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PubMed2002

The role of dopamine in motor symptoms in the R6/2 transgenic mouse model of Huntington's disease.

In both Huntington's disease (HD) patients and genetic mouse models of HD, there is a pre-symptomatic loss of dopamine (DA) receptors, suggesting that dysfunctional dopaminergic neurotransmission may be involved in early HD presentation. However, the role of DA in HD symptoms is not fully understood. In this study, we examined the possibility that dysfunctional dopaminergic neurotransmission contributes to the progressive decline in motor function of a transgenic mouse model of HD (R6/2 line). We found that R6/2 mice display an age-dependent abnormal behavioural response to (+)-methamphetamine (METH) and a dose-dependent increase in sensitivity to METH toxicity compared with wild-type (WT) mice. R6/2 mice also showed an attenuated response to cocaine, indicating that DA release may be compromised. Striatal DA levels were reduced in R6/2 mice by 9 weeks of age. Replacement of DA by chronic treatment with laevodopa (L-DOPA, administered as Sinemet) caused short-term improvements in activity and rearing behaviour, and abolished abnormal spontaneous hindlimb grooming. However, long-term treatment with L-DOPA had deleterious effects on survival and rotarod performance of R6/2 mice. These results suggest that dysfunctional DA neurotransmission contributes to phenotype development in R6/2 mice and thus also may be important in symptom progression in HD.

Aging↗
PubMed1999

Muscle relaxant activity of methocarbamol enantiomers in mice.

Documented studies support the emerging idea that drug enantiomers could have different pharmacological activity. Our bibliographical data have shown that so far no report has been published on the pharmacological activity of individual enantiomers of methocarbamol. This study was conducted to characterize the muscle relaxant activity of methocarbamol enantiomers. The rotarod test was used to compare the muscle relaxant activity of racemic methocarbamol and pure enantiomers after intraperitoneal administration of the enantiomers to mice. The results show that (+)-R-methocarbamol has higher muscle relaxant activity compared with racemic methocarbamol or (-)-S-methocarbamol.

Animals↗
PubMed1999

Behavioral phenotyping of transgenic and knockout mice: experimental design and evaluation of general health, sensory functions, motor abilities, and specific behavioral tests.

Rigorous experimental design can minimize the high risk of false positives and false negatives in the behavioral phenotyping of a new transgenic or knockout mouse. Use of well established, quantitative, reproducible behavioral tasks, appropriate Ns, correct statistical methods, consideration of background genes contributed by the parental strains, and attention to litter and gender issues, will maximize meaningful comparisons of -/-, +/-, and +/+ genotypes. Strategies developed and used by our laboratory are described in this review. Preliminary observations evaluate general health and neurological reflexes. Sensory abilities and motor functions are extensively quantitated. Specific tests include observations of home cage behaviors, body weight, body temperature, appearance of the fur and whiskers, righting reflex, acoustic startle, eye blink, pupil constriction, vibrissae reflex, pinna reflex, Digiscan open field locomotion, rotarod motor coordination, hanging wire, footprint pathway, visual cliff, auditory threshold, pain threshold, and olfactory acuity. Hypothesis testing then focuses on at least three well-validated tasks within each relevant behavioral domain. Specific tests for mice are described herein for the domains of learning and memory, feeding, nociception, and behaviors relevant to discrete symptoms of human anxiety, depression, schizophrenia, and drug addiction. An example of our approach is illustrated in the behavioral phenotyping of C/EBPdelta knockout mice, which appear to be normal on general health, neurological reflexes, sensory and motor tasks, and the Morris water task, but show remarkably enhanced performance on contextual fear conditioning.

Animals↗
PubMed1982

The relationship between plasma concentration of valproic acid and its anticonvulsant and behavioural effects in the rat.

