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PubMed2005

The analgesic effect of low dose focal irradiation in a mouse model of bone cancer is associated with spinal changes in neuro-mediators of nociception.

Despite the widespread use of radiotherapy to treat painful bone metastases, the mechanism underlying the analgesic effect of low dose ionizing radiation is unknown. Bone cancer pain is mostly associated with an inflammatory response dominated by local activation of osteoclasts and by astrogliosis in the spinal cord. We determined the effects of a 6 Gy irradiation given focally on osteolytic sarcoma cells inoculated in humeri of mice. Pain behavior was assessed using the rota-rod and the grip force test. Seven days post-irradiation (day 17 post-tumor implantation) the performance of mice markedly improved on the rotarod (non-irradiated, 67+/-16s vs irradiated, 223 +/- 22 s; P = 0.0005), and the grip force test (non-irradiated, 34 +/- 4 g vs irradiated, 55 +/- 2 g; P = 0.001). This improvement was similar to the analgesia achieved with 30 mg/kg of the cyclooxygenase (COX) inhibitor ketorolac (Rota-rod, 67 +/- 16 s vs 178 +/- 35 s; P = 0.01: grip force test, 34 +/- 4 g, vs 60 +/- 5 g; P = 0.003). Following irradiation, the tumor mass and the number of osteoclasts did not decrease while the expression of two pro-inflammatory cytokines (monocyte chemoattractant protein (MCP)-1 and tumor necrosis factor (TNF)-alpha) increased. Tumor irradiation led to clear differences in the spinal cord. These include a decrease in glial activity (astrocytes and microglial cells) as well as pain mediators such as dynorphin, COX-2 and chemotactic cytokine receptor (CCR2). We conclude that the analgesic effect of low dose irradiation of bone cancer is associated with the alteration of nociceptive transmission in the central nervous system.

Analgesia↗
PubMed1997

Drug-free evaluation of rat models of parkinsonism and nigral grafts using a new automated rotarod test.

A variety of tests are available for the evaluation of behavioural deficits in rat models of hemiparkinsonism; many, however, are of limited applicability or insufficiently objective. The drug-induced turning behaviour test is widely used. A disadvantage of this test is that the use of drugs may lead to misleading results. Here, we describe a drug-free rotarod test that was used to evaluate the effects of unilateral 6-hydroxydopamine lesions, nigral grafts, and subrotational doses of apomorphine. The rotarod unit was automated and interfaced to a personal computer allowing automatic recording of the time that each rat was able to stay on the rod at different rotational speeds (i.e., progressively increasing the difficulty of the task). A combination of lesion-induced deficits resembling those of Parkinson's disease appears to be involved in falling from the rod. The test shows high effectiveness for identifying rats with maximal dopaminergic lesions, but is also effective for identifying partial lesions. Rotarod performance profiles were useful for investigating the effects of intrastriatal nigral grafts, since low rotation speeds revealed differences from lesioned rats (i.e., improvements) while higher speeds revealed differences from normal rats (i.e., remaining deficits and partial lesions). The test was effective regardless of whether rats were trained on the rod before lesion, after lesion, or after grafting. Injections of apomorphine (0.0125 and 0.0250 mg/kg) did not induce consistent improvements. These results indicate that the rotarod test is a useful drug-free procedure for overall evaluation of basic motor abilities in rat models of parkinsonism and treatment-induced changes.

Amphetamine↗
PubMed2001

Therapeutic benefit of intravenous administration of bone marrow stromal cells after cerebral ischemia in rats.

