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Sample records for potentiates locomotor sensitization

  1. DeltaFosB induction in orbitofrontal cortex potentiates locomotor sensitization despite attenuating the cognitive dysfunction caused by cocaine.

    PubMed

    Winstanley, Catharine A; Green, Thomas A; Theobald, David E H; Renthal, William; LaPlant, Quincey; DiLeone, Ralph J; Chakravarty, Sumana; Nestler, Eric J

    2009-09-01

    The effects of addictive drugs change with repeated use: many individuals become tolerant of their pleasurable effects but also more sensitive to negative sequelae (e.g., anxiety, paranoia, and drug craving). Understanding the mechanisms underlying such tolerance and sensitization may provide valuable insight into the basis of drug dependency and addiction. We have recently shown that chronic cocaine administration reduces the ability of an acute injection of cocaine to affect impulsivity in rats. However, animals become more impulsive during withdrawal from cocaine self-administration. We have also shown that chronic administration of cocaine increases expression of the transcription factor DeltaFosB in the orbitofrontal cortex (OFC). Mimicking this drug-induced elevation in OFC DeltaFosB through viral-mediated gene transfer mimics these behavioural changes: DeltaFosB over-expression in OFC induces tolerance to the effects of an acute cocaine challenge but sensitizes rats to the cognitive sequelae of withdrawal. Here we report novel data demonstrating that increasing DeltaFosB in the OFC also sensitizes animals to the locomotor-stimulant properties of cocaine. Analysis of nucleus accumbens tissue taken from rats over-expressing DeltaFosB in the OFC and treated chronically with saline or cocaine does not provide support for the hypothesis that increasing OFC DeltaFosB potentiates sensitization via the nucleus accumbens. These data suggest that both tolerance and sensitization to cocaine's many effects, although seemingly opposing processes, can be induced in parallel via the same biological mechanism within the same brain region, and that drug-induced changes in gene expression within the OFC play an important role in multiple aspects of addiction. PMID:19135469

  2. Effects of Sodium Butyrate on Methamphetamine-Sensitized Locomotor Activity

    PubMed Central

    Harkness, John H.; Hitzemann, Robert J.; Edmunds, Stephanie; Phillips, Tamara J.

    2012-01-01

    Neuroadaptations associated with behavioral sensitization induced by repeated exposure to methamphetamine (MA) appear to be involved in compulsive drug pursuit and use. Increased histone acetylation, an epigenetic effect resulting in altered gene expression, may promote sensitized responses to psychostimulants. The role of histone acetylation in the expression and acquisition of MA-induced locomotor sensitization was examined by measuring the effect of histone deacetylase inhibition by sodium butyrate (NaB). For the effect on expression, vehicle or NaB (630 mg/kg, intraperitoneally) was administered 30 min prior to MA challenge in mice treated repeatedly with MA (10 days of 2 mg/kg MA) or saline (10 days), and then locomotor response to MA challenge was measured. NaB treatment increased the locomotor response to MA in both acutely MA treated and sensitized animals. For acquisition, NaB was administered 30 min prior to each MA exposure (10 days of 1 or 2 mg/kg), but not prior to the MA challenge test. Treatment with NaB during the sensitization acquisition period significantly increased locomotor activation by MA in sensitized mice only. NaB alone did not significantly alter locomotor activity. Acute NaB or MA, but not the combination, appeared to increase striatal acetylation at histone H4. Repeated treatment with MA, but not NaB or MA plus NaB, increased striatal acetylation at histone H3. Although increased histone acetylation may alter the expression of genes involved in acute locomotor response to MA and in the acquisition of MA-induced sensitization, results for acetylation at H3 and H4 showed little correspondence with behavior. PMID:23137698

  3. Effects of Nicotine on Ethanol-Induced Locomotor Sensitization: A Model of Neuroadaptation

    PubMed Central

    Gubner, Noah R.; Phillips, Tamara J.

    2015-01-01

    Co-morbid use of nicotine-containing tobacco products and alcohol (ethanol) is prevalent in young adults initiating use and in alcohol dependent adults, suggesting that these drugs in combination may increase risk to develop dependence on one or both drugs. Neuroadaptations caused by repeated drug exposure are related to the development of drug dependence and vulnerability to relapse. Locomotor sensitization has been used as a behavioral measure used to detect changes in neural drug sensitivity that are thought to contribute to drug dependence and relapse. Locomotor sensitization was measured in the current studies to examine potential differences in the effects of nicotine and ethanol given alone and in combination. Baseline activity levels of DBA/2J mice were assessed on 2 days, then mice were treated for ten days with saline, nicotine (1 or 2 mg/kg of nicotine tartrate), ethanol (1 or 2 g/kg), or nicotine plus ethanol and locomotor activity was assessed every third day. On the following day, all mice were challenged with ethanol to measure the expression of sensitization. Mice treated with both nicotine and ethanol exhibited greater stimulation than predicted from the combined independent effects of these drugs, consistent with our previously published results. The combined effects of nicotine and ethanol on locomotor sensitization were dependent on the dose of ethanol and whether testing was performed after the drugs were given together, or after challenge with ethanol alone. These results suggest that nicotine and ethanol in combination can have neuroadaptive effects that differ from the independent effects of these drugs. PMID:25857831

  4. Effects of nicotine on ethanol-induced locomotor sensitization: A model of neuroadaptation.

    PubMed

    Gubner, Noah R; Phillips, Tamara J

    2015-07-15

    Co-morbid use of nicotine-containing tobacco products and alcohol (ethanol) is prevalent in young adults initiating use and in alcohol dependent adults, suggesting that these drugs in combination may increase risk to develop dependence on one or both drugs. Neuroadaptations caused by repeated drug exposure are related to the development of drug dependence and vulnerability to relapse. Locomotor sensitization has been used as a behavioral measure used to detect changes in neural drug sensitivity that are thought to contribute to drug dependence and relapse. Locomotor sensitization was measured in the current studies to examine potential differences in the effects of nicotine and ethanol given alone and in combination. Baseline activity levels of DBA/2J mice were assessed on 2 days, then mice were treated for 10 days with saline, nicotine (1 or 2mg/kg of nicotine tartrate), ethanol (1 or 2g/kg), or nicotine plus ethanol and locomotor activity was assessed every third day. On the following day, all mice were challenged with ethanol to measure the expression of sensitization. Mice treated with both nicotine and ethanol exhibited greater stimulation than predicted from the combined independent effects of these drugs, consistent with our previously published results. The combined effects of nicotine and ethanol on locomotor sensitization were dependent on the dose of ethanol and whether testing was performed after the drugs were given together, or after challenge with ethanol alone. These results suggest that nicotine and ethanol in combination can have neuroadaptive effects that differ from the independent effects of these drugs. PMID:25857831

  5. Interactions between modafinil and cocaine during the induction of conditioned place preference and locomotor sensitization in mice: Implications for addiction

    PubMed Central

    Shuman, Tristan; Cai, Denise J.; Sage, Jennifer R.; Anagnostaras, Stephan G.

    2013-01-01

    Modafinil is a wake-promoting drug effective at enhancing alertness and attention with a variety of approved and off-label applications. The mechanism of modafinil is not well understood but initial studies indicated a limited abuse potential. A number of recent publications, however, have shown that modafinil can be rewarding under certain conditions. The present study assessed the reinforcing properties of modafinil using conditioned place preference and locomotor sensitization in mice. Experiment 1 examined a high dose of modafinil (75 mg/kg) as well as its interactions with cocaine (15 mg/kg). Cocaine alone and modafinil co-administered with cocaine induced sensitization of locomotor activity; modafinil alone showed little or no locomotor sensitization. Animals given modafinil alone, cocaine alone, and modafinil plus cocaine exhibited a strong and roughly equivalent place preference. When tested for sensitization using a low challenge dose of modafinil, cross-sensitization was observed in all cocaine-pretreated mice. Experiment 2 examined a low dose of modafinil that is similar to the dose administered to humans and has been shown to produce cognitive enhancements in mice. Low dose modafinil (0.75 mg/kg) did not produce conditioned place preference or locomotor sensitization. Together, these results suggest that modafinil has the potential to produce reward, particularly in cocaine addicts, and should be used with caution. However, the typical low dose administered likely moderates these effects and may account for lack of addiction seen in humans. PMID:22963989

  6. Cocaine counteracts LPS-induced hypolocomotion and triggers locomotor sensitization expression.

    PubMed

    Tortorelli, Lucas Silva; Engelke, Douglas Senna; Lunardi, Paula; Mello E Souza, Tadeu; Santos-Junior, Jair Guilherme; Gonçalves, Carlos-Alberto

    2015-01-01

    Neuroimmune signalling underlies addiction and comorbid depression. Clinical observations indicate that infections and chronic lesions are more frequent in drug users and elevated inflammatory states are evident in cocaine dependents. Therefore, lipopolysaccharide (LPS) and inflammatory cytokines represent an important tool for the investigation of sickness, depressive illness and addiction behaviour. A major component of addiction is the progressive and persistent increase in locomotor activity after repeated drug administration and even prolonged periods of abstinence. The aim of this study was to investigate the response of locomotor sensitization when a non-sensitizing dose of cocaine is paired with a systemic inflammatory stimulus. LPS and cocaine were administered intraperitonealy in young-adult male C57bl/6 mice during a 5-day acquisition phase. After a 48-h withdrawal period all groups were challenged with cocaine to evaluate locomotor expression. During the acquisition phase, the LPS-treated groups displayed characteristic hypolocomotion related to sickness behaviour. The low dose of cocaine did not increase the distance travelled, characterizing a non-sensitization dose. Groups that received both LPS and cocaine did not display hypolocomotion, indicating that cocaine might counteract hypolocomotion sickness behaviour. Moreover, during challenge, only these animals expressed locomotor sensitization. Our results indicate that LPS could facilitate the expression of locomotor sensitization in mice and that the immune system may modulate cocaine-induced sensitization. PMID:25835320

  7. Prefrontal microRNA-221 Mediates Environmental Enrichment-Induced Increase of Locomotor Sensitivity to Nicotine

    PubMed Central

    Gomez, Adrian M.; Altomare, Diego; Sun, Wei-Lun; Midde, Narasimha M.; Ji, Hao; Shtutman, Michael; Turner, Jill R.; Creek, Kim E.

    2016-01-01

    phosphorylated cAMP-response element-binding protein in the medial prefrontal cortex of impoverished condition but not enriched condition rats. Conclusion: These findings suggest that environmental enrichment, via upregulation of prefrontal microRNA-221 expression, suppresses the nicotine-induced activation of extracellular signal-regulated kinase and cAMP-response element-binding protein, which provides a potential mechanism underlying enhanced locomotor sensitivity to nicotine. PMID:26232787

  8. Rapid Sensitization of Physiological, Neuronal, and Locomotor Effects of Nicotine: Critical Role of Peripheral Drug Actions

    PubMed Central

    Lenoir, Magalie; Tang, Jeremy S.; Woods, Amina S.