The relationship between the plasma concentration of valproic acid (VPA) and anticonvulsant or neurotoxic effects was studied in the rat. Anticonvulsant activity was assessed against; (1) maximal seizures induced either by electroshock or by intravenous injection of pentylenetetrazol; and (2) kindled amygdaloid epilepsy. Drug-induced neurotoxicity was determined by the rotarod test and by observation of behaviour. In the maximal seizure tests, tonic hindlimb extension was always abolished at plasma valproic acid concentrations of 225 microgram ml-1 and above. Tonic forelimb extension was not consistently blocked until the plasma drug concentration exceeded 530 microgram ml-1. In fully-kindled rats, plasma valproic acid concentrations of 300 microgram ml-1 and above markedly reduced the duration of amygdala afterdischarge activity and the intensity of behavioural seizures produced by amygdala stimulation. Analysis of the data from individual kindled rats revealed that there was a significant correlation between the estimated plasma concentration of valproic acid and the degree of seizure protection. Impairment of rotarod performance and marked ataxia occurred at plasma valproic acid concentrations above 510 microgram ml-1 and loss of righting reflex became evident at 970 microgram ml-1. From these results, it is concluded that the plasma concentration of valproic acid is closely correlated with the anticonvulsant and neurotoxic effects observed in individual rats after acute administration of sodium valproate.

Administration, Oral↗
PubMed2006

Matrix metalloproteinase-2 facilitates wound healing events that promote functional recovery after spinal cord injury.

Matrix metalloproteinases (MMPs) are proteolytic enzymes that are involved in both injury and repair mechanisms in the CNS. Pharmacological blockade of MMPs, limited to the first several days after spinal cord injury, improves locomotor recovery. This beneficial response is, however, lost when treatment is extended beyond the acutely injured cord to include wound healing and tissue remodeling. This suggests that some MMPs play a beneficial role in wound healing. To test this hypothesis, we investigated the role of MMP-2, which is actively expressed during wound healing, in white matter sparing and axonal plasticity, the formation of a glial scar, and locomotor recovery after spinal cord injury. MMP-2 increased between 7 and 14 d after injury, where it was immunolocalized in reactive astrocytes bordering the lesion epicenter. There was reduced white matter sparing and fewer serotonergic fibers, caudal to the lesion in injured MMP-2 null animals. MMP-2 deficiency also resulted in increased immunoreactivity to chondroitin sulfate proteoglycans and a more extensive astrocytic scar. Most importantly, locomotion in an open field, performance on a rotarod, and grid walking were significantly impaired in injured MMP-2 null mice. Our findings suggest that MMP-2 promotes functional recovery after injury by regulating the formation of a glial scar and white matter sparing and/or axonal plasticity. Thus, strategies exploiting MMPs as therapeutic targets must balance these beneficial effects during wound healing with their adverse interactions in the acutely injured spinal cord.

Animals↗
PubMed1997

Effects of dihydropyridine Ca2+ channel blockers on the discriminative stimulus and the motor impairing effects of (+/-)-Bay K 8644.

Functional interactions between the dihydropyridine Ca2+ channel activator, (+/-)-Bay K 8644 (methyl-1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoromethyphenyl )-pyridine-5-carboxylate), and several dihydropyridine L-type Ca2+ channel blockers were investigated on rotarod performance in mice and in rats trained to discriminate between (+/-)Bay K 8644 and saline. When administered alone, (+/-)-Bay K 8644 produced dose-dependent impairments of rotarod activity with an ED50 of 1.3 mg/kg. Pretreatment with nifedipine (10-30 mg/kg) produced dose-dependent rightward shifts of the (+/-)-Bay K 8644 dose-response curve. In contrast, pretreatment with several other dihydropyridine L-type Ca2+ channel blockers, including nicardipine, nimodipine, isradipine and nitrendipine, did not modify the (+/-)-Bay K 8644 dose-effect function. Rats learned to discriminate between (+/-)-Bay K 8644 (0.5 mg/kg) and saline in an average of 65 training sessions. In substitution tests, the Ca2+ channel activator engendered dose-related increases in the percentage of rats selecting the drug-associated lever with an ED50 of 0.19 mg/kg. Pretreatment with nifedipine (10 mg/kg) produced a rightward shift of the (+/-)-Bay K 8644 dose-response function. Pretreatment with nicardipine (2.5 mg/kg) only partially antagonised the training dose of (+/-)-Bay K 8644 whereas nimodipine (0.6-10 mg/kg) did not affect the (+/-)-Bay K 8644 discriminative stimulus. The results of the present study show that the behavioural effects of the dihydropyridine Ca2+ channel activator are differentially modified by dihydropyridine L-type Ca2+ channel blockers. These results may suggest that dihydropyridine blockers possess different intrinsic activities or act at different binding sites.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed2001

