoptosis due to HOXA5 misexpression is a major cause of loss of superficial lamina cells in Hoxa5SV2 mice.

Animals↗
PubMed2005

Post-lesion transcommissural olivocerebellar reinnervation improves motor function following unilateral pedunculotomy in the neonatal rat.

In the adult mammalian central nervous system, reinnervation and recovery from trauma are limited. During development, however, post-lesion plasticity may generate alternate paths providing models to investigate reinnervation and repair. Sometimes, these paths are maladaptive, although the relationship between dysfunction and anatomical abnormality remains unknown. After unilateral transection of the neonatal rat olivocerebellar path (pedunculotomy), axons from the remaining inferior olive reinnervate Purkinje cells in the denervated hemicerebellum with appropriate topography and synaptic function. However, whether this new pathway confers beneficial behavioural effects remains unknown. We studied the behavioural sequelae in rats with and without transcommissural reinnervation using righting and vestibular-drop reflexes, simple locomotion (bridge), complex locomotion (wire) and motor coordination (rotarod) tests. In animals pedunculotomised on day 3 (Px3), which develop olivocerebellar reinnervation, dynamic postural adjustments and complex motor skills develop normally, whereas simple gait is broad-based and slightly delayed. In contrast, Px11 animals, which do not develop reinnervation, have delayed maturation of postural reflexes, gait and complex locomotor skills. In addition, when compared to control animals, their performance in locomotory tasks was slower and the complex task impaired. On the rotarod, control and Px3 animals learned to coordinate their gait and walked for longer at 10 and 20 rpm than Px11 animals. These results show that transcommissural olivocerebellar reinnervation is associated with almost normal motor development and the ability to synchronise gait at slow and moderate speeds, i.e. this reinnervation confers significant behavioural function and is therefore truly compensatory.

Age Factors↗
PubMed1991

Dissociation of antinociceptive and motor effects of supraspinal opioid agonists in the rat.

This study compared the antinociceptive and motor effects produced by intracerebroventricular administration of selective mu- (DAMGO) and delta- (DPDPE) opioid receptor agonists in the rat. Changes in nociceptive thresholds were measured using the Randall-Selitto paw-withdrawal test and changes in motor coordination were evaluated using the rotarod treadmill test. Both DAMGO and DPDPE produced statistically significant, dose-dependent increases in mechanical nociceptive thresholds compared to vehicle controls. However, in the motor coordination studies, neither opioid agonist produced statistically significant changes in rotarod performance scores. The dissociation of antinociceptive and motor effects at this supraspinal site differs from the strong association between antinociceptive and motor effects produced by intrathecal administration of the same opioid agonists.

Analgesics↗
PubMed2000

Motor impairment produced by ethanol and site-selective NMDA receptor antagonists in mice: tolerance and cross-tolerance.

Current perspectives on clinical use of N-methyl-D-aspartate (NMDA) receptor antagonists infer acute and repeated administration schedules for management of different pathological states. Development of tolerance and cross-tolerance between different antagonists may significantly affect their clinical effectiveness. Since ethanol was repeatedly demonstrated to act as NMDA receptor antagonist, ethanol use may also have its impact on the effects of NMDA receptor ligands. Using the rotarod test in mice, the present study evaluated development of tolerance and cross-tolerance between ethanol (3.2 g/kg, p.o.), competitive NMDA receptor antagonist, D-CPPene (5.6 mg/kg, i.p.), and low-affinity NMDA receptor channel blocker, memantine (30 mg/kg, i.p.), that were administered for seven days once a day after the daily rotarod training session. Acute tests with ethanol (0.3, 1, 1.7, 3.2 g/kg), D-CPPene (0.3, 1, 3, 5.6 mg/kg) and memantine (1, 3, 10, 30 mg/kg) revealed that (a) each of these drugs dose-dependently disrupted rotarod performance in drug-naive mice; (b) in ethanol- and D-CPPene-treated mice, tolerance was observed to ethanol and D-CPPene but not to memantine; moreover, effects of memantine were even more pronounced in D-CPPene-treated subjects; and (c) repeated memantine administration decreased acute motor impairing effects of ethanol, D-CPPene and memantine. Thus, the history of ethanol use or abuse may influence pharmacological activity of NMDA receptor antagonists and this effect is dependent on type of the NMDA receptor antagonist applied.