    2013-01-01

    Repeated exposure to nicotine and other psychostimulant drugs produces persistent increases in their psychomotor and physiological effects (sensitization), a phenomenon related to the drugs' reinforcing properties and abuse potential. Here we examined the role of peripheral actions of nicotine in nicotine-induced sensitization of centrally mediated physiological parameters (brain, muscle, and skin temperatures), cortical and VTA EEG, neck EMG activity, and locomotion in freely moving rats. Repeated injections of intravenous nicotine (30 μg/kg) induced sensitization of the drug's effects on all these measures. In contrast, repeated injections of the peripherally acting analog of nicotine, nicotine pyrrolidine methiodide (nicotinePM, 30 μg/kg, i.v.) resulted in habituation (tolerance) of the same physiological, neuronal, and behavioral measures. However, after repeated nicotine exposure, acute nicotinePM injections induced nicotine-like physiological responses: powerful cortical and VTA EEG desynchronization, EMG activation, a large brain temperature increase, but weaker hyperlocomotion. Additionally, both the acute locomotor response to nicotine and nicotine-induced locomotor sensitization were attenuated by blockade of peripheral nicotinic receptors by hexamethonium (3 mg/kg, i.v.). These data suggest that the peripheral actions of nicotine, which precede its direct central actions, serve as a conditioned interoceptive cue capable of eliciting nicotine-like physiological and neural responses after repeated nicotine exposure. Thus, by providing a neural signal to the CNS that is repeatedly paired with the direct central effects of nicotine, the drug's peripheral actions play a critical role in the development of nicotine-induced physiological, neural, and behavioral sensitization. PMID:23761889

  9. Glycyrrhizae Radix Methanol Extract Attenuates Methamphetamine-Induced Locomotor Sensitization and Conditioned Place Preference

    PubMed Central

    Zhao, ZhengLin; Zhang, Jie; Jung, Ji Yun; Chang, Suchan; Zhou, FuBo; Zhao, JunChang; Lee, Bong Hyeo; Yang, Chae Ha; Zhao, RongJie

    2014-01-01

    Glycyrrhizae Radix modulates the neurochemical and locomotor alterations induced by acute psychostimulants in rodents via GABAb receptors. This study investigated the influence of methanol extract from Glycyrrhizae Radix (MEGR) on repeated methamphetamine- (METH-) induced locomotor sensitization and conditioned place preference (CPP). A cohort of rats was treated with METH (1 mg/kg/day) for 6 consecutive days, subjected to 6 days of withdrawal, and then challenged with the same dose of METH to induce locomotor sensitization; during the withdrawal period, the rats were administered MEGR (60 or 180 mg/kg/day). A separate cohort of rats was treated with either METH or saline every other day for 6 days in METH-paired or saline-paired chambers, respectively, to induce CPP. These rats were also administered MEGR (180 mg/kg) prior to every METH or CPP expression test. Pretreatment with MEGR (60 and 180 mg/kg/day) attenuated the expression of METH-induced locomotor sensitization dose-dependently, and 180 mg/kg MEGR significantly inhibited the development and expression of METH-induced CPP. Furthermore, administration of a selective GABAb receptor antagonist (SCH50911) prior to MEGR treatment effectively blocked the inhibitory effects of MEGR on locomotor sensitization, but not CPP. These results suggest that Glycyrrhizae Radix blocked repeated METH-induced behavioral changes via GABAb receptors. PMID:25386216

  10. Initial locomotor sensitivity to cocaine varies widely among inbred mouse strains.

    PubMed

    Wiltshire, T; Ervin, R B; Duan, H; Bogue, M A; Zamboni, W C; Cook, S; Chung, W; Zou, F; Tarantino, L M

    2015-03-01

    Initial sensitivity to psychostimulants can predict subsequent use and abuse in humans. Acute locomotor activation in response to psychostimulants is commonly used as an animal model of initial drug sensitivity and has been shown to have a substantial genetic component. Identifying the specific genetic differences that lead to phenotypic differences in initial drug sensitivity can advance our understanding of the processes that lead to addiction. Phenotyping inbred mouse strain panels are frequently used as a first step for studying the genetic architecture of complex traits. We assessed locomotor activation following a single, acute 20 mg/kg dose of cocaine (COC) in males from 45 inbred mouse strains and observed significant phenotypic variation across strains indicating a substantial genetic component. We also measured levels of COC, the active metabolite, norcocaine and the major inactive metabolite, benzoylecgonine, in plasma and brain in the same set of inbred strains. Pharmacokinetic (PK) and behavioral data were significantly correlated, but at a level that indicates that PK alone does not account for the behavioral differences observed across strains. Phenotypic data from this reference population of inbred strains can be utilized in studies aimed at examining the role of psychostimulant-induced locomotor activation on drug reward and reinforcement and to test theories about addiction processes. Moreover, these data serve as a starting point for identifying genes that alter sensitivity to the locomotor stimulatory effects of COC. PMID:25727211

  11. Initial locomotor sensitivity to cocaine varies widely among inbred mouse strains

    PubMed Central

    Wiltshire, T.; Ervin, R. B.; Duan, H.; Bogue, M. A.; Zamboni, W. C.; Cook, S.; Chung, W.; Zou, F.; Tarantino, L. M.

    2015-01-01

    Initial sensitivity to psychostimulants can predict subsequent use and abuse in humans. Acute locomotor activation in response to psychostimulants is commonly used as an animal model of initial drug sensitivity and has been shown to have a substantial genetic component. Identifying the specific genetic differences that lead to phenotypic differences in initial drug sensitivity can advance our understanding of the processes that lead to addiction. Phenotyping inbred mouse strain panels are frequently used as a first step for studying the genetic architecture of complex traits. We assessed locomotor activation following a single, acute 20 mg/kg dose of cocaine (COC) in males from 45 inbred mouse strains and observed significant phenotypic variation across strains indicating a substantial genetic component. We also measured levels of COC, the active metabolite, norcocaine and the major inactive metabolite, benzoylecgonine, in plasma and brain in the same set of inbred strains. Pharmacokinetic (PK) and behavioral data were significantly correlated, but at a level that indicates that PK alone does not account for the behavioral differences observed across strains. Phenotypic data from this reference population of inbred strains can be utilized in studies aimed at examining the role of psychostimulant-induced locomotor activation on drug reward and reinforcement and to test theories about addiction processes. Moreover, these data serve as a starting point for identifying genes that alter sensitivity to the locomotor stimulatory effects of COC. PMID:25727211

  12. The Effects of 4-Methylethcathinone on Conditioned Place Preference, Locomotor Sensitization, and Anxiety-Like Behavior: A Comparison with Methamphetamine

    PubMed Central

    Xu, Peng; Qiu, Yi; Zhang, Yizhi; Βai, Yanping; Xu, Pengfei; Liu, Yuan; Kim, Jee Hyun

    2016-01-01

    Background: 4-Methylethcathinone is a drug that belongs to the second generation of synthetic cathinones, and recently it has been ranked among the most popular “legal highs”. Although it has similar in vitro neurochemical actions to other drugs such as cocaine, the behavioral effects of 4-methylethcathinone remain to be determined. Methods: The addictive potential and locomotor potentiation by 4-methylethcathinone were investigated in rats using the conditioned place preference and sensitization paradigm. Methamphetamine was used as a positive control. Because synthetic cathinones can have psychological effects, we also examined anxiety-like behavior using the elevated plus maze. Results: A conditioning dose of 10mg/kg 4-methylethcathinone was able to induce conditioned place preference and reinstatement (following 2 weeks of withdrawal). Acute or repeated injections of 4-methylethcathinone at 3 or 10mg/kg failed to alter locomotor activity. At 30mg/kg, however, acute 4-methylethcathinone increased locomotor activity compared with saline, while chronic 4-methylethcathinone induced a delayed and attenuated sensitization compared with methamphetamine. Additionally, repeated daily injections of 4-methylethcathinone (30mg/kg) reduced, whereas methamphetamine increased time spent by rats in the open arm of an elevated plus maze compared with saline injections. Interestingly, a 2-week withdrawal period following chronic injections of 4-methylethcathinone or methamphetamine increased time spent in the open arm in all rats. Conclusions: The rewarding properties of 4-methylethcathinone were found to be dissociated from its effects on locomotor activity. Additionally, chronic 4-methylethcathinone use may trigger abnormal anxious behaviors. These behavioral effects caused by 4-methylethcathinone appear to last even after a withdrawal period. PMID:26612552

  13. Argon blocks the expression of locomotor sensitization to amphetamine through antagonism at the vesicular monoamine transporter-2 and mu-opioid receptor in the nucleus accumbens.

    PubMed

    David, H N; Dhilly, M; Degoulet, M; Poisnel, G; Meckler, C; Vallée, N; Blatteau, J-É; Risso, J-J; Lemaire, M; Debruyne, D; Abraini, J H

    2015-01-01

    We investigated the effects of the noble gas argon on the expression of locomotor sensitization to amphetamine and amphetamine-induced changes in dopamine release and mu-opioid neurotransmission in the nucleus accumbens. We found (1) argon blocked the increase in carrier-mediated dopamine release induced by amphetamine in brain slices, but, in contrast, potentiated the decrease in KCl-evoked dopamine release induced by amphetamine, thereby suggesting that argon inhibited the vesicular monoamine transporter-2; (2) argon blocked the expression of locomotor and mu-opioid neurotransmission sensitization induced by repeated amphetamine administration in a short-term model of sensitization in rats; (3) argon decreased the maximal number of binding sites and increased the dissociation constant of mu-receptors in membrane preparations, thereby indicating that argon is a mu-receptor antagonist; (4) argon blocked the expression of locomotor sensitization and context-dependent locomotor activity induced by repeated administration of amphetamine in a long-term model of sensitization. Taken together, these data indicate that argon could be of potential interest for treating drug addiction and dependence. PMID:26151922

  14. Melatonin treatment during the incubation of sensitization attenuates methamphetamine-induced locomotor sensitization and MeCP2 expression.

    PubMed

    Wu, Jintao; Zhu, Dexiao; Zhang, Jing; Li, Guibao; Liu, Zengxun; Sun, Jinhao

    2016-02-01

    Behavior sensitization is a long-lasting enhancement of locomotor activity after exposure to psychostimulants. Incubation of sensitization is a phenomenon of remarkable augmentation of locomotor response after withdrawal and reflects certain aspects of compulsive drug craving. However, the mechanisms underlying these phenomena remain elusive. Here we pay special attention to the incubation of sensitization and suppose that the intervention of this procedure will finally decrease the expression of sensitization. Melatonin is an endogenous hormone secreted mainly by the pineal gland. It is effective in treating sleep disorder, which turns out to be one of the major withdrawal symptoms of methamphetamine (MA) addiction. Furthermore, melatonin can also protect neuronal cells against MA-induced neurotoxicity. In the present experiment, we treated mice with low dose (10mg/kg) of melatonin for 14 consecutive days during the incubation of sensitization. We found that melatonin significantly attenuated the expression of sensitization. In contrast, the vehicle treated mice showed prominent enhancement of locomotor activity after incubation. MeCP2 expression was also elevated in the vehicle treated mice and melatonin attenuated its expression. Surprisingly, correlation analysis suggested significant correlation between MeCP2 expression in the nucleus accumbens (NAc) and locomotion in both saline control and vehicle treated mice, but not in melatonin treated ones. MA also induced MeCP2 over-expression in PC12 cells. However, melatonin failed to reduce MeCP2 expression in vitro. Our results suggest that melatonin treatment during the incubation of sensitization attenuates MA-induced expression of sensitization and decreases MeCP2 expression in vivo. PMID:26416230

  15. Evidence for a role of endogenous neurotensin in the development of sensitization to the locomotor stimulant effect of morphine.

    PubMed

    Lévesque, Karine; Lamarche, Caroline; Rompré, Pierre-Paul

    2008-10-10

    This experiment was aimed at exploring the role of endogenous neurotensin in the development of sensitization to the locomotor stimulant effect of morphine. During the induction phase (Days 1, 3, 5 and 7), male Long-Evans adult rats were treated with the neurotensin antagonist SR-48692 (160, 320 or 640 microg/kg, i.p.) or its vehicle, followed by morphine (5.0 mg/kg, i.p.) or its vehicle, and their locomotor activity (ambulatory, non-ambulatory and vertical activity) was measured for 2 h. One week after the last injection, each group received a single injection of morphine (2.5 mg/kg, i.p.) and their locomotor activity was again measured for 2 h (sensitization test, day 14). Results show that SR-48692 alone did not change locomotion. Morphine stimulated locomotor activity, an effect that was stronger on day 7 than on day 1. The two higher doses of SR-48692 attenuated the acute stimulant effect of morphine and prevented the observed increase from day 1 to day 7. The sensitization test on day 14 showed that rats pre-treated with morphine alone displayed significantly stronger ambulatory and vertical activity than vehicle pre-treated rats, a sensitization effect that was attenuated by SR-48692. The present results suggest that endogenous neurotensin contributes to the acute locomotor stimulant effect of morphine and to the induction of its sensitization. PMID:18706409

  16. Individual Differences in Ethanol Locomotor Sensitization Are Associated with Dopamine D1 Receptor Intra-Cellular Signaling of DARPP-32 in the Nucleus Accumbens

    PubMed Central

    Abrahao, Karina Possa; Oliveira Goeldner, Francine; Souza-Formigoni, Maria Lucia Oliveira