Influence of the selective ORL1 receptor agonist, Ro64-6198, on rodent neurological function.

Identification of synthetic agonists and antagonists at orphan receptors represents an important step for understanding their physiological function and therapeutic potential. Accordingly, we have recently described a non-peptide agonist at the opioid receptor like (ORL1) receptor (1S,3aS)-8-(2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one (Ro64-6198; Jenck et al., PNAS 94 (2000) 4938; Wichmann et al., Eur. J. Med. Chem. 35 (2000) 839). We have investigated the effects of this compound in various tests of rodent neurological function, utilising ORL1 knockout mice to examine the pharmacological specificity of Ro64-6198. In male C57BL/6J mice, effects on balance and motor co-ordination were detected following low doses (0.3-1mg/kg IP) of Ro64-6198. At higher doses (1-3mg/kg IP), effects on swim behaviour and hypothermia was observed. At 10mg/kg, each effect became more profound and a severe neurological disturbance appeared, including loss of righting reflex. These effects of Ro64-6198 (10mg/kg IP) were absent in ORL1 receptor knockout mice. In male, hooded Lister rats, Ro64-6198 (6-10mg/kg IP), produced some disturbance of neurological function, including hypoactivity, rotarod performance, grip strength and mild hypothermia. An impairment of food responding under a variable interval (VI) 20s schedule of reinforcement was noted at 3mg/kg. These results confirm Ro64-6198 to be a highly selective pharmacological tool to investigate ORL1 receptor function in vivo and, furthermore, that activation of this receptor is accompanied by a variety of effects on neurological function.

Animals↗
PubMed1992

Behavioral characterization of the new potent nonselective dopamine agonist pergolide.

Pergolide (LY127809, CAS 66104-23-2), a non-selective dopamine agonist, was evaluated for broad behavioral properties in a wide range of pharmacological tests. The selective dopamine2(D2) agonist, bromocriptine, served as a reference standard for those tests where behavioral activity was noted with pergolide. Pergolide and bromocriptine were administered orally to mice at doses of 0.3-30 and 3-300 mg/kg, respectively. Both compounds produced biphasic effects on spontaneous activity, increased hexobarbital-induced sleep time, and lowered mouse body temperature. Qualitative changes with pergolide were observed with some mice showing hyporeactiveness, ptosis, slowed respiration and placing loss. Reserpine-induced hypothermia was reversed by pergolide with significant increases in the body temperature of reserpine-treated mice. However, a further reduction in the body temperature of reserpinized hypothermic mice was seen following bromocriptine administration. Acetic acid-induced writhing and performance on the rotarod were both impaired by higher doses of pergolide. Bromocriptine administration also reduced writhing at higher doses but did not alter performance on the rotarod. Pergolide had no effect on seizure activity as evaluated by electroshock, pentylenetetrazol (pentetrazol) or strychnine. Oxotremorine-induced tremors and salivation, grip strength, and tail-flick were not affected by pergolide. Neither pergolide nor bromocriptine altered established shuttle-avoidance behavior in rats at oral doses of 0.1 to 30 mg/kg. Behavioral assessment of pergolide in dogs was complicated by severe emetic responses at clinically relevant doses greater than 0.003 mg/kg. In summary, these data suggest that pergolide produces a behavioral profile which is characteristic of dopaminergics.(ABSTRACT TRUNCATED AT 250 WORDS)

Analgesics↗
PubMedDate not supplied

Comparative study in mice of tetrazepam and other centrally active skeletal muscle relaxants.