Animals↗
PubMed2006

Intranasal administration of IGF-I improves behavior and Purkinje cell pathology in SCA1 mice.

Spinocerebellar ataxia type 1 (SCA1) is a neurodegenerative disease caused by the expansion of polyglutamine repeat within ataxin-1 protein. Cerebellar Purkinje cells are the primary targets of SCA1 pathology. These cells synthesize insulin-like growth factor-I (IGF-I) and express its receptors during their entire life. The aim of present study was to determine if intranasally administered IGF-I to SCA1 transgenic mice suppresses toxic effects of ataxin-1. Two-week old SCA1 heterozygous animals were randomly divided into two treatment groups of IGF-I (30 and 60 microg IGF-I/animal) and a vehicle-treated control group. The wildtype animals served as normal controls. IGF-I or vehicle was administered at 48 h intervals for the total of 10 doses. Animals were then subjected to rotarod test, sacrificed, brains removed and processed for immunohistochemical and Western blot analysis. Radiolabeled IGF-I and bioactive TAT peptide accumulated in the brains of SCA1 mice following intranasal administration validating the use of intranasal route. SCA1 mice showed SCA1 pathology with impaired motor function and downregulation of calcium binding proteins as compared to wildtype mice. However, 30 and 60 microg IGF-I-treated animals showed improved performance on the rotarod as compared to vehicle-treated SCA1 mice with significant improvement (p < 0.05) on day 3 in 60 microg IGF-I group. The immunohistochemical data further showed partial recovery in the expression of calbindin D28k and protein kinase C-gamma in Purkinje cells in IGF-I-treated SCA1 animals. Our results indicate that suppression of ataxin-1-mediated adverse effects by intranasal IGF-I treatment may be of a therapeutic value to treat SCA1.

Administration, Intranasal↗
PubMed1992

Use of the accelerating rotarod for assessment of motor performance decrement induced by potential anticonvulsant compounds in nerve agent poisoning.

The accelerating rotarod was used to assess motor performance decrement in rats after administration of candidate anticonvulsant compounds (acetazolamide, amitriptyline, chlordiazepoxide, diazepam, diazepam-lysine, lorazepam, loprazolam, midazolam, phenobarbital and scopolamine) against nerve agent poisoning. All compounds were tested as the commercially available injectable preparation except for diazepam-lysine and loprazolam, which are not FDA approved. A peak effect time, as well as a dose to decrease performance time by 50% from control (PDD50), was determined. The calculated PDD50 (mumol/kg) values and peak effect times were midazolam, 1.16 at 15 min; loprazolam, 1.17 at 15 min; diazepam-lysine, 4.17 at 30 min; lorazepam, 4.98 at 15 min; diazepam, 5.27 at 15 min; phenobarbital, 101.49 at 45 min; chlordiazepoxide, 159.21 at 30 min; scopolamine, amitriptyline and acetazolamide did not demonstrate a performance decrement at any of the doses tested. The PDD50 values were compared with doses which have been utilized against nerve agent-induced convulsions or published ED50 values from standard anticonvulsant screening tests (maximal electroshock [MES] and subcutaneous pentylenetetrazol [scMET]). The results suggest that at anticonvulsant doses against nerve agents, all the benzodiazepines and phenobarbital have the potential to cause a performance decrement, whereas candidate anticonvulsants of the non-benzodiazepine or non-barbiturate type would not be expected to demonstrate this effect on motor performance. It is concluded that compounds such as acetazolamide, amitriptyline and scopolamine offer alternatives to the highly decrementing benzodiazepines and phenobarbital and should be further tested as anticonvulsant candidates against nerve agent intoxication.

Acetazolamide↗