BACKGROUND AND PURPOSE: We tested the hypothesis that intravenous infusion of bone marrow derived-marrow stromal cells (MSCs) enter the brain and reduce neurological functional deficits after stroke in rats. METHODS: Rats (n=32) were subjected to 2 hours of middle cerebral artery occlusion (MCAO). Test groups consisted of MCAO alone (group 1, n=6); intravenous infusion of 1x10(6) MSCs at 24 hours after MCAO (group 2, n=6); or infusion of 3x10(6) MSCs (group 3, n=7). Rats in groups 1 to 3 were euthanized at 14 days after MCAO. Group 4 consisted of MCAO alone (n=6) and group 5, intravenous infusion of 3x10(6) MSCs at 7 days after MCAO (n=7). Rats in groups 4 and 5 were euthanized at 35 days after MCAO. For cellular identification, MSCs were prelabeled with bromodeoxyuridine. Behavioral tests (rotarod, adhesive-removal, and modified Neurological Severity Score [NSS]) were performed before and at 1, 7, 14, 21, 28, and 35 days after MCAO. Immunohistochemistry was used to identify MSCs or cells derived from MSCs in brain and other organs. RESULTS Significant recovery of somatosensory behavior and Neurological Severity Score (P<0.05) were found in animals infused with 3x10(6) MSCs at 1 day or 7 days compared with control animals. MSCs survive and are localized to the ipsilateral ischemic hemisphere, and a few cells express protein marker phenotypic neural cells. CONCLUSIONS: MSCs delivered to ischemic brain tissue through an intravenous route provide therapeutic benefit after stroke. MSCs may provide a powerful autoplastic therapy for stroke.

Animals↗
PubMed2006

Long-term behavioral consequences of soman poisoning in mice.

We investigated the long-term (up to 90 days) consequences of soman intoxication in mice on weight, motor performances (grip strength, rotarod) and mnemonic cognitive processes (T-maze, Morris water maze test). First, a relative weight loss of 20%, measured 3 days after intoxication, was evidenced as a threshold beyond which neuropathological damage was observed in the hippocampus. Animals were then distributed into either low weight loss (LWL) or high weight loss (HWL) groups according to the relative 20% weight loss threshold. Compared to controls, both groups of poisoned mice quickly exhibited a decrease in their motor performance subsequent to an acute soman toxicity phase. Then, total motor recovery occurred for the LWL group. Comparatively, HWL mice showed only transient recovery prior to a second decrease phase due to soman-induced delayed toxicity. One month after intoxication, mnemonic cognitive performances of the LWL group were similar to controls while the HWL group did not exhibit any learning skill. Three months after poisoning, compared to controls, the LWL group showed similar mnemonic performances in the maze test but a mild deficit in the Morris water maze task. At the same time, learning skills slightly recovered in the HWL group. Mnemonic cognitive data are discussed in relation to the neuropathology, neurogenesis and sprouting occurring in the hippocampus of soman-intoxicated animals.

Animals↗
PubMed1997

An automated rotarod method for quantitative drug-free evaluation of overall motor deficits in rat models of parkinsonism.

A variety of tests have been proposed for evaluation of motor deficits in rat models of hemiparkinsonism. The most widely used test, the "rotational behaviour" test, is based upon motor asymmetry induced by drug administration, leading to problems of sensitization, conditioning and priming. In addition, lesion-induced rotational behaviour is sometimes overcompensated by treatments (grafts) while other deficits are unaffected. However, rotational behaviour is reproducible and easy to quantify. On the contrary, most drug-free tests have proved of limited applicability because of subjective scaling, excessive interaction between the experimenter and animals, motivational effects, excessively complex tasks, etc., making it difficult to compare results from different laboratories. In this paper, we present a rotarod based method for automated drug-free evaluation of overall motor deficits in the rat model of hemiparkinsonism, and for identifying treatment-induced changes. Animals are pre-trained on the rotarod and then tested at a series of increasing rod speeds; from this set of values a unique score for each animal is computed (the overall rotarod performance, ORP) summarizing its performance at different speeds. This value is easy to compute and greatly simplifies statistical comparisons. Major advantages of the test are: (i) it does not require drugs, but is nevertheless highly objective, reproducible and easy to quantify; and (ii) falling of animals from rotating rod seems to depend on a combination of lesion-induced deficits which become more evident when rats are forced to move at faster speeds. Since the test is not based exclusively on motor asymmetry, it may also be useful for characterization of bilaterally lesioned animals, for which drug-induced rotational behaviour tests cannot be used.