Tetrazepam is a 1,4 benzodiazepine (BZD) clinically used in France and Germany as a muscle relaxant. The activity of tetrazepam was compared to that of diazepam, baclofen, mephenesin and chlormezanone in mice, in pharmacological models which are predictive of muscle relaxant and sedative properties. Tetrazepam was active in all the 6 tests of muscle relaxation (traction, chimney, inclined screen, grip force, horizontal grid and morphine-induced Straub tail). The overall muscle relaxant potency of tetrazepam was inferior to that of diazepam, but was clearly superior to that of chlormezanone and mephenesin. Baclofen was less active than tetrazepam in 3 tests (traction, horizontal grid, and grip strength), but more active in the other 3 tests. The administration of the benzodiazepine receptor antagonist Ro 15-1788 blocked the effects of tetrazepam and diazepam in 2 representative tests, morphine-induced Straub tail and the rotarod test, but did not modify the activities of the other centrally acting muscle relaxants in these same models. The selectivity ratio (ED50 rotarod or ED50 locomotor activity/ED50 in each muscle relaxant test) for tetrazepam was superior to that of diazepam and all the other muscle relaxant drugs examined. It is concluded that tetrazepam exerts its muscle relaxant activity by stimulating central BZD receptors, and presents the advantage of a wide dissociation between muscle relaxant and sedative potencies.

Animals↗
PubMed2006

Ho15J: a new hotfoot allele in a hot spot in the gene encoding the delta2 glutamate receptor.

Hotfoot, a recessive mouse mutation characterized by ataxia and jerky movements of the hindlimbs, is caused by various mutations in the gene (Grid2) encoding the delta2 glutamate receptor (GluRdelta2). So far, at least 20 alleles, arising either spontaneously or through the random insertion of transgenes, have been described. Interestingly, most hotfoot mutants have deletions of one or more exons coding for portions of the most amino-terminal domain of GluRdelta2. However, because live mice colonies are no longer available for most hotfoot mutants, the possibility that the loss of a part of an intron might affect the splicing of other exons or the general efficiency of transcription could not be ruled out. Here, we report that a newly identified hotfoot mutant, ho15J, was caused by an intragenic deletion of the Grid2 gene, which indeed resulted in a new type of 52-amino-acid deletion in the most amino-terminal domain of GluRdelta2. Like GluRdelta2 proteins in ho4J mutants, GluRdelta2 proteins in ho15J mice were retained in the soma of Purkinje cells, where they were degraded. Long-term depression, a form of synaptic plasticity underlying information storage in the cerebellum, was abrogated, and ho15J mice showed severe motor discoordination on rotarod tests. The agreement between the PCR results for genomic DNA and the RT-PCR results for the ho15J allele supports the view that PCR analyses of grid2 genomic DNA can predict alterations in mRNA and protein. In addition, the present findings underscore the importance of the most amino-terminal domain in GluRdelta2 signaling and cerebellar functions.

Alleles↗
PubMed1990

[The effect of diazepam on exploratory behavior and its strain differences in inbred rats].

The effect of diazepam on exploratory behavior was investigated in two inbred strains of rats, Fischer 344 (F344) and Lewis (LEW). The total numbers of head-dips and head-dipping duration in the rat hole-board test, and the total number of rearing and locomotor activity in the open-field test were measured after diazepam administration. The numbers of head-dips and rearings, and head-dipping duration and locomotor activity in naive F344 were significantly greater than those in naive LEW (P less than 0.001), suggesting that LEW is more emotional than F344. Diazepam, 0.31 and 0.63 mg/kg for F344 and 0.31-1.25 mg/kg for LEW, increased head-dips, head-dipping duration and rearings. However, there were no strain differences in enhancing effect of diazepam on locomotor activity. On the contrary, higher doses of diazepam, 0.94-2.50 mg/kg for F344 and 2.50 mg/kg for LEW, decreased head-dips, head-dipping duration, and rearings. However, the effect of diazepam on rotarod performance in LEW was similar to that in F344. These results suggest that F344 is more sensitive to sedative effect of diazepam than LEW, and that the sensitivity to diazepam may be strongly influenced by genetic factors.