    2014-01-01

    In mice there are clear individual differences in the development of behavioral sensitization to ethanol, a progressive potentiation of its psychomotor stimulant effect. Variability in the behavioral responses to ethanol has been associated with alcohol preference. Here we investigated if the functional hyperresponsiveness of D1 receptors observed in ethanol sensitized mice leads to an increased activation of DARPP-32, a central regulatory protein in medium spiny neurons, in the nucleus accumbens - a brain region known to play a role in drug reinforcement. Swiss Webster mice received ethanol (2.2 g/kg/day) or saline i.p. administrations for 21 days and were weekly evaluated regarding their locomotor activity. From those treated with ethanol, the 33% with the highest levels of locomotor activity were classified as “sensitized” and the 33% with the lowest levels as "non-sensitized”. The latter presented similar locomotor levels to those of saline-treated mice. Different subgroups of mice received intra-accumbens administrations of saline and, 48 h later, SKF-38393, D1 receptor agonist 0.1 or 1 µg/side. Indeed, sensitized mice presented functional hyperresponsiveness of D1 receptors in the accumbens. Two weeks following the ethanol treatment, other subgroups received systemic saline or SKF 10 mg/kg, 20 min before the euthanasia. The nucleus accumbens were dissected for the Western Blot analyses of total DARPP-32 and phospho-Thr34-DARPP-32 expression. D1 receptor activation induced higher phospho-Thr34-DARPP-32 expression in sensitized mice than in non-sensitized or saline. The functionally hyperresponsiveness of D1 receptors in the nucleus accumbens is associated with an increased phospho-Thr34-DARPP-32 expression after D1 receptor activation. These data suggest that an enduring increase in the sensitivity of the dopamine D1 receptor intracellular pathway sensitivity represents a neurobiological correlate associated with the development of locomotor

  17. Membrane potential oscillations in reticulospinal and spinobulbar neurons during locomotor activity.

    PubMed

    Einum, James F; Buchanan, James T

    2005-07-01

    Feedback from the spinal locomotor networks provides rhythmic modulation of the membrane potential of reticulospinal (RS) neurons during locomotor activity. To further understand the origins of this rhythmic activity, the timings of the oscillations in spinobulbar (SB) neurons of the spinal cord and in RS neurons of the posterior and middle rhombencephalic reticular nuclei were measured using intracellular microelectrode recordings in the isolated brain stem-spinal cord preparation of the lamprey. A diffusion barrier constructed just caudal to the obex allowed induction of locomotor activity in the spinal cord by bath application of an excitatory amino acid to the spinal bath. All of the ipsilaterally projecting SB neurons recorded had oscillatory membrane potentials with peak depolarizations in phase with the ipsilateral ventral root bursts, whereas the contralaterally projecting SB neurons were about evenly divided between those in phase with the ipsilateral ventral root bursts and those in phase with the contralateral bursts. In the brain stem under these conditions, 75% of RS neurons had peak depolarizations in phase with the ipsilateral ventral root bursts while the remainder had peak depolarizations during the contralateral bursts. Addition of a high-Ca2+, Mg2+ solution to the brain stem bath to reduce polysynaptic activity had little or no effect on oscillation timing in RS neurons, suggesting that direct inputs from SB neurons make a major contribution to RS neuron oscillations under these conditions. Under normal conditions when the brain is participating in the generation of locomotor activity, these spinal inputs will be integrated with other inputs to RS neurons. PMID:15744013

  18. The Glucagon-Like Peptide 1 Analogue Exendin-4 Attenuates the Nicotine-Induced Locomotor Stimulation, Accumbal Dopamine Release, Conditioned Place Preference as well as the Expression of Locomotor Sensitization in Mice

    PubMed Central

    Egecioglu, Emil; Engel, Jörgen A.; Jerlhag, Elisabet

    2013-01-01

    The gastrointestinal peptide glucagon-like peptide 1 (GLP-1) is known to regulate consummatory behavior and is released in response to nutrient ingestion. Analogues of this peptide recently emerged as novel pharmacotherapies for treatment of type II diabetes since they reduce gastric emptying, glucagon secretion as well as enhance glucose-dependent insulin secretion. The findings that GLP-1 targets reward related areas including mesolimbic dopamine areas indicate that the physiological role of GLP-1 extends beyond food intake and glucose homeostasis control to include reward regulation. The present series of experiments was therefore designed to investigate the effects of the GLP-1 receptor agonist, Exendin-4 (Ex4), on established nicotine-induced effects on the mesolimbic dopamine system in mice. Specifically, we show that treatment with Ex4, at a dose with no effect per se, attenuate nicotine-induced locomotor stimulation, accumbal dopamine release as well as the expression of conditioned place preference in mice. In accordance, Ex4 also blocks nicotine-induced expression of locomotor sensitization in mice. Given that development of nicotine addiction largely depends on the effects of nicotine on the mesolimbic dopamine system these findings indicate that the GLP-1 receptor may be a potential target for the development of novel treatment strategies for nicotine cessations in humans. PMID:24204788

  19. The dorsomedial shell of the nucleus accumbens facilitates cocaine-induced locomotor activity during the induction of behavioral sensitization.

    PubMed

    Todtenkopf, M S; Carreiras, T; Melloni, R H; Stellar, J R

    2002-04-01

    The mesolimbic dopamine system has been intensely studied as the neural circuit mediating the locomotor response to psychostimulants and behavioral sensitization. In particular, the dopaminergic innervation of the nucleus accumbens has been implicated as a site responsible for the manifestations of behavioral sensitization. Previous studies have demonstrated an augmented release of dopamine in the nucleus accumbens upon a systemic injection of a psychostimulant. In addition, alterations in the dopaminergic innervation patterns in this brain region have been demonstrated in animals that received repeated injections of cocaine. Furthermore, lesions of projection sites that have terminations in the nucleus accumbens have demonstrated alterations in psychostimulant induced locomotion, both acutely, as well as in sensitization paradigms. Since dopamine in the nucleus accumbens is believed to regulate several excitatory amino acid inputs, the present study examined the effects of a localized electrolytic lesion in the dorsomedial shell of the nucleus accumbens in order to better understand the functional role this brain region has in behavioral sensitization. All animals received bi-daily injections of 15 mg/kg i.p. cocaine. Only those demonstrating behavioral sensitization after a subsequent challenge dose were included in the analysis. Following acute exposure to cocaine, lesioned animals did not show any difference in their locomotor response when compared with sham controls. However, after repeated exposure to cocaine, sensitized animals demonstrated a significant attenuation in locomotor behavior when compared with sensitized sham controls. This decrease in horizontal locomotion persisted 2 days into withdrawal, yet dissipated in the sensitized animals that were challenged 2 weeks following their last injection. The data presented here demonstrate that the dorsomedial shell of the nucleus accumbens plays an important role in the initial stages of behavioral

  20. Cocaine-induced locomotor sensitization in rats correlates with nucleus accumbens activity on manganese-enhanced MRI.

    PubMed

    Perrine, Shane A; Ghoddoussi, Farhad; Desai, Kirtan; Kohler, Robert J; Eapen, Ajay T; Lisieski, Michael J; Angoa-Perez, Mariana; Kuhn, Donald M; Bosse, Kelly E; Conti, Alana C; Bissig, David; Berkowitz, Bruce A

    2015-11-01

    A long-standing goal of substance abuse research has been to link drug-induced behavioral outcomes with the activity of specific brain regions to understand the neurobiology of addiction behaviors and to search for drug-able targets. Here, we tested the hypothesis that cocaine produces locomotor (behavioral) sensitization that correlates with increased calcium channel-mediated neuroactivity in brain regions linked with drug addiction, such as the nucleus accumbens (NAC), anterior striatum (AST) and hippocampus, as measured using manganese-enhanced MRI (MEMRI). Rats were treated with cocaine for 5 days, followed by a 2-day drug-free period. The following day, locomotor sensitization was quantified as a metric of cocaine-induced neuroplasticity in the presence of manganese. Immediately following behavioral testing, rats were examined for changes in calcium channel-mediated neuronal activity in the NAC, AST, hippocampus and temporalis muscle, which was associated with behavioral sensitization using MEMRI. Cocaine significantly increased locomotor activity and produced behavioral sensitization compared with saline treatment of control rats. A significant increase in MEMRI signal intensity was determined in the NAC, but not AST or hippocampus, of cocaine-treated rats compared with saline-treated control rats. Cocaine did not increase signal intensity in the temporalis muscle. Notably, in support of our hypothesis, behavior was significantly and positively correlated with MEMRI signal intensity in the NAC. As neuronal uptake of manganese is regulated by calcium channels, these results indicate that MEMRI is a powerful research tool to study neuronal activity in freely behaving animals and to guide new calcium channel-based therapies for the treatment of cocaine abuse and dependence. PMID:26411897

  1. Adenosine (A)(2A)receptor modulation of nicotine-induced locomotor sensitization. A pharmacological and transgenic approach.

    PubMed

    Jastrzębska, Joanna; Nowak, Ewa; Smaga, Irena; Bystrowska, Beata; Frankowska, Małgorzata; Bader, Michael; Filip, Małgorzata; Fuxe, Kjell

    2014-06-01

    Preclinical evidence indicates an important role of adenosine (A)(2A) receptors in drug addiction while their therapeutic relevance is still a matter of debate. We examined the influence of the A(2A) receptor agonist CGS 21680 and the antagonist KW 6002 on nicotine sensitization and conditioned locomotor activity in adult (8-week old) male Sprague-Dawley rats (WT). Moreover, behavioral responses to nicotine were studied in rats overexpressing A(2A) receptors under the control of the neuronal specific enolase (NSE) promotor. Changes in the levels of dopamine, glutamate and γ-aminobutyric acid in wild type (WT) and NSEA(2A) rats were determined with using LC-MS. KW 6002 significantly enhanced expression of nicotine sensitization and conditioned locomotion, while CGS 21680 reduced all these effects in WT rats. A reduction of the expression of nicotine-evoked conditioned locomotor activity was also observed in the NSEA(2A) animals. The transgenic rats displayed a reduced basal tissue level of glutamate in the prefrontal cortex and hippocampus while dopamine basal levels in the nucleus accumbens were raised. Chronic nicotine treatment caused a significant reduction in the glutamate tissue level in the dorsal and ventral striatum, prefrontal cortex and cerebellum in wild type rats. In NSEA(2A) animals the same drug treatment instead produced a rise of glutamate levels in the hippocampus and dorsal striatum. Taken together, A(2A) receptor signaling in the rat brain can counteract locomotor sensitization and conditioned locomotion to nicotine which are related to nicotine reward-learning. It is suggested that treatment with A(2A) receptor agonists can help counteract the abuse actions of nicotine. PMID:24632528

  2. Amphetamine locomotor sensitization is accompanied with an enhanced high K⁺-stimulated Dopamine release in the rat medial prefrontal cortex.

    PubMed

    Casanova, José Patricio; Velis, Gabriela Paz; Fuentealba, José Antonio

    2013-01-15

    In the present work, we assessed dopamine extracellular levels in the medial Prefrontal Cortex of rats repeatedly treated with amphetamine during early abstinence. Rats were injected once daily with amphetamine for five consecutive days. A sensitized locomotor response was observed in 55% of animals treated. After two days of abstinence, an amphetamine challenge dose was given to all rats and locomotor activity was measured to assess expression of sensitization. A persistence of heightened locomotor response to amphetamine was observed in rats that developed sensitization. Twenty four hours after amphetamine challenge, microdialysis experiments were carried out to evaluate basal and stimulated dopamine extracellular levels in the medial Prefrontal Cortex. Rats that developed and expressed amphetamine locomotor sensitization showed a significantly greater high potassium-stimulated dopamine release compared to Non-sensitized and Saline rats. These results show that the increased dopamine releasability in the medial Prefrontal Cortex occurs soon after development of amphetamine locomotor sensitization, and might be underlying the early expression of sensitization. PMID:23047059

  3. The effect of early environmental manipulation on locomotor sensitivity and methamphetamine conditioned place preference reward.