Animals↗
PubMed1983

Relationship of the biodisposition of the stereoisomers of nicotine in the central nervous system to their pharmacological actions.

The stereoisomers of nicotine were evaluated for their effectiveness in producing antinociception and altering spontaneous activity and Rotarod performance in rats. (-)-Nicotine was found to be 6, 15 and 30 times more active than its unnatural enantiomer, (+)-nicotine, in the spontaneous activity, Rotarod and antinociceptive tests, respectively. Biodispositional studies revealed that the time course (-)-[3H]nicotine closely paralleled the time course of effects on spontaneous activity and Rotarod performance but not antinociception, which suggested that multiple mechanisms were involved in the actions of nicotine. In addition, the distribution studies showed the brain and plasma levels of (-)-[3H]nicotine were higher than those of (+)-[3H] nicotine, which indicate that the pharmacological stereoselectivity of nicotine is less than originally determined. Finally, the greatest difference in the regional localization in brain of the stereoisomers was found in cerebral cortex, hippocampus and corpus striatum.

Analgesia↗
PubMed1984

The role of congeners in the effects of different alcoholic beverages.

Five different alcoholic beverages were tested in rats to determine if congener content contributed to the hypothermia or motor impairment produced by the beverages. Solutions of cognac, scotch, tequila, vodka, and commercially supplied ethanol were diluted with physiological saline to form solutions containing 16% w/v ethanol, as verified by gas chromatographic analysis. All beverages were administered in doses containing 0 (saline), 1.6, 3.2, 4.8, or 6.4 g/kg ethanol (gastric intubation) in test sessions separated by 7 days (repeated measures design, N = 8 rats per group). Measurements of rectal temperature and motor impairment (rotarod performance) made at 0, 60, and 120 minutes postinjection revealed no noteworthy differences in either measure at 60 or 120 minutes postinjection at any of the 4 doses tested. Thus, no evidence for a contribution of congeners to beverage effects was observed.

Alcoholic Beverages↗
PubMed2001

Removing zinc from synaptic vesicles does not impair spatial learning, memory, or sensorimotor functions in the mouse.

Zinc-enriched (ZEN) neurons are distributed widely throughout the brain and spinal cord. Synaptic vesicle zinc in these neurons is thought to function as a neuromodulator upon its release into the synaptic cleft. Consistent with this possibility, zinc or zinc chelators can alter spatial learning, working memory, and nociception in rodents. Here we use zinc transporter-3 (ZnT3) knockout mice, which are depleted of synaptic vesicle zinc, to assess the consequences of removing this potential neuromodulator on the behavior of adult mice. ZnT3 knockout mice performed equally as well as wild-type mice in the rotarod, pole, and cagetop tests of motor coordination. They exhibited normal thermal nociception in the hot-plate and tail-flick tests, and had similar olfactory, auditory and sensorimotor gating capabilities as wild-type mice. ZnT3 knockout mice behaved similarly as wild-type mice in the open field test and in the elevated plus maze test of anxiety. They exhibited normal learning and memory in the passive avoidance, Morris water maze, and fear conditioning tasks, and normal working and reference memory in a water version of the radial arm maze. We conclude that synaptic vesicle zinc is not essential for mice to be able to perform these tasks, despite the abundance of ZEN neurons in the relevant regions of the CNS. Either the neuromodulatory effects of zinc are not relevant for the tasks tested here, or mice are able to compensate easily for the absence of synaptic vesicle zinc.

Animals↗
PubMed2004

The heterozygous reeler mouse: behavioural phenotype.