Animals↗
PubMed1998

Therapeutic effects of complex motor training on motor performance deficits induced by neonatal binge-like alcohol exposure in rats . I. Behavioral results.

The effects of complex motor task learning on subsequent motor performance of adult rats exposed to alcohol on postnatal days 4 through 9 were studied. Male and female Long-Evans rats were assigned to one of three treatments: (1) alcohol exposure (AE) via artificial rearing to 4.5.g kg-1 day-1 of ethanol in a binge-like manner (two consecutive feedings), (2) gastrostomy control (GC) fed isocaloric milk formula via artificial rearing, and (3) suckling control (SC), where pups remained with lactating dams. After completion of the treatments, the pups were fostered back to lactating dams, and after weaning they were raised in standard cages (two-three animals per cage) until they were 6 months old. Rats from each of the postnatal treatments then spent 20 days in one of three conditions: (1) inactive condition (IC), (2) motor control condition (MC) (running on a flat oval track), or (3) rehabilitation condition (RC) (learning to traverse a set of 10 elevated obstacles). After that all the animals were tested on three tasks, sensitive to balance and coordination deficits (parallel bars, rope climbing and traversing a rotating rod). On parallel bars, both male and female rats demonstrated the same pattern of outcomes: AE-IC rats made significantly more mistakes (slips and falls) than IC rats from both control groups. After 20 days of training in the RC condition, there were no differences between AE and both SC and GC animals in their ability to perform on the parallel bars test. On rope climbing, female animals showed a similar pattern of abilities: AE-IC rats were the worst group; exercising did not significantly improve the AE rats' ability to climb, whereas the RC groups (SC, GC and AE) all performed near asymptote and there were no significant differences among three neonatal treatment groups. There was a substantial effect of the male rats' heavier body weight on climbing ability, and this may have prevented the deficits in AE rats behavior from being detected. Nevertheless, male animals from all three postnatal treatments (SC, GC and AE) were significantly better on this task after RC. Female and male rats from all three postnatal groups demonstrated significantly better performance on the rotarod task after 20 days of 'rehabilitation'. These results suggest that complex motor skill learning improves some of the motor performance deficits produced by postnatal exposure to alcohol and can potentially serve as a model for rehabilitative intervention.

Aging↗
PubMed1990

The pharmacological properties of the imidazobenzodiazepine, FG 8205, a novel partial agonist at the benzodiazepine receptor.

1. The pharmacological properties of the benzodiazepine receptor ligand, FG 8205 (7-chloro-5,6-dihydro-5-methyl-6-oxo-3-(5-isopropyl-1,2,4-oxadiazol++ +-3-yl)-4H- imidazol[1,5a][1,4]benzodiazepine) have been examined. 2. FG 8205 potently displaced [3H]-flumazenil binding in rat cortical membranes with a Ki of 3.3 nM, but was inactive at 13 neurotransmitter recognition sites. 3. Consistent with a partial agonist profile, the affinity of FG 8205 for the benzodiazepine recognition site was increased in the presence of gamma-aminobutyric acid (GABA, 300 microM) by a degree (-log [IC50 in the presence of GABA/IC50 alone] = 0.34) significantly less than found for diazepam (0.46). FG 8205 also potentiated the inhibitory potency of the GABAA-receptor agonist, isoguvacine, on the hippocampal CA1 population spike and, again, the maximum shift (-log dose-ratio = 0.2) was significantly less than that seen with diazepam (0.4). 4. In anticonvulsant studies, the ED50 doses of FG 8205 and diazepam needed to antagonize seizures induced by pentylenetetrazol (PTZ) or by sound in audiogenic seizure prone mice were similar with values of 0.2-0.3 mg kg-1, i.p. However, even high doses of FG 8205 (50 mg kg-1) did not protect against seizures induced by electroshock. 5. FG 8205 released responding suppressed by footshock in a rat operant conditioned emotional response task over the dose range 0.5-50 mg kg-1 (i.p.). Similar doses of FG 8205 had a marked taming effect in cynomolgus monkeys. However, measures of sedation and ataxia (as measured by rotarod in the mouse, climbing behaviour in the rat, and by scoring arousal and co-ordination in primates) were slight and only transiently affected by FG 8205, and FG 8205 significantly antagonized the rotarod performance deficit induced by diazepam in the mouse. 6. While the potentiation by FG 8205 of the response to isoguvacine in the rat hippocampal slice and the anxiolytic-like effects of the compound in both rats and primates were reversed by the benzodiazepine receptor antagonist, flumazenil, high doses of the antagonist were able only marginally to block the protective effects of FG 8205 against seizures induced by PTZ in the mouse. 7. Thus, FG 8205 does not show the marked motor impairment characteristic of full agonists at the benzodiazepine receptor, consistent with its partial agonist profile in in vitro assay systems. Nevertheless, the compound has sufficient intrinsic activity to maintain high efficacy in anticonvulsant and anxiolytic tests.