    PubMed

    Hensleigh, E; Pritchard, L M

    2014-07-15

    Early life stress leads to several effects on neurological development, affecting health and well-being later in life. Instances of child abuse and neglect are associated with higher rates of depression, risk taking behavior, and an increased risk of drug abuse later in life. This study used repeated neonatal separation of rat pups as a model of early life stress. Rat pups were either handled and weighed as controls or separated for 180 min per day during postnatal days 2-8. In adulthood, male and female rats were tested for methamphetamine conditioned place preference reward and methamphetamine induced locomotor activity. Tissue samples were collected and mRNA was quantified for the norepinephrine transporter in the prefrontal cortex and the dopamine transporter in the nucleus accumbens. Results indicated rats given methamphetamine formed a conditioned place preference, but there was no effect of early separation or sex. Separated males showed heightened methamphetamine-induced locomotor activity, but there was no effect of early separation for females. Overall females were more active than males in response to both saline and methamphetamine. No differences in mRNA levels were observed across any conditions. These results suggest early neonatal separation affects methamphetamine-induced locomotor activity in a sex-dependent manner but has no effects on methamphetamine conditioned place preference. PMID:24713150

  4. THE EFFECT OF EARLY ENVIRONMENTAL MANIPULATION ON LOCOMOTOR SENSITIVITY AND METHAMPHETAMINE CONDITIONED PLACE PREFERENCE REWARD

    PubMed Central

    Hensleigh, E.; Pritchard, L. M.

    2014-01-01

    Early life stress leads to several effects on neurological development, affecting health and well-being later in life. Instances of child abuse and neglect are associated with higher rates of depression, risk taking behavior, and an increased risk of drug abuse later in life. This study used repeated neonatal separation of rat pups as a model of early life stress. Rat pups were either handled and weighed as controls or separated for 180 minutes per day during postnatal days 2-8. In adulthood, male and female rats were tested for methamphetamine conditioned place preference reward and methamphetamine induced locomotor activity. Tissue samples were collected and mRNA was quantified for the norepinephrine transporter in the prefrontal cortex and the dopamine transporter in the nucleus accumbens. Results indicated rats given methamphetamine formed a conditioned place preference, but there was no effect of early separation or sex. Separated males showed heightened methamphetamine-induced locomotor activity, but there was no effect of early separation for females. Overall females were more active than males in response to both saline and methamphetamine. No differences in mRNA levels were observed across any conditions. These results suggest early neonatal separation affects methamphetamine-induced locomotor activity in a sex-dependent manner but has no effects on methamphetamine conditioned place preference. PMID:24713150

  5. The expression of methiopropamine-induced locomotor sensitization requires dopamine D2, but not D1, receptor activation in the rat.

    PubMed

    Yoon, Hyung Shin; Cai, Wen Ting; Lee, Young Hun; Park, Kyung Tae; Lee, Yong Sup; Kim, Jeong-Hoon

    2016-09-15

    Methiopropamine (MPA) is a structural analog to methamphetamine and is categorized as a novel psychoactive substance that needs to be controlled. However, no study has been performed to determine whether MPA actually develops an addiction-like behavior similar to those arising from other psychomotor stimulants. Thus, we attempted to determine whether MPA produces locomotor sensitization in a manner similar to amphetamine. In the first experiment, rats were pre-exposed to either saline or one of three different doses of MPA (0.2, 1.0, or 5.0mg/kg, IP) with a total of four injections, respectively. After a 2-week withdrawal period, when they were challenged with the same dose of MPA, only the group that was pre-exposed to high dose of MPA (5.0mg/kg) showed sensitized locomotor activity. In the second experiment, all rats were pre-exposed to MPA (5.0mg/kg) only. Interestingly, the expression of MPA-induced locomotor sensitization was inhibited by a pre-injection of a dopamine D2 receptor antagonist, eticlopride (0.05mg/kg, IP), though not by a dopamine D1 receptor antagonist, SCH23390 (0.01mg/kg, IP). These results suggest that repeated injection of MPA in the rat provokes certain neuronal changes involving specific, likely D2, dopamine receptor-mediated pathways that contribute to the expression of MPA-induced locomotor sensitization. PMID:27265782

  6. Sensitivity of the hypothalamic paraventricular nucleus to the locomotor-activating effects of neuromedin U in obesity

    PubMed Central

    Novak, Colleen M.; Zhang, Minzhi; Levine, James A.

    2009-01-01

    Obesity is associated with a decrease in energy expenditure relative to energy intake. The decrease in physical activity associated with obesity in several species, including humans, contributes to decreased energy expenditure. Several hormones and neuropeptides that affect appetite also modulate physical activity, including neuromedin U (NMU), a peptide found in the gut and brain. We have demonstrated that NMU microinjected into the hypothalamic paraventricular nucleus (PVN) in rats increases the energy expenditure associated with physical activity, called non-exercise activity thermogenesis (NEAT). Here we examined whether obesity in rats is related to decreased sensitivity of the PVN to the locomotor-activating effect of NMU. Diet-induced obese (DIO) rats and lean, diet-resistant (DR) rats were given PVN microinjections of increasing doses of NMU both before and after one month on a high-fat diet. We found that NMU increases physical activity, energy expenditure, and NEAT in a dose-dependent manner in both DR and DIO rats, both before and after one month on the high-fat diet. Before high-fat feeding, the obesity-prone and lean rats showed similar levels of physical activity after intra-PVN microinjections of NMU. After one month of the high-fat diet, however, the obesity-resistant rats showed significantly more NMU-induced physical activity compared to the obese DIO rats. Taken together with previous studies, these results suggest that obesity may represent a state associated with decreased central sensitivity to neuropeptides such as NMU that increase physical activity and therefore energy expenditure. PMID:17706946

  7. Escalation of food-maintained responding and sensitivity to the locomotor stimulant effects of cocaine in mice

    PubMed Central

    Goeders, James E.; Murnane, Kevin S.; Banks, Matthew L.; Fantegrossi, William E.

    2009-01-01

    Escalation of drug self-administration is a consequence of extended drug access and is thought to be specifically related to addiction, but few studies have investigated whether intake of non-drug reinforcers may also escalate with extended-access. The goal of these studies was to determine the effects of limited and extended-access to food reinforcers on behavioral and pharmacological endpoints in mice. In distinct groups, responding on a lever was maintained by liquid reinforcement, or nose-poke responses were maintained by sucrose pellets or liquid food in sessions lasting 1 hour (limited-access) or 10 hours (extended-access). The reinforcing strength of each food, as well as reinforcer-associated cues, was tested before and after extended-access using a progressive ratio (PR) schedule, and locomotor activity in response to novelty and increasing doses of cocaine was assessed in an open field setting in all animals after access to food reinforcers. Escalation of lever-pressing behavior reinforced by liquid food, but not nose-poke behavior reinforced by liquid food or sucrose pellets, was observed across successive extended-access sessions. A concomitant increase in the reinforcing strength of liquid food and its associated cues was apparent in mice that escalated their responding, but not in mice that did not escalate. Finally, extended reinforcer access leading to behavioral escalation was accompanied by an increased sensitivity to the psychostimulant effects of cocaine compared to limited-access. These findings indicate that behavioral escalation can develop as a consequence of extended-access to a non-drug reinforcer, although both the nature of the reinforcer (liquid versus solid food) and the topography of the operant response (lever versus nose-poke) modulate its development. These data also suggest that some of the behavioral and pharmacological corrolaries of behavioral escalation observed following extended-access to drug self-administration may not be

  8. Effects of gender on locomotor sensitivity to amphetamine, body weight, and fat mass in regulator of G protein signaling 9 (RGS9) knockout mice.

    PubMed

    Walker, Paul D; Jarosz, Patricia A; Bouhamdan, Mohamad; MacKenzie, Robert G

    2015-01-01

    Regulator of G-protein signaling (RGS) protein 9-2 is enriched in the striatum where it modulates dopamine and opioid receptor-mediated signaling. RGS9 knockout (KO) mice show increased psychostimulant-induced behavioral sensitization, as well as exhibit higher body weights and greater fat accumulation compared to wild-type (WT) littermates. In the present study, we found gender influences on each of these phenotypic characteristics. Female RGS9 KO mice exhibited greater locomotor sensitization to amphetamine (1.0mg/kg) treatment as compared to male RGS9 KO mice. Male RGS9 KO mice showed increased body weights as compared to male WT littermates, while no such differences were detected in female mice. Quantitative magnetic resonance showed that male RGS9 KO mice accumulated greater fat mass vs. WT littermates at 5months of age. Such observations could not be explained by increased caloric consumption since male and female RGS9 KO mice demonstrated equivalent daily food intake as compared to their respective WT littermates. Although indirect calorimetry methods found decreased oxygen consumption and carbon dioxide production during the 12-hour dark phase in male RGS9 KO vs. WT mice which are indicative of less energy expenditure, male RGS9 KO mice exhibited lower levels of locomotor activity during this period. Genotype had no effect on metabolic activities when KO and WT groups were compared under fasting vs. feeding treatments. In summary, these results highlight the importance of factoring gender into the experimental design since many studies conducted in RGS9 KO mice utilize locomotor activity as a measured outcome. PMID:25455864

  9. Intra-ventral tegmental area HIV-1 Tat1–86 attenuates nicotine-mediated locomotor sensitization and alters mesocorticolimbic ERK and CREB signaling in rats

    PubMed Central

    Zhu, Jun; Midde, Narasimha M.; Gomez, Adrian M.; Sun, Wei-Lun; Harrod, Steven B.

    2015-01-01

    Cigarette smoking prevalence in the HIV-positive individuals is profoundly higher than that in the HIV-negative individuals. We have demonstrated that HIV-1 transgenic rats exhibit attenuated nicotine-mediated locomotor activity, altered cAMP response element binding protein (CREB) and extracellular regulated kinase (ERK1/2) signaling in the mesocorticolimbic regions. This study investigated the role of HIV-1 transactivator of transcription (Tat) protein in the alterations of nicotine-mediated behavior and the signaling pathway observed in the HIV-1 transgenic rats. Rats received bilateral microinjection of recombinant Tat1–86 (25 μg/side) or vehicle directed at ventral tegmental area (VTA) followed by locomotor testing in response to 13 daily intravenous injections of nicotine (0.05 mg/kg, freebase, once/day) or saline. Further, we examined the phosphorylated levels of CREB (pCREB) and ERK1/2 (pERK1/2) in the prefrontal cortex (PFC), nucleus accumbens (NAc) and VTA. Tat diminished baseline activity in saline control rats, and attenuated nicotine-induced behavioral sensitization. Following repeated saline injection, the basal levels of pERK1 in the NAc and VTA and pERK2 in VTA were lower in the vehicle control group, relative to the Tat group. After repeated nicotine injection, pERK1 in NAc and VTA and pERK2 in VTA were increased in the vehicle group, but not in the Tat group. Moreover, repeated nicotine injections decreased pCREB in the PFC and VTA in the Tat group but not in the vehicle group. Thus, these findings indicate that the direct injection of Tat at the VTA may mediate CREB and ERK activity in response to nicotine-induced locomotor activity. PMID:26150803

  10. A dose-response study of separate and combined effects of the serotonin agonist 8-OH-DPAT and the dopamine agonist quinpirole on locomotor sensitization, cross-sensitization, and conditioned activity.

    PubMed

    Johnson, Eric F; Szechtman, Henry

    2016-08-01

    Chronic treatment with the dopamine D2/D3 agonist, quinpirole, or the serotonin 1A agonist, 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT), induces behavioral sensitization. It is not known whether both drugs produce sensitization through a shared mechanism. Here, we examine whether quinpirole and 8-OH-DPAT show cross-sensitization and impact sensitization, as would be expected from shared mechanisms. Male rats (N=208) were assigned randomly to 16 groups formed by crossing four doses of quinpirole (0, 0.03125, 0.0625, or 0.125 mg/kg) with four doses of 8-OH-DPAT (0, 0.03125, 0.625, or 0.125 mg/kg). After a course of 10 drug treatments administered twice per week in locomotor activity chambers, all groups were challenged on separate tests with quinpirole (0.1 mg/kg), 8-OH-DPAT (0.1 mg/kg), or saline, and locomotor activity was evaluated. Challenge tests with quinpirole and 8-OHDPAT showed no cross-sensitization between the drugs. Chronic quinpirole (0.125 mg/kg) administration induced a sensitized quinpirole response that was attenuated dose-dependently by chronic 8-OH-DPAT cotreatment. Cotreatment with quinpirole (0.0625 mg/kg) and 8-OH-DPAT (all doses) induced quinpirole sensitization. Chronic 8-OH-DPAT (0.125 mg/kg) induced a sensitized 8-OHDPAT response that was prevented by chronic cotreatment with the lowest but not the highest dose of quinpirole. Cotreatment with 8-OHDPAT (0.0625) and quinpirole (0.125 mg/kg) induced sensitization to 8-OH-DPAT. The saline challenge test showed elevated locomotor activity in chronic quinpirole (0.125 mg/kg) and 8-OHDPAT (0.0625, 0.125 mg/kg) alone groups, and in seven of nine cotreated groups. The absence of cross-sensitization suggests separate mechanisms of sensitization to quinpirole and 8-OH-DPAT. Cotreatment effects suggest that induction of sensitization can be modulated by serotonin 1A and D2/D3 activity. PMID:26871406

  11. Availability of N-Methyl-d-Aspartate Receptor Coagonists Affects Cocaine-Induced Conditioned Place Preference and Locomotor Sensitization: Implications for Comorbid Schizophrenia and Substance Abuse.