The aim of this study was to investigate whether heterozygous reeler mice (+/rl) could be used as a genetic mouse model of schizophrenia, as previously suggested [J. Med. Chem. 44 (2001) 477]. The behavioural phenotype of male and female +/rl mice (young adult: 50-70 days old, and fully adult: >75 days old) was compared to their wild type (+/+) littermates. A complex behavioural test battery was employed: Irwin test, rotarod, spontaneous locomotor activity, social behaviour, light-dark transition test, startle response and prepulse inhibition, and hot-plate test. Overall, +/rl mice did not differ from their +/+ littermates at either age, although fully adult +/rl male mice spent more time engaged in social investigation. Some of the behavioural measures investigated were influenced by gender. Young female mice were more active in the light/dark transition test than males, while males were more aggressive than females during social interaction. In addition, performance on the rotarod was shown to deteriorate with age. Our data are in agreement with previous findings [Soc. Neurosci. Abst. 27 (2001) 238; J. Psychopharmacol. 17 (2003) A43], but contrary to those of Costa et al. [Curr. Opin. Pharmacol. 2 (2002) 56], although mice used in the present and previous studies were derived from the same genetic stock at Jackson Laboratories, USA. The present study clearly shows that, compared to its +/+ littermates, the +/rl mouse (young/fully adult) exhibits normal behaviour in a wide range of behavioural measures and suggest that these mice may not be suitable for use as a genetic animal model of schizophrenia.

Acoustic Stimulation↗
PubMed2001

Assessment of sensorimotor and cognitive deficits induced by a moderate traumatic injury in the right parietal cortex of the rat.

The purpose of this study was to set-up a battery of behavioral tests to assess sensorimotor and cognitive deficits following a moderate traumatic brain injury (TBI) in rats. Coordinated walking ability was evaluated in an accelerated rotarod test. Vestibulomotor function and fine motor coordination were assessed by using a beam-walking task. Rotarod and beam-walking performances were both altered in injured rats compared to sham-operated and control rats. A more pronounced and longer-lasting deficit was measured in the beam-walking test. Cognitive function was studied by using the Lashley maze paradigm. A spatial localization deficit was significant for 4 weeks posttrauma in TBI rats. The beam-walking task and the Lashley maze are robust and sensitive methods in detecting sensorimotor and cognitive impairment after TBI in rats, respectively. These tests are proposed for evaluating the ability of new pharmacological agents to improve the functional recovery after a TBI in rats.

Animals↗
PubMed1984

Changes in motor activity with age and the effects of pharmacologic treatment.

In a previous study the decline in the motor performance of old rats was determined to be differential. In this study, whether, and to what extent, this decline can be pharmacologically influenced was tested. Therefore, 27 month old rats were orally treated with several nootropics and d-amphetamine for six weeks. Food and water intake were determined. The rats were tested on spontaneous activity and on the tilting plane, climbing, and rotarod tests. The results showed that the nootropics only effected pronounced improvements on complex motor tasks such as on the rotarod test. In contrast, amphetamine treatment caused rather negative effects. This could be observed in the motor performance as well as in the food and water intake. Young rats did not have this sort of reaction to amphetamine. The nootropics were all well tolerated. Additionally, it was obvious that the untreated rats also showed a slight improvement in motor performance due to repeated practice.

Aging↗
PubMed1992

Comparative studies on the neuro- and reproductive toxicity of acrylamide and its epoxide metabolite glycidamide in the rat.

The neurotoxicity of acrylamide (AA) has been the subject of extensive studies at the morphological and functional levels in both animals and man. The concern for human exposure to monomeric AA derives partly from its extensive use in molecular biology laboratories where, in the United States alone, 100,000-200,000 persons are potentially exposed. Initial work in this laboratory aiming at the development of techniques for using hemoglobin adducts as biomarkers for human exposure to AA, revealed the formation of glycidamide as a reactive epoxide metabolite of acrylamide in the rat (Chem. Res. Toxicol. 3, 406, 1990). In rats treated with 0-100 mg/kg of AA significant dose-rate effects were observed on adduct formation by both AA and glycidamide. The high rate of formation of the metabolite, especially at low doses where approximately 60% of AA was converted to glycidamide in vivo, prompted us to investigate its potential role in the induction of neurotoxic and reproductive effects attributed to AA exposure. In initial neurotoxicological experiments, the effects of the parent compound (8-14 days, 25 and 50 mg/kg/day) and the metabolite (8-14 days, 50 and 100 mg/kg/day) were compared. While at the higher dose both compounds affected the rats' performance on the rotarod, only acrylamide had a significant effect in the hindlimb splay test, which is considered a more sensitive indicator of peripheral neuropathy. On the other hand, a stronger effect was seen for glycidamide than for AA on the male reproductive system, especially on sperm cell viability.(ABSTRACT TRUNCATED AT 250 WORDS)

Acrylamide↗
PubMed2001

The use of behavioral test batteries: effects of training history.