Animals↗
PubMed1989

Are changes in neuronal calcium channels involved in ethanol tolerance?

Effects on the development of tolerance to ethanol of concurrent administration of the dihydropyridine calcium channel antagonist, nitrendipine, were investigated. Ethanol tolerance was induced in rats by repeated i.p. injections and measured by performance on the rotarod apparatus. Concurrent injections of nitrendipine prevented the development of tolerance to the ataxic action of ethanol. A similar effect was seen with the calcium channel antagonist PN 200-110 on tolerance to the general anesthetic effects of ethanol in mice. As previously reported, chronic ethanol administration increased the number of dihydropyridine binding sites in rat cerebral cortex. This was also prevented by the nitrendipine treatment; repeated administration of both ethanol and nitrendipine caused a decrease in the number of binding sites. The effect of nitrendipine on the tolerance was not due to alterations in body temperature, changes in blood pressure, differences in brain ethanol concentrations or residual nitrendipine in the brain at the time of testing. The results suggest that alterations in dihydropyridine-sensitive calcium channels may be involved in the adaptations that occur on chronic treatment with ethanol.

Alcoholism↗
PubMed2005

Encapsulated vascular endothelial growth factor-secreting cell grafts have neuroprotective and angiogenic effects on focal cerebral ischemia.

OBJECT: The authors evaluated the neuroprotective and angiogenic effects of a continuous and low-dose infusion of vascular endothelial growth factor (VEGF)-165 on cerebral ischemia in rats. METHODS: The authors introduced VEGF complementary (c)DNA into baby hamster kidney (BHK) cells and established a cell line that produces human VEGF165 (BHK-VEGF). The BHK-VEGF cells and BHK cells that had been transfected with an expression vector that did not contain human VEGF165 cDNA (BHK-control) were encapsulated. Both capsules were implanted into rat striata. Six days after capsule implantation, the right middle cerebral artery (MCA) was occluded. Some animals were killed 24 hours after occlusion to measure the volume of the resulting infarct and to perform immunohistochemical studies. Other animals were used for subsequent behavioral studies 1, 7, and 14 days after MCA occlusion. The encapsulated BHK-VEGF cell grafts significantly reduced the volume of the infarct and the number of apoptotic cells in the penumbral area when compared with the effect of the BHK-control cell capsule. In addition, angiogenesis and gliogenesis significantly increased in the region around the capsule in animals that received BHK-VEGF cell capsules without an increase in focal cerebral blood flow; this did not occur in animals that received the BHK-control cell capsule. In behavioral studies rats that received the BHK-VEGF cell capsule displayed significant recovery while participating in the accelerating rotarod test after stroke. CONCLUSIONS: Continuous intracerebral administration of low-dose VEGF165 through encapsulated grafts of VEGF-producing cells produces neuroprotective and angiogenic effects. These effects improve subsequent motor function.

Animals↗
PubMed1992

Acute neurobehavioural toxicity of trichothecene T-2 toxin in the rat.