    PubMed

    Puhl, Matthew D; Berg, Alexandra R; Bechtholt, Anita J; Coyle, Joseph T

    2015-06-01

    Schizophrenia is associated with high prevalence of substance abuse. Recent research suggests that dysregulation of N-methyl-d-aspartate receptor (NMDAR) function may play a role in the pathophysiology of both schizophrenia and drug addiction, and thus, may account for this high comorbidity. Our laboratory has developed two transgenic mouse lines that exhibit contrasting NMDAR activity based on the availability of the glycine modulatory site (GMS) agonists d-serine and glycine. Glycine transporter 1 knockdowns (GlyT1(+/-)) exhibit NMDAR hyperfunction, whereas serine racemase knockouts (SR(-/-)) exhibit NMDAR hypofunction. We characterized the behavior of these lines in a cocaine-induced (20 mg/kg) conditioned place preference (CPP) and locomotor sensitization paradigm. Compared with wild-type mice, GlyT1(+/-) mice displayed hastened extinction of CPP and robust cocaine-induced reinstatement. SR(-/-) mice appeared to immediately "forget" the learned preference, because they did not exhibit cocaine-induced reinstatement and also displayed attenuated locomotor sensitization. Treatment of GlyT1(+/-) mice with gavestinel (10 mg/kg on day 1; 5 mg/kg on days 2-17), a GMS antagonist, attenuated cocaine-induced CPP and caused them to immediately "forget" the learned preference. Treatment of SR(-/-) mice with d-serine (300 mg/kg on day 1; 150 mg/kg on days 2-17) to normalize brain levels caused them to avoid the cocaine-paired side of the chamber during extinction. These results highlight NMDAR dysfunction as a possible neural mechanism underlying comorbid schizophrenia and substance abuse. Also, these findings suggest drugs that directly or indirectly activate the NMDAR GMS could be an effective treatment of cocaine abuse. PMID:25788713

  12. SLO-1-Channels of Parasitic Nematodes Reconstitute Locomotor Behaviour and Emodepside Sensitivity in Caenorhabditis elegans slo-1 Loss of Function Mutants

    PubMed Central

    Schniederjans, Monika; Miltsch, Sandra M.; Krücken, Jürgen; Guest, Marcus; Holden-Dye, Lindy; Harder, Achim; von Samson-Himmelstjerna, Georg

    2011-01-01

    The calcium-gated potassium channel SLO-1 in Caenorhabditis elegans was recently identified as key component for action of emodepside, a new anthelmintic drug with broad spectrum activity. In this study we identified orthologues of slo-1 in Ancylostoma caninum, Cooperia oncophora, and Haemonchus contortus, all important parasitic nematodes in veterinary medicine. Furthermore, functional analyses of these slo-1 orthologues were performed using heterologous expression in C. elegans. We expressed A. caninum and C. oncophora slo-1 in the emodepside-resistant genetic background of the slo-1 loss-of-function mutant NM1968 slo-1(js379). Transformants expressing A. caninum slo-1 from C. elegans slo-1 promoter were highly susceptible (compared to the fully emodepside-resistant slo-1(js379)) and showed no significant difference in their emodepside susceptibility compared to wild-type C. elegans (p = 0.831). Therefore, the SLO-1 channels of A. caninum and C. elegans appear to be completely functionally interchangeable in terms of emodepside sensitivity. Furthermore, we tested the ability of the 5′ flanking regions of A. caninum and C. oncophora slo-1 to drive expression of SLO-1 in C. elegans and confirmed functionality of the putative promoters in this heterologous system. For all transgenic lines tested, expression of either native C. elegans slo-1 or the parasite-derived orthologue rescued emodepside sensitivity in slo-1(js379) and the locomotor phenotype of increased reversal frequency confirming the reconstitution of SLO-1 function in the locomotor circuits. A potent mammalian SLO-1 channel inhibitor, penitrem A, showed emodepside antagonising effects in A. caninum and C. elegans. The study combined the investigation of new anthelmintic targets from parasitic nematodes and experimental use of the respective target genes in C. elegans, therefore closing the gap between research approaches using model nematodes and those using target organisms. Considering the still

  13. The skin sensitization potential of four alkylalkanolamines.

    PubMed

    Leung, H W; Blaszcak, D L

    1998-04-01

    The skin sensitization potential of 4 alkylalkanolamines (N-methylethanolamine, N,N-dimethylethanolamine, N-methyldiethanolamine and N,N-diethylethanolamine), was evaluated in a guinea pig maximation procedure by the method of Magnusson and Kligman. While all 4 alkylalkanolamines tested were irritating to the guinea pig skin, only N-methylethanolamine showed potential to induce allergic contact dermatitis. None of the remaining 3 alkylalkanolamines exhibited clear skin responses suggestive of sensitization. PMID:9554055

  14. Microinjection of CART (cocaine- and amphetamine-regulated transcript) peptide into the nucleus accumbens inhibits the cocaine-induced upregulation of dopamine receptors and locomotor sensitization.

    PubMed

    Peng, Qinghua; Sun, Xi; Liu, Ziyong; Yang, Jianghua; Oh, Ki-Wan; Hu, Zhenzhen

    2014-09-01

    Repeated exposure to addictive drugs enhances dopamine receptor (DR) signaling and the ultimate phosphorylation of the cyclic adenosine 5'-monophosphate (cAMP)-response element-binding protein (CREB)-regulated cocaine- and amphetamine-regulated transcript (CART) expression in the nucleus accumbens (NAcc). These effects are known to contribute to the expression of behavioral sensitization. CART peptides are neuropeptides that modulate drug reward and reinforcement. The present experiments investigated the effects of CART 55-102 microinjection into the NAcc on (1) the phosphorylation of CREB, (2) cAMP/protein kinase A (PKA) signaling and (3) extracellular signal-regulated kinase (ERK) phosphorylated kinase signaling. Here, we show that repeated microinjections into the NAcc of CART 55-102 peptides (1.0 or 2.5μg, 0.5μl/side) attenuates cocaine-induced enhancements of D1R, D2R and D3R phosphorylation in this sites. Furthermore, the microinjection of CART 55-102 followed by repeated injections of cocaine (15mg/kg) dose-dependently blocked the enhancement of cAMP levels, PKA activity and pERK and pCREB levels on the fifth day of cocaine administration. The cocaine-induced locomotor activity and behavioral sensitization in rats were also inhibited by the 5-day-microinjection of CART peptides. These results suggest that the phosphorylation of CREB by cocaine in the NAcc was blocked by the CART 55-102 peptide via the inhibition of D1R and D2R stimulation, D3R phosphorylation, cAMP/PKA signaling and ERK phosphorylated kinase signaling. These effects may have played a compensatory inhibitory role in the behavioral sensitization of rats that received microinjections of CART 55-102. PMID:24953280

  15. MDMA (ecstasy) modulates locomotor and prefrontal cortex sensory evoked activity.

    PubMed

    Atkins, Kristal; Burks, Tilithia; Swann, Alan C; Dafny, Nachum

    2009-12-11

    Ingestion of 3, 4-methylenedioxymethamphetamine (MDMA) leads to heightened response to sensory stimulation; thus, MDMA is referred to as "ecstasy" because it produces pleasurable enhancement of such sensation. There have been no electrophysiological studies that report the consequences of MDMA on sensory input. The present study was initiated to study the effects of acute and chronic MDMA on locomotor activity and sensory evoked field potential from freely behaving rats previously implanted with permanent electrodes in the prefrontal cortex (PFC). The main findings of this study are that: (1) acute MDMA augments locomotor behavior and attenuates the incoming sensory input, (2) chronic treatment of MDMA elicits behavioral sensitization, (3) chronic administration of MDMA results in attenuation of the baseline activity of the sensory evoked field potential, and (4) administration of rechallenge MDMA result in enhancement of the PFC sensory evoked field potential. PMID:19769950

  16. Assessing locomotor-stimulating effects of cocaine in rodents.

    PubMed

    Morgan, Drake; Dupree, Jameson P; Bibbey, Alex D; Sizemore, Glen M

    2012-01-01

    Locomotor activity procedures are useful for characterizing the behavioral effects of a drug, the influence of pharmacological, neurobiological, and environmental manipulations on drug sensitivity, and changes in activity following repeated administration (e.g., tolerance or sensitization) are thought to be related to the development of an addiction-like behavioral phenotype. The effects of cocaine on locomotor activity have been relatively extensively characterized. Many of the published studies use between-subject experimental designs, even though changes in sensitivity within a particular individual due to experimental manipulations, or behavioral and pharmacological histories is potentially the most important outcome as these changes may relate to differential development of an addiction-like phenotype in some, but not all, animals (including humans). The two behavioral protocols described herein allow extensive within-subject analyses. The first protocol uses daily locomotor activity levels as a stable baseline to assess the effects of experimental manipulations, and the second uses a pre- versus post-session experimental design to demonstrate the importance of drug-environment interactions in determining the behavioral effects of cocaine. PMID:22231824

  17. Capacity of novelty-induced locomotor activity and the hole-board test to predict sensitivity to the conditioned rewarding effects of cocaine.

    PubMed

    Arenas, M Carmen; Daza-Losada, Manuel; Vidal-Infer, Antonio; Aguilar, Maria A; Miñarro, José; Rodríguez-Arias, Marta

    2014-06-22

    Novelty-seeking in rodents, defined as enhanced specific exploration of novel situations, is considered to predict the response of animals to drugs of abuse and, thus, allow "drug-vulnerable" individuals to be identified. The main objective of this study was to assess the predictive ability of two well-known paradigms of the novelty-seeking trait - novelty-induced locomotor activity (which distinguishes High- and Low-Responder mice, depending on their motor activity) and the hole-board test (which determines High- and Low-Novelty Seeker mice depending on the number of head dips they perform) - to identify subjects that would subsequently be more sensitive to the conditioned rewarding effects of cocaine in a population of young adult (PND 56) and adolescent (PND 35) OF1 mice of both sexes. Conditioned place preference (CPP), a useful tool for evaluating the sensitivity of individuals to the incentive properties of addictive drugs, was induced with a sub-threshold dose of cocaine (1 mg/kg, i.p.). Our results showed that novelty-induced motor activity had a greater predictive capacity to identify "vulnerable-drug" individuals among young-adult mice (PND 56), while the hole-board test was more effective in adolescents (PND 35). High-NR young-adults, which presented higher motor activity in the first ten minutes of the test (novelty-reactivity), were 3.9 times more likely to develop cocaine-induced CPP than Low-NR young-adults. When total activity (1h) was evaluated (novelty-habituation), only High-R (novelty-non-habituating) young-adult male and Low-R (novelty-habituating) female mice produced a high conditioning score. However, only High-Novelty Seeker male and female adolescents and Low-Novelty Seeker female young-adult animals (according to the hole-board test), acquired cocaine-induced CPP. These findings should contribute to the development of screening methods for identifying at-risk human drug users and prevention strategies for those with specific

  18. Food restriction alters N'-propyl-4,5,6,7-tetrahydrobenzothiazole-2,6-diamine dihydrochloride (pramipexole)-induced yawning, hypothermia, and locomotor activity in rats: evidence for sensitization of dopamine D2 receptor-mediated effects.