Our laboratory uses a specific test battery for the initial assessment of phenotypic behavioral differences of transgenic, knockout, and inbred strains of mice. Our standard battery includes: open field activity, light-dark exploration, rotarod, prepulse inhibition (PPI), acoustic startle habituation, conditioned fear, Morris water maze, and hot plate. Tests are run in the order listed, from least invasive to most invasive, to decrease the chance that behavioral responses are altered by prior test history. The studies presented here were designed around two questions. The first study asks if differences exist between mice that have undergone testing on different tasks and mice that are naïve to the test experience. The second study asks if the test order affects how an animal performs on subsequent tests. In the first experiment, C57BL/6J male mice were evaluated on all of the tests described above. The behavior of these 'test battery' mice was compared to aged matched naïve mice that were only tested on one test from the battery. Results indicate that on some tests, the behavior of 'test battery' mice was significantly different from the behavior of naïve mice, while on other tests there were no differences. For example, test battery mice responded differently in the open-field, rotarod, and hot-plate test, but behaved similar on the PPI and conditioned fear. Experiments in the second study were performed on male 129/SvEvTac (129S6) and C57BL/6J male mice. An abbreviated battery of tasks was used and the results suggest that certain test variables are sensitive to test order, whereas others are resistant. These two studies demonstrate that some behavioral tests appear to be sensitive to previous testing experience, while other tests are immune.

Animals↗
PubMed2004

Neuronal MEK is important for normal fear conditioning in mice.

The extracellular signal-regulated kinase (ERK) cascade has received much attention for its possible role in neuronal synaptic plasticity. Although ERK activation has been linked to learning behaviors and activity-dependent neuronal function, much of the acquired data has relied upon pharmacological agents that suppress ERK function in both neurons and nonneuronal cells. To determine the function of neuronal ERK activity in learning, a new line of transgenic mice was generated wherein dominant-negative MEK1, the upstream obligate activator of ERK1/2, was expressed by using a neuronal-specific and pan-neuronal Talpha1 alpha-tubulin promoter element. Mice expressing this construct exhibited decreased ERK1/2 activity in the hippocampus and thus were tested for learning impairments. In a battery of control tests, including open field, rotarod, and shock threshold, the transgenic mice displayed no deficits and performed as well as their wild-type littermate counterparts. However, the mice displayed a significant impairment in contextual fear conditioning compared with the wild-type littermates. These findings indicate that the MEK1/ERK1/2 cascade within neurons plays an important role in the processes of learning and memory.

Animals↗
PubMed1997

Anticonvulsant activity of azirino[1,2-d][1,4]benzodiazepines and related 1,4-benzodiazepines in mice.