The acute effects of single oral doses, 0.4 and 2.0 mg/kg, of trichothecene T-2 mycotoxin on behaviour, motor performance and nociception were studied in male Wistar rats. Both doses are sublethal and did not cause overt acute signs of intoxication. In the open field test, 2.0 mg/kg of T-2 toxin increased motionlessness and decreased sniffing (P less than 0.05) 4 hr after the administration. The higher dose shortened step-through latencies in the test trial of the 24-hr passive avoidance test (two-way shuttle box). The exponential data analysis showed that, in those rats that did not learn to avoid the dark (unsafe) compartment of the box, the retention after 2.0 mg/kg of T-2 toxin was only 25% of that in controls (P less than 0.001). T-2 toxin had no effect on motor coordination in the rotarod test and in the bridge walking test 7-8 hr after administration. T-2 toxin had no effect on nociception in the hot place test 8.5 hr after administration. The results suggest that T-2 toxin has some inactivating effects on behaviour of rats, and it seems to cause an impairment in the passive avoidance test at dose 2.0 mg/kg.

Animals↗
PubMed2000

Behavior and mutagenesis screens: the importance of baseline analysis of inbred strains.

Random mutagenesis as a means of identifying the function of genes has been used extensively in a variety of model organisms. Until recently it has been used primarily in the identification of single-gene traits that cause visible and developmental mutations. However, this genetic approach also has the power to identify genes that control complex biological systems such as behavior. Mutagenesis screens for behavioral mutations require careful consideration of many factors, including choice of both assays and background strains for use in mutagenesis and subsequent mapping of the affected gene or genes. This paper describes behavioral assays for monitoring motor coordination on the accelerating rotarod, anxiety-related behaviors in the elevated zero maze and sensorimotor reactivity, gating, and habituation of acoustic startle. These five physiological or neurological behaviors can represent potential endophenotypes for a variety of neurological and psychiatric disorders. The significant degree of strain- and sex-specific differences in the performance of four inbred strains of mice (C57BL/6J, C3HeB/FeJ, DBA/2J, and 129/SvlmJ) in these behavioral assays illustrates the importance of performing baseline analysis prior to behavioral mutagenesis screens and genetic mapping of selected mutations.

Animals↗
PubMed1994

Antinociceptive actions of dexmedetomidine and the kappa-opioid agonist U-50,488H against noxious thermal, mechanical and inflammatory stimuli.

The antinociceptive efficacies of both intrathecally (i.t.) and systemically administered dexmedetomidine (a selective alpha-2 adrenoceptor agonist) and U-50,488H [trans(+/-)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]- benzene-acetamide] (a kappa-opioid receptor agonist) were studied during peripheral inflammation induced by carrageenan. The antinociceptive tests were the hot plate (HP), the tail flick (TF) and the paw pressure tests (PP). The motor incoordination, if any, produced by both i.t. and s.c. dexmedetomidine were evaluated with the rotarod. The interaction between dexmedetomidine and U-50,488H and between atipamezole (a selective alpha-2 adrenoceptor antagonist) and U-50,488H were also assessed. The carrageenan injection induced not only peripheral hyperalgesia but also central sensitization, as assessed by decreased PP and TF latencies, respectively. The i.t. dexmedetomidine (0.15, 0.45, 1.35, 4.05) micrograms) resulted in dose-dependent increases in the PP thresholds and TF latencies in both the control rats and the rats with unilateral inflammation, without causing changes in motor coordination, whereas on s.c. administration of dexmedetomidine (3-100 micrograms/kg), antinociception was produced in PP only at doses (30 micrograms/kg) that already interfered with rotarod performance. U-50,488H was ineffective i.t. (5-200 micrograms) but, on s.c. administration (2.5-22.5 mg/kg), dose-dependent increases were found in the PP thresholds and TF latencies of the rats with unilateral inflammation. Atipamezole, in a dose (3 mg/kg) that has been shown to block the antinociceptive effects of dexmedetomidine, did not modify the antinociceptive effects of U-50,488H.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