    PubMed

    Collins, Gregory T; Calinski, Diane M; Newman, Amy Hauck; Grundt, Peter; Woods, James H

    2008-05-01

    Food restriction enhances sensitivity to the reinforcing effects of a variety of drugs of abuse including opiates, nicotine, and psychostimulants. Food restriction has also been shown to alter a variety of behavioral and pharmacological responses to dopaminergic agonists, including an increased sensitivity to the locomotor stimulatory effects of direct- and indirect-dopamine agonists, elevated extracellular dopamine levels in responses to psychostimulants, as well as suppression of agonist-induced yawning. Behavioral and molecular studies suggest that augmented dopaminergic responses observed in food-restricted animals result from a sensitization of the dopamine D2 receptor; however, little is known about how food restriction affects dopamine D3 receptor function. The current studies were aimed at better defining the effects of food restriction on D2 and D3 receptor function by assessing the capacity of N'-propyl-4,5,6,7-tetrahydrobenzothiazole-2,6-diamine dihydrochloride (pramipexole) to induce yawning, penile erection (PE), hypothermia, and locomotor activity in free-fed and food-restricted rats. Food restriction resulted in a suppression of pramipexole-induced yawning, a sensitized hypothermic response, and an enhanced locomotor response to pramipexole, effects that are suggestive of an enhanced D2 receptor activity; no effect on pramipexole-induced PE was observed. Antagonist studies further supported a food restriction-induced enhancement of the D2 receptor activity because the D2 antagonist 3-[4-(4-chlorophenyl)-4-hydroxypiperidin-l-yl]methyl-1H-indole (L741,626) recovered pramipexole-induced yawning to free-fed levels, whereas yawning and PE were suppressed following pretreatment with the D3 antagonist N-{4-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-trans-but-2-enyl}-4-pyridine-2-yl-benzamide hydrochloride (PG01037). The results of the current studies suggest that food restriction sensitized rats to the D2-mediated effects of pramipexole while having no effect

  19. The 'GALS' locomotor screen.

    PubMed Central

    Doherty, M; Dacre, J; Dieppe, P; Snaith, M

    1992-01-01

    The locomotor system is complex and difficult to examine. A selective clinical process to detect important locomotor abnormalities and functional disability could prove valuable. A screen based on a tested 'minimal' history and examination system is described, together with a simple method of recording. The screen is fast and easy to perform. As well as providing a useful introduction to examination of the locomotor system, the screen includes objective observation of functional movements relevant to activities of daily living. Its inclusion in the undergraduate clerking repertoire could improve junior doctors' awareness and recognition of rheumatic disease and general disability. It could also provide a valuable screening test for use in general practice. Images PMID:1444632

  20. Locomotor exercise in weightlessness

    NASA Technical Reports Server (NTRS)

    Thornton, W.; Whitmore, H.

    1991-01-01

    The requirements for exercise in space by means of locomotion are established and addressed with prototype treadmills for use during long-duration spaceflight. The adaptation of the human body to microgravity is described in terms of 1-G locomotor biomechanics, the effects of reduced activity, and effective activity-replacement techniques. The treadmill is introduced as a complement to other techniques of force replacement with reference given to the angle required for exercise. A motor-driven unit is proposed that can operate at a variety of controlled speeds and equivalent grades. The treadmills permit locomotor exercise as required for long-duration space travel to sustain locomotor and cardiorespiratory capacity at a level consistent with postflight needs.

  1. Effect of caffeine on cocaine locomotor stimulant activity in rats.

    PubMed

    Misra, A L; Vadlamani, N L; Pontani, R B

    1986-03-01

    The effect of caffeine on the locomotor stimulant activity induced by intravenous cocaine in rats was investigated. Low doses of caffeine (20 mg/kg IP) potentiated the locomotor activity induced by 1, 2.5 mg/kg intravenous doses of cocaine and higher doses of caffeine (50, 100 mg/kg IP) had no significant effect. The locomotor stimulant effect of 20 mg/kg IP dose of caffeine per se in vehicle was significantly higher and that with 100 mg/kg dose significantly lower than that of the vehicle control. Thus caffeine produced dose-dependent effects on cocaine-induced locomotor stimulant activity, with low dose potentiating and higher doses having no significant effect on such activity. Pharmacokinetic or dispositional factors did not appear to play a role in potentiation of cocaine locomotor stimulant activity by caffeine. PMID:3703910

  2. Quantitative Trait Loci for Locomotor Behavior in Drosophila melanogaster

    PubMed Central

    Jordan, Katherine W.; Morgan, Theodore J.; Mackay, Trudy F. C.

    2006-01-01

    Locomotion is an integral component of most animal behaviors and many human diseases and disorders are associated with locomotor deficits, but little is known about the genetic basis of natural variation in locomotor behavior. Locomotion is a complex trait, with variation attributable to the joint segregation of multiple interacting quantitative trait loci (QTL), with effects that are sensitive to the environment. We assessed variation in a component of locomotor behavior (locomotor reactivity) in a population of 98 recombinant inbred lines of Drosophila melanogaster and mapped four QTL affecting locomotor reactivity by linkage to polymorphic roo transposable element insertion sites. We used complementation tests of deficiencies to fine map these QTL to 12 chromosomal regions and complementation tests of mutations to identify 13 positional candidate genes affecting locomotor reactivity, including Dopa decarboxylase (Ddc), which catalyzes the final step in the synthesis of serotonin and dopamine. Linkage disequilibrium mapping in a population of 164 second chromosome substitution lines derived from a single natural population showed that polymorphisms at Ddc were associated with naturally occurring genetic variation in locomotor behavior. These data implicate variation in the synthesis of bioamines as a factor contributing to natural variation in locomotor reactivity. PMID:16783013

  3. Utility of ethological analysis to overcome locomotor confounds in elevated maze models of anxiety.

    PubMed

    Weiss, S M; Wadsworth, G; Fletcher, A; Dourish, C T

    1998-01-01

    The elevated plus-maze is a commonly used model to identify putative anxiolytic and anxiogenic drugs. However, the validity of elevated plus-maze and other recently developed variants such as the elevated zero-maze has recently been questioned on the grounds that both the reference anxiolytic drug chlordiazepoxide and the psychostimulant d-amphetamine increase open arm exploration and stimulate locomotor activity. These findings suggest that measures of "anxiety" in the elevated maze cannot be adequately dissociated from simple changes in locomotor activity, which may confound the interpretation of results obtained using these models. A variety of approaches to assess drug effects on locomotor activity in the elevated maze have been suggested, including the use of total and closed arm entries, as well as supplementary tests such as exploration of the holeboard apparatus. However, all these approaches utilise the measurement of exploration in a novel environment, and as such, could potentially be influenced by either changes in anxiety or locomotor activity. Recently, it has been shown that ethological measures of "risk assessment", such as stretched-attend postures and head-dipping, are sensitive indicators of drug-effects in the elevated maze. The present study assessed the utility of ethological analysis in dissociating locomotor activity from "anxiety" by comparing the effects of d-amphetamine to those of chlordiazepoxide in the rat elevated zero-maze. The results showed that both chlordiazepoxide and d-amphetamine increase the amount of time spent in the open arms and reduce "risk assessment" without increasing line crossing or rearing. These results confirm that under certain test conditions, psychostimulants are capable of producing "false-positives" in elevated maze models, and that both traditional methods and the ethological measures used in this study fail to unequivocally dissociate drug effects on anxiety from effects on locomotor activity. Further

  4. Species sensitivities and prediction of teratogenic potential.

    PubMed Central

    Schardein, J L; Schwetz, B A; Kenel, M F

    1985-01-01

    Many chemicals shown to be teratogenic in laboratory animals are not known to be teratogenic in humans. However, it remains to be determined if the unresponsiveness of humans is due to lessened sensitivity, to generally subteratogenic exposure levels, or to the lack of an appropriate means of identifying human teratogens. On the other hand, with the exception of the coumarin anticoagulant drugs, those agents well accepted as human teratogens have been shown to be teratogenic in one or more laboratory species. Yet, no single species has clearly distinguished itself as being more advantageous in the detection of human teratogens over any other. Among the species used for testing, the rat and mouse most successfully model the human reaction, but the rabbit is less likely than other species to give a false positive finding. Among species less commonly used for testing, primates offered a higher level of predicability than others. Regarding concordance of target malformations, the mouse and rat produced the greatest number of concordant defects, but they also were responsible for the most noncorcordant responses as well. Since no other species is clearly more predictive of the human response, it is concluded that safety decisions should be based on all reproductive and developmental toxicity data in light of the agent's known pharmacokinetic, metabolic and toxicologic parameters. PMID:3905381

  5. Sex differences in locomotor effects of morphine in the rat

    PubMed Central

    Craft, Rebecca M.; Clark, James L.; Hart, Stephen P.; Pinckney, Megan K.

    2007-01-01

    Sex differences in reinforcing, analgesic and other effects of opioids have been demonstrated; however, the extent to which sex differences in motoric effects of opioids contribute to apparent sex differences in their primary effects is not known. The goal of this study was to compare the effects of the prototypic mu opioid agonist morphine on locomotor activity in male vs. female rats. Saline or morphine (1-10 mg/kg) was administered s.c. to adult Sprague-Dawley rats, which were placed into a photobeam apparatus for 3-5 hr to measure activity. Modulation of morphine's effects by gonadal hormones and by handling (either during the test session or for 4 days before the test session) were examined. Morphine initially suppressed and later increased locomotor activity in both sexes relative to their saline-injected controls, but males were more sensitive than females to the initial locomotor suppressant effect of morphine. Intermittent, brief handling during the 3-hr test session blunted morphine-induced locomotor activation in both sexes. Females in proestrus were the most sensitive to morphine's locomotor-stimulant effect, with females in estrus showing the least response to morphine. Gonadectomized (GDX) males with or without testosterone were equally sensitive to morphine's effects, whereas GDX females treated with estradiol showed a blunted response to morphine's effects, similar to intact females in estrus. Brief handling on each of 4 consecutive days pre-test attenuated morphine's locomotor suppressant effect in males but had no effect in females, thereby eliminating the sex difference. These data suggest that sex differences in morphine's effects on locomotor activity can be attributed to gonadal hormones in females, and to differential stress-induced modulation of morphine's effects in males vs. females. PMID:17217999

  6. *Biomarkers of acute respiratory allergen exposure: Screening for sensitization potential

    EPA Science Inventory

    Effective hazard screening will require the development of high-throughput or in vitro assays for the identification of potential sensitizers. The goal of this preliminary study was to identify potential biomarkers that differentiate the response to allergens vs non-allergens fol...

  7. Timing of Locomotor Recovery from Anoxia Modulated by the white Gene in Drosophila.

    PubMed

    Xiao, Chengfeng; Robertson, R Meldrum

    2016-06-01

    Locomotor recovery from anoxia follows the restoration of disordered ion distributions and neuronal excitability. The time taken for locomotor recovery after 30 sec anoxia (around 10 min) is longer than the time for the propagation of action potentials to be restored (<1 min) in Drosophila wild type. We report here that the white (w) gene modulates the timing of locomotor recovery. Wild-type flies displayed fast and consistent recovery of locomotion from anoxia, whereas mutants of w showed significantly delayed and more variable recovery. Genetic analysis including serial backcrossing revealed a strong association between the w locus and the timing of locomotor recovery, and haplo-insufficient function of w(+) in promoting fast recovery. The locomotor recovery phenotype was independent of classic eye pigmentation, although both are associated with the w gene. Introducing up to four copies of mini-white (mw(+)) into w1118 was insufficient to promote fast and consistent locomotor recovery. However, flies carrying w(+) duplicated to the Y chromosome showed wild-type-like fast locomotor recovery. Furthermore, Knockdown of w by RNA interference (RNAi) in neurons but not glia delayed locomotor recovery, and specifically, knockdown of w in subsets of serotonin neurons was sufficient to delay the locomotor recovery. These data reveal an additional role for w in modulating the timing of locomotor recovery from anoxia. PMID:27029736

  8. Non-animal test methods for predicting skin sensitization potentials.

    PubMed

    Mehling, Annette; Eriksson, Tove; Eltze, Tobias; Kolle, Susanne; Ramirez, Tzutzuy; Teubner, Wera; van Ravenzwaay, Bennard; Landsiedel, Robert

    2012-08-01

    Contact allergies are complex diseases, and it is estimated that 15-20 % of the general population suffers from contact allergy, with increasing prevalence. Evaluation of the sensitization potential of a substance is usually carried out in animal models. Nowadays, there is much interest in reducing and ultimately replacing current animal tests. Furthermore, as of 2013, the EU has posed a ban on animal testing of cosmetic ingredients that includes skin sensitization. Therefore, predictive and robust in vitro tests are urgently needed. In order to establish alternatives to animal testing, the in vitro tests must mimic the very complex interactions between the sensitizing chemical and the different parts of the immune system. This review article summarizes recent efforts to develop in vitro tests for predicting skin sensitizers. Cell-based assays, in chemico methods and, to a lesser extent, in silico methods are presented together with a discussion of their current status. With considerable progress having been achieved during the last years, the rationale today is that data from different non-animal test methods will have to be combined in order to obtain reliable hazard and potency information on potential skin sensitizers. PMID:22707154

  9. Inhibiting activator protein-1 activity alters cocaine-induced gene expression and potentiates sensitization.

    PubMed

    Paletzki, R F; Myakishev, M V; Polesskaya, O; Orosz, A; Hyman, S E; Vinson, C

    2008-04-01

    We have expressed A-FOS, an inhibitor of activator protein-1 (AP-1) DNA binding, in adult mouse striatal neurons. We observed normal behavior including locomotion and exploratory activities. Following a single injection of cocaine, locomotion increased similarly in both the A-FOS expressing and littermate controls. However, following repeated injections of cocaine, the A-FOS expressing mice showed increased locomotion relative to littermate controls, an increase that persisted following a week of withdrawal and subsequent cocaine administration. These results indicate that AP-1 suppresses this behavioral response to cocaine. We analyzed mRNA from the striatum before and 4 and 24 h after a single cocaine injection in both A-FOS and control striata using Affymetrix microarrays (430 2.0 Array) to identify genes mis-regulated by A-FOS that may mediate the increased locomotor sensitization to cocaine. A-FOS expression did not change gene expression in the basal state or 4 h following cocaine treatment relative to controls. However, 24 h after an acute cocaine treatment, 84 genes were identified that were differentially expressed between the A-FOS and control mice. Fifty-six genes are down-regulated while 28 genes are up-regulated including previously identified candidates for addiction including brain-derived neurotrophic factor and period homolog 1. Using a random sample of identified genes, quantitative PCR was used to verify the microarray studies. The chromosomal location of these 84 genes was compared with human genome scans of addiction to identify potential genes in humans that are involved in addiction. PMID:18355967

  10. Effects of coal mine wastewater on locomotor and non-locomotor activities of empire gudgeons (Hypseleotris compressa).

    PubMed

    Lanctôt, C; Melvin, S D; Fabbro, L; Leusch, F D L; Wilson, S P

    2016-05-01

    Coal mining represents an important industry in many countries, but concerns exist about the possible adverse effects of minewater releases on aquatic animals and ecosystems. Coal mining generates large volumes of complex wastewater, which often contains high concentrations of dissolved solids, suspended solids, metals, hydrocarbons, salts and other compounds. Traditional toxicological testing has generally involved the assessment of acute toxicity or chronic toxicity with longer-term tests, and while such tests provide useful information, they are poorly suited to ongoing monitoring or rapid assessment following accidental discharge events. As such, there is considerable interest in developing rapid and sensitive approaches to environmental monitoring, and particularly involving the assessment of sub-lethal behavioural responses in locally relevant aquatic species. We therefore investigated behavioural responses of a native Australian fish to coal mine wastewater, to evaluate its potential use for evaluating sub-lethal effects associated with wastewater releases on freshwater ecosystems. Empire gudgeons (Hypseleotris compressa) were exposed to wastewater from two dams located at an open cut coal mine in Central Queensland, Australia and activity levels were monitored using the Multispecies Freshwater Biomonitor® (LimCo International GmbH). A general decrease in locomotor activity (i.e., low frequency movement) and increase in non-locomotor activity (i.e., high frequency movement including ventilation and small fin movement) was observed in exposed fish compared to those in control water. Altered activity levels were observable within the first hour of exposure and persisted throughout the 15-d experiment. Results demonstrate the potential for using behavioural endpoints as tools for monitoring wastewater discharges using native fish species, but more research is necessary to identify responsible compounds and response thresholds, and to understand the relevance

  11. Modelling the locomotor energetics of extinct hominids.

    PubMed

    Kramer, P A

    1999-10-01

    Bipedality is the defining characteristic of Hominidae and, as such, an understanding of the adaptive significance and functional implications of bipedality is imperative to any study of human evolution. Hominid bipedality is, presumably, a solution to some problem for the early hominids, one that has much to do with energy expenditure. Until recently, however, little attention could be focused on the quantifiable energetic aspects of bipedality as a unique locomotor form within Primates because of the inability to measure empirically the energy expenditure of non-modern hominids. A recently published method provides a way of circumventing the empirical measurement dilemma by calculating energy expenditure directly from anatomical variables and movement profiles. Although the origins of bipedality remain clouded, two discernible forms of locomotor anatomy are present in the hominid fossil record: the australopithecine and modern configurations. The australopithecine form is best represented by AL 288-1, a partial skeleton of Australopithecus afarensis, and is characterized as having short legs and a wide pelvis. The modern form is represented by modern humans and has long legs and a narrow pelvis. Human walking is optimized to take advantage of the changing levels of potential and kinetic energy that occur as the body and limbs move through the stride cycle. Although this optimization minimizes energy expenditure, some energy is required to maintain motion. I quantify this energy by developing a dynamic model that uses kinematic equations to determine energy expenditure. By representing both configurations with such a model, I can compare their rates of energy expenditure. I find that the australopithecine configuration uses less energy than that of a modern human. Despite arguments presented in the anthropological literature, the shortness of the legs of AL 288-1 provides no evidence that she was burdened with a compromised or transitional locomotor anatomy

  12. Development of a spinal locomotor rheostat.

    PubMed

    Zhang, Hong-Yan; Issberner, Jon; Sillar, Keith T

    2011-07-12

    Locomotion in immature animals is often inflexible, but gradually acquires versatility to enable animals to maneuver efficiently through their environment. Locomotor activity in adults is produced by complex spinal cord networks that develop from simpler precursors. How does complexity and plasticity emerge during development to bestow flexibility upon motor behavior? And how does this complexity map onto the peripheral innervation fields of motorneurons during development? We show in postembryonic Xenopus laevis frog tadpoles that swim motorneurons initially form a homogenous pool discharging single action potential per swim cycle and innervating most of the dorsoventral extent of the swimming muscles. However, during early larval life, in the prelude to a free-swimming existence, the innervation fields of motorneurons become restricted to a more limited sector of each muscle block, with individual motorneurons reaching predominantly ventral, medial, or dorsal regions. Larval motorneurons then can also discharge multiple action potentials in each cycle of swimming and differentiate in terms of their firing reliability during swimming into relatively high-, medium-, or low-probability members. Many motorneurons fall silent during swimming but can be recruited with increasing locomotor frequency and intensity. Each region of the myotome is served by motorneurons spanning the full range of firing probabilities. This unfolding developmental plan, which occurs in the absence of movement, probably equips the organism with the neuronal substrate to bend, pitch, roll, and accelerate during swimming in ways that will be important for survival during the period of free-swimming larval life that ensues. PMID:21709216

  13. Sensitivity of Mediterranean groundwater resources to potential climate futures

    NASA Astrophysics Data System (ADS)

    Hartmann, Andreas; Gleeson, Tom; Wagener, Thorsten

    2014-05-01

    A large fraction of the Mediterranean water supply originates from karst aquifers that evolved through the dissolution of carbonate rock. Climate simulations indicate that the Mediterranean will experience a strong increase in temperature and a significant decrease in precipitation within the next 100 years. To be prepared, policy-makers need quantitative and reliable estimates of potential changes to karst water resources. In this study we present the result of a very first attempt to quantify karst water resources over the whole Mediterranean region. Instead of considering groundwater volumes, we consider the flux of water into the aquifer, called groundwater recharge, as a useful indicator for groundwater sustainability. We developed a process-based karst recharge model that is driven by large-scale meteorological observations or downscaled climate scenarios. Using a new metric for quantifying the sensitivity of recharge to climatic changes (termed recharge elasticity) we can explore the sensitivity of Mediterranean karstic groundwater resources to future climatic boundary conditions.

  14. Murine and human CFTR exhibit different sensitivities to CFTR potentiators.

    PubMed

    Cui, Guiying; McCarty, Nael A

    2015-10-01

    Development of therapeutic molecules with clinical efficacy as modulators of defective CFTR includes efforts to identify potentiators that can overcome or repair the gating defect in mutant CFTR channels. This has taken a great leap forward with the identification of the potentiator VX-770, now available to patients as "Kalydeco." Other small molecules with different chemical structure also are capable of potentiating the activity of either wild-type or mutant CFTR, suggesting that there are features of the protein that may be targeted to achieve stimulation of channel activity by structurally diverse compounds. However, neither the mechanisms by which these compounds potentiate mutant CFTR nor the site(s) where these compounds bind have been identified. This knowledge gap partly reflects the lack of appropriate experimental models to provide clues toward the identification of binding sites. Here, we have compared the channel behavior and response to novel and known potentiators of human CFTR (hCFTR) and murine (mCFTR) expressed in Xenopus oocytes. Both hCFTR and mCFTR were blocked by GlyH-101 from the extracellular side, but mCFTR activity was increased with GlyH-101 applied directly to the cytoplasmic side. Similarly, glibenclamide only exhibited a blocking effect on hCFTR but both blocked and potentiated mCFTR in excised membrane patches and in intact oocytes. The clinically used CFTR potentiator VX-770 transiently increased hCFTR by ∼13% but potentiated mCFTR significantly more strongly. Our results suggest that mCFTR pharmacological sensitivities differ from hCFTR, which will provide a useful tool for identifying the binding sites and mechanism for these potentiators. PMID:26209275

  15. Locomotor Experience and Use of Social Information Are Posture Specific

    ERIC Educational Resources Information Center

    Adolph, Karen E.; Tamis-LeMonda, Catherine S.; Ishak, Shaziela; Karasik, Lana B.; Lobo, Sharon A.

    2008-01-01

    The authors examined the effects of locomotor experience on infants' perceptual judgments in a potentially risky situation--descending steep and shallow slopes--while manipulating social incentives to determine where perceptual judgments are most malleable. Twelve-month-old experienced crawlers and novice walkers were tested on an adjustable…

  16. The Braincase and Endosseous Labyrinth of Plioplatecarpus peckensis (Mosasauridae, Plioplatecarpinae), With Functional Implications for Locomotor Behavior.

    PubMed

    Cuthbertson, Robin S; Maddin, Hillary C; Holmes, Robert B; Anderson, Jason S

    2015-09-01

    Adaptations of mosasaurs to the aquatic realm have been extensively studied from the perspective of modifications to the post-cranial skeleton. In recent years, imaging techniques such as computed tomography have permitted the acquisition of anatomical data from previously inaccessible sources. An exquisitely preserved specimen of the plioplatecarpine mosasaur Plioplatecarpus peckensis presents an opportunity to examine the detailed structure of the braincase, as well as the form of the otic capsule endocast. These data elaborate upon previous descriptions of the braincase of Plioplatecarpus, and provide a detailed, three dimensional reconstruction of the osseous labyrinth for the first time. The otic capsule endocasts reveal that the size of the labyrinth relative to head size is comparable to that of other squamates, suggesting that labyrinth size was not a factor in increasing sensitivity. However, all three semicircular canals are tall and strongly arced to a degree comparable to, and even exceeding, that observed in arboreal and aquatic lizards. Comparison of the sensitivity of the canals in each of the three major axes of rotation suggests Plioplatecarpus peckensis may have been most sensitive to movements in the pitch axis. Although early mosasaurs were probably anguilliform swimmers, most are thought to have been subcarangiform to thunniform locomotors with a near-rigid body form and likely decreased maneuverability. The data from the labyrinth presented here add a potential new dimension to this model of locomotion for further consideration, wherein changes in orientation, such as pitch, may have been more common locomotor behaviors than previously thought. PMID:26052684

  17. Large pi-aromatic molecules as potential sensitizers for highly efficient dye-sensitized solar cells.

    PubMed

    Imahori, Hiroshi; Umeyama, Tomokazu; Ito, Seigo

    2009-11-17

    Recently, dye-sensitized solar cells have attracted much attention relevant to global environmental issues. Thus far, ruthenium(II) bipyridyl complexes have proven to be the most efficient TiO(2) sensitizers in dye-sensitized solar cells. However, a gradual increment in the highest power conversion efficiency has been recognized in the past decade. More importantly, considering that ruthenium is a rare metal, novel dyes without metal or using inexpensive metal are desirable for highly efficient dye-sensitized solar cells. Large pi-aromatic molecules, such as porphyrins, phthalocyanines, and perylenes, are important classes of potential sensitizers for highly efficient dye-sensitized solar cells, owing to their photostability and high light-harvesting capabilities that can allow applications in thinner, low-cost dye-sensitized solar cells. Porphyrins possess an intense Soret band at 400 nm and moderate Q bands at 600 nm. Nevertheless, the poor light-harvesting properties relative to the ruthenium complexes have limited the cell performance of porphyrin-sensitized TiO(2) cells. Elongation of the pi conjugation and loss of symmetry in porphyrins cause broadening and a red shift of the absorption bands together with an increasing intensity of the Q bands relative to that of the Soret band. On the basis of the strategy, the cell performance of porphyrin-sensitized solar cells has been improved intensively by the enhanced light absorption. Actually, some push-pull-type porphyrins have disclosed a remarkably high power conversion efficiency (6-7%) that was close to that of the ruthenium complexes. Phthalocyanines exhibit strong absorption around 300 and 700 nm and redox features that are similar to porphyrins. Moreover, phthalocyanines are transparent over a large region of the visible spectrum, thereby enabling the possibility of using them as "photovoltaic windows". However, the cell performance was poor, owing to strong aggregation and lack of directionality in the

  18. Locomotor Expertise Predicts Infants' Perseverative Errors

    ERIC Educational Resources Information Center

    Berger, Sarah E.

    2010-01-01

    This research examined the development of inhibition in a locomotor context. In a within-subjects design, infants received high- and low-demand locomotor A-not-B tasks. In Experiment 1, walking 13-month-old infants followed an indirect path to a goal. In a control condition, infants took a direct route. In Experiment 2, crawling and walking…

  19. Biomarkers of acute respiratory allergen exposure: Screening for sensitization potential

    SciTech Connect

    Pucheu-Haston, Cherie M.; Copeland, Lisa B.; Vallanat, Beena; Boykin, Elizabeth; Ward, Marsha D.W.

    2010-04-15

    Effective hazard screening will require the development of high-throughput or in vitro assays for the identification of potential sensitizers. The goal of this preliminary study was to identify potential biomarkers that differentiate the response to allergens vs non-allergens following an acute exposure in naive individuals. Female BALB/c mice received a single intratracheal aspiration exposure to Metarhizium anisopliae crude antigen (MACA) or bovine serum albumin (BSA) in Hank's Balanced Salt Solution (HBSS) or HBSS alone. Mice were terminated after 1, 3, 6, 12, 18 and 24 h. Bronchoalveolar lavage fluid (BALF) was evaluated to determine total and differential cellularity, total protein concentration and LDH activity. RNA was isolated from lung tissue for microarray analysis and qRT-PCR. MACA administration induced a rapid increase in BALF neutrophils, lymphocytes, eosinophils and total protein compared to BSA or HBSS. Microarray analysis demonstrated differential expression of genes involved in cytokine production, signaling, inflammatory cell recruitment, adhesion and activation in 3 and 12 h MACA-treated samples compared to BSA or HBSS. Further analyses allowed identification of approx 100 candidate biomarker genes. Eleven genes were selected for further assessment by qRT-PCR. Of these, 6 demonstrated persistently increased expression (Ccl17, Ccl22, Ccl7, Cxcl10, Cxcl2, Saa1), while C3ar1 increased from 6-24 h. In conclusion, a single respiratory exposure of mice to an allergenic mold extract induces an inflammatory response which is distinct in phenotype and gene transcription from the response to a control protein. Further validation of these biomarkers with additional allergens and irritants is needed. These biomarkers may facilitate improvements in screening methods.

  20. Biomarkers of acute respiratory allergen exposure: screening for sensitization potential.

    PubMed

    Pucheu-Haston, Cherie M; Copeland, Lisa B; Vallanat, Beena; Boykin, Elizabeth; Ward, Marsha D W

    2010-04-15

    Effective hazard screening will require the development of high-throughput or in vitro assays for the identification of potential sensitizers. The goal of this preliminary study was to identify potential biomarkers that differentiate the response to allergens vs non-allergens following an acute exposure in naïve individuals. Female BALB/c mice received a single intratracheal aspiration exposure to Metarhizium anisopliae crude antigen (MACA) or bovine serum albumin (BSA) in Hank's Balanced Salt Solution (HBSS) or HBSS alone. Mice were terminated after 1, 3, 6, 12, 18 and 24 h. Bronchoalveolar lavage fluid (BALF) was evaluated to determine total and differential cellularity, total protein concentration and LDH activity. RNA was isolated from lung tissue for microarray analysis and qRT-PCR. MACA administration induced a rapid increase in BALF neutrophils, lymphocytes, eosinophils and total protein compared to BSA or HBSS. Microarray analysis demonstrated differential expression of genes involved in cytokine production, signaling, inflammatory cell recruitment, adhesion and activation in 3 and 12 h MACA-treated samples compared to BSA or HBSS. Further analyses allowed identification of approximately 100 candidate biomarker genes. Eleven genes were selected for further assessment by qRT-PCR. Of these, 6 demonstrated persistently increased expression (Ccl17, Ccl22, Ccl7, Cxcl10, Cxcl2, Saa1), while C3ar1 increased from 6-24 h. In conclusion, a single respiratory exposure of mice to an allergenic mold extract induces an inflammatory response which is distinct in phenotype and gene transcription from the response to a control protein. Further validation of these biomarkers with additional allergens and irritants is needed. These biomarkers may facilitate improvements in screening methods. PMID:20045013

  1. Functional redundancy of ventral spinal locomotor pathways.

    PubMed

    Loy, David N; Magnuson, David S K; Zhang, Y Ping; Onifer, Stephen M; Mills, Michael D; Cao, Qi-lin; Darnall, Jessica B; Fajardo, Lily C; Burke, Darlene A; Whittemore, Scott R

    2002-01-01

    Identification of long tracts responsible for the initiation of spontaneous locomotion is critical for spinal cord injury (SCI) repair strategies. Pathways derived from the mesencephalic locomotor region and pontomedullary medial reticular formation responsible for fictive locomotion in decerebrate preparations project to the thoracolumbar levels of the spinal cord via reticulospinal axons in the ventrolateral funiculus (VLF). However, white matter regions critical for spontaneous over-ground locomotion remain unclear because cats, monkeys, and humans display varying degrees of locomotor recovery after ventral SCIs. We studied the contributions of myelinated tracts in the VLF and ventral columns (VC) to spontaneous over-ground locomotion in the adult rat using demyelinating lesions. Animals received ethidium bromide plus photon irradiation producing discrete demyelinating lesions sufficient to stop axonal conduction in the VLF, VC, VLF-VC, or complete ventral white matter (CV). Behavior [open-field Basso, Beattie, and Bresnahan (BBB) scores and grid walking] and transcranial magnetic motor-evoked potentials (tcMMEP) were studied at 1, 2, and 4 weeks after lesion. VLF lesions resulted in complete loss or severe attenuation of tcMMEPs, with mean BBB scores of 18.0, and no grid walking deficits. VC lesions produced behavior similar to VLF-lesioned animals but did not significantly affect tcMMEPs. VC-VLF and CV lesions resulted in complete loss of tcMMEP signals with mean BBB scores of 12.7 and 6.5, respectively. Our data support a diffuse arrangement of axons within the ventral white matter that may comprise a system of multiple descending pathways subserving spontaneous over-ground locomotion in the intact animal. PMID:11756515

  2. Contrast Sensitivity versus Visual Evoked Potentials in Multiple Sclerosis

    PubMed Central

    Shandiz, Javad Heravian; Nourian, Abbas; Hossaini, Mercedeh Bahr; Moghaddam, Hadi Ostadi; yekta, Abbas-Ali; Sharifzadeh, Laleh; Marouzi, Parviz

    2010-01-01

    Purpose To compare the Cambridge contrast sensitivity (CS) test and visual evoked potentials (VEP) in detecting visual impairment in a population of visually symptomatic and asymptomatic patients affected by clinically definite multiple sclerosis (MS). Methods Fifty patients (100 eyes) presenting with MS and 25 healthy subjects (50 eyes) with normal corrected visual acuity were included in this study. CS was determined using the Cambridge Low Contrast Grating test and VEP was obtained in all eyes. Findings were evaluated in two age strata of 10–29 and 30–49 years. Results Of the 42 eyes in the 10–29 year age group, CS was abnormal in 22 (52%), VEP was also abnormal in 22 (52%), but only 12 eyes (28%) had visual symptoms. Of the 58 eyes in the 30–49 year group, CS was abnormal in 7 (12%), VEP was abnormal in 34 (58%), while only 11 eyes were symptomatic. No single test could detect all of the abnormal eyes. Conclusion The Cambridge Low Contrast Grating test is useful for detection of clinical and subclinical visual dysfunction especially in young patients with multiple sclerosis. Nevertheless, only a combination of CS and VEP tests can detect most cases of visual dysfunction associated with MS. PMID:22737353

  3. An in vitro human skin test for assessing sensitization potential.

    PubMed

    Ahmed, S S; Wang, X N; Fielding, M; Kerry, A; Dickinson, I; Munuswamy, R; Kimber, I; Dickinson, A M

    2016-05-01

    Sensitization to chemicals resulting in an allergy is an important health issue. The current gold-standard method for identification and characterization of skin-sensitizing chemicals was the mouse local lymph node assay (LLNA). However, for a number of reasons there has been an increasing imperative to develop alternative approaches to hazard identification that do not require the use of animals. Here we describe a human in-vitro skin explant test for identification of sensitization hazards and the assessment of relative skin sensitizing potency. This method measures histological damage in human skin as a readout of the immune response induced by the test material. Using this approach we have measured responses to 44 chemicals including skin sensitizers, pre/pro-haptens, respiratory sensitizers, non-sensitizing chemicals (including skin-irritants) and previously misclassified compounds. Based on comparisons with the LLNA, the skin explant test gave 95% specificity, 95% sensitivity, 95% concordance with a correlation coefficient of 0.9. The same specificity and sensitivity were achieved for comparison of results with published human sensitization data with a correlation coefficient of 0.91. The test also successfully identified nickel sulphate as a human skin sensitizer, which was misclassified as negative in the LLNA. In addition, sensitizers and non-sensitizers identified as positive or negative by the skin explant test have induced high/low T cell proliferation and IFNγ production, respectively. Collectively, the data suggests the human in-vitro skin explant test could provide the basis for a novel approach for characterization of the sensitizing activity as a first step in the risk assessment process. PMID:26251951

  4. Ceftriaxone attenuates locomotor activity induced by acute and repeated cocaine exposure in mice.

    PubMed

    Tallarida, Christopher S; Corley, Gladys; Kovalevich, Jane; Yen, William; Langford, Dianne; Rawls, Scott M

    2013-11-27

    Ceftriaxone (CTX) decreases locomotor activation produced by initial cocaine exposure and attenuates development of behavioral sensitization produced by repeated cocaine exposure. An important question that has not yet been answered is whether or not CTX reduces behavioral sensitization to cocaine in cases in which the antibiotic is administered only during the period of cocaine absence that follows repeated cocaine exposure and precedes reintroduction to cocaine. We investigated this question using C57BL/6 mice. Mice pretreated with cocaine (15mg/kg×14 days) and then challenged with cocaine (15mg/kg) after 30 days of cocaine absence displayed sensitization of locomotor activity. For combination experiments, CTX injected during the 30 days of cocaine absence attenuated behavioral sensitization produced by cocaine challenge. In the case in which CTX was injected together with cocaine for 14 days, development of behavioral sensitization to cocaine challenge was also reduced. CTX attenuated the increase in locomotor activity produced by acute cocaine exposure; however, its efficacy was dependent on the dose of cocaine as inhibition was detected against 30mg/kg, but not 15mg/kg, of cocaine. These results from mice indicate that CTX attenuates locomotor activity produced by acute and repeated cocaine exposure and counters cocaine's locomotor activating properties in a paradigm in which the antibiotic is injected during the period of forced cocaine absence that follows repeated cocaine exposure. PMID:24120434

  5. Rapid, Opioid-sensitive Mechanisms Involved in Transient Receptor Potential Vanilloid 1 Sensitization*S⃞

    PubMed Central

    Vetter, Irina; Cheng, Wei; Peiris, Madusha