The anticonvulsant properties of several 1,4-benzodiazepine and azirino[1,2-d][1,4]benzodiazepine (ABDZ) derivatives were studied after intraperitoneal (IP) administration in DBA/2 mice (a strain genetically susceptible to sound-induced seizures) and in Swiss mice. The anticonvulsant effects were evaluated on seizures evoked by means of auditory stimulation (109 dB, 12-16 kHz) in animals placed singly under a hemispheric Perspex dome or on seizures induced by administration of pentylenetetrazole. The 1,4-benzodiazepines were generally more potent than the related ABDZ derivatives. The rank order of potency for anticonvulsant activity was flunitrazepam > diazepam > pinazepam > ABDZ5 > ABDZ4 > prazepam > halazepam > ABDZ1 > ABDZ3 > camazepam > ABDZ6 > ABDZ2. The impairment of locomotor performance following IP administration of these derivatives was also evaluated by means of the rotarod test. The rank order of potency for impairment of coordinated motor movements was pinazepam > flunitrazepam > diazepam > ABDZ5 > prazepam > halazepam > ABDZ4 > ABDZ3 > ABDZ1 > camazepam > ABDZ2 = ABDZ6. The potency of various 1,4-benzodiazepines and ABDZs as inhibitors of specific [3H]flumazenil binding to membranes from cerebellum or cortex was evaluated. In general, ABDZs were active as anticonvulsants and inhibited [3H]flumazenil binding in the micromolar range. Radioligand binding studies carried out in stable cell lines demonstrated that none of the ABDZs tested showed a particular subtype specificity. The pharmacological actions of ABDZ4 and ABDZ5, which appeared to be the most potent ABDZs as anticonvulsants, were significantly reduced by treatment with flumazenil (8.24 mumol/kg IP), suggesting a clear involvement of benzodiazepine mechanisms in the anticonvulsant activity of these compounds or their metabolites. The anticonvulsant activity of ABDZ4 and ABDZ5 was also evaluated against seizures induced in DBA/2 mice by two beta-carbolines: methyl-beta-carboline-3-carboxylate (beta-CCM) and methyl-6,6-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM). Both ABDZ4 and ABDZ5 give better protection against seizures induced by beta-CCM than DMCM, suggesting a preferential action on the benzodiazepine receptor subtype BDZ1.

Animals↗
PubMedDate not supplied

Acetone potentiation and influence on the reversibility of 2,5-hexanedione-induced neurotoxicity studied with behavioural and morphometric methods in rats.

The neurobehavioural and morphologic changes and the reversibility in 2,5-hexanedione-induced polyneuropathy in rats were studied. The potentiation and influence of acetone on the reversibility of the induced neurotoxicity was also evaluated. Male rats were treated for 6 weeks with 0.5% w/v 2,5-hexanedione alone or in combination with 0.50% w/v acetone in the drinking water. During the treatment period, neurobehavioural tests (ambulation and rearing in open field, balance on the accelerating rotarod and fore-and hindlimb muscle strength measurements) were performed weekly. After 6 weeks half of the rats was sacrificed and histopathological lesions in the sciatic nerve and tibial nerve were evaluated by morphometry. Neurotoxicity was induced by 2,5-hexanedione, and acetone caused a potentiation of this effect in open field ambulation and rearing and in the rotarod test. In the pathological evaluation, giant axonal swelling was observed after 2,5-hexanedione and 2,5-hexanedione plus acetone. In nerve fibre cross sections, a significant change of the distribution of fibre area size was observed in animals treated with 2,5-hexanedione. Aggravation of the lesions was seen in rats treated with both 2,5-hexanedione and acetone. The other half of the animals was used to study the reversibility of the neurotoxic effects within a dose-free period of 10 weeks. Reversibility of the effect on ambulation was complete within the recovery period, but the effects on rearing and balance in the rotarod test were only reversible within the 10 weeks in the 2,5-hexanedione-treated rats and not in the combined 2,5-hexanedione and acetone-treated rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetone↗
PubMed2006

Postnatal methylmercury exposure induces hyperlocomotor activity and cerebellar oxidative stress in mice: dependence on the neurodevelopmental period.

During the early postnatal period the central nervous system (CNS) is extremely sensitive to external agents. The present study aims at the investigation of critical phases where methylmercury (MeHg) induces cerebellar toxicity during the suckling period in mice. Animals were treated with daily subcutaneous injections of MeHg (7 mg/kg of body weight) during four different periods (5 days each) at the early postnatal period: postnatal day (PND) 1-5, PND 6-10, PND 11-15, or PND 16-20. A control group was treated with daily subcutaneous injections of a 150 mM NaCl solution (10 ml/kg of body weight). Subjects exposed to MeHg at different postnatal periods were littermate. At PND 35, behavioral tests were performed to evaluate spontaneous locomotor activity in the open field and motor performance in the rotarod task. Biochemical parameters related to oxidative stress (levels of glutathione and thiobarbituric acid reactive substances, as well as glutathione peroxidase and glutathione reductase activity) were evaluated in cerebellum. Hyperlocomotor activity and high levels of cerebellar thiobarbituric acid reactive substances were observed in animals exposed to MeHg during the PND 11-15 or PND 16-20 periods. Cerebellar glutathione reductase activity decreased in MeHg-exposed animals. Cerebellar glutathione peroxidase activity was also decreased after MeHg exposure and the lowest enzymatic activity was found in animals exposed to MeHg during the later days of the suckling period. In addition, low levels of cerebellar glutathione were found in animals exposed to MeHg during the PND 16-20 period. The present results show that the postnatal exposure to MeHg during the second half of the suckling period causes hyperlocomotor activity in mice and point to this phase as a critical developmental stage where mouse cerebellum is a vulnerable target for the neurotoxic and pro-oxidative effects of MeHg.

Animals↗
PubMed1996

Azirino[1, 2-d][1, 4]benzodiazepine derivatives and related 1,4-benzodiazepines as anticonvulsant agents in DBA/2 mice.

1. The behavioral and anticonvulsant effects of several 1, 4-benzodiazepine (BDZ) and azirino[1,2-d] [1, 4]benzodiazepine (ABDZ) derivatives were studied after intraperitoneal administration in DBA/2 mice, a strain genetically susceptible to sound-induced seizures. 2. The anticonvulsant effects were evaluated on seizures evoked by means of auditory stimulation (109 dB, 12-16 kHz) in animals placed singly under a Perspex dome. 3. The 1,4-benzodiazepines were generally more potent than the related azirino[1,2-d] [1,4]benzodiazepine derivatives which, however, showed a remarkable anticonvulsant activity. The rank order of potency for anticonvulsant activity was flunitrazepam > diazepam > pinazepam > ABDZ5 > ABDZ4 > prazepam > halazepam > ABDZ1 > ABDZ3 > camazepam > ABDZ6 > ABDZ2. 4. The impairment of locomotor performance following intraperitoneal (IP) administration of the aforementioned derivatives was also evaluated by means of rotarod test. The rank order of potency for impairment of coordinated motor movements was pinazepam > flunitrazepam > diazepam > ABDZ5 > prazepam > halazepam > ABDZ4 > ABDZ3 > ABDZ1 > camazepam > ABDZ2 = ABDZ6. 5. A hypothermic activity was observed after the highest doses of the benzodiazepines studied. 6. The potency of various 1,4-benzodiazepines and azirino[1, 2-d][1,4]benzodiazepines as inhibitors of specific [3H]flumazenil binding to membranes from cerebellum or cortex was evaluated. In general, they inhibited [3H]flumazenil binding at the micromolar range. However, some ABDZ derivatives, although active as anticonvulsants, failed to displace [3H]flumazenil. 7. The azirino[1,2-d] [1,4]benzodiazepine derivatives are more lipophilic than the related benzodiazepines, but the different degree of anticonvulsant activity and impairment of coordinated motor movements cannot be directly related to the lipophilicity of the compounds studied. 8. The pharmacologic actions of ABDZ4 and ABDZ5, which appeared as the most potent anticonvulsants of the azirino[1,2-d] [1,4]benzodiazepine derivatives, were significantly reduced by treatment with flumazenil (8.24 mumol/kg IP) suggesting a clear involvement of benzodiazepine mechanisms in the anticonvulsant activity of these compounds or their metabolites. 9. The anticonvulsant activity of ABDZ4 and ABDZ5 was also evaluated against seizures induced by the two beta-carbolines, methyl beta-carboline-3-carboxylate (beta-CCM) and methyl6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM), in DBA/2 mice. Both ABDZ4 and ABDZ5 gave better protection against the seizures induced by beta-CCM than DMCM, suggesting a preferential action on BDZ1 receptors.

Acoustic Stimulation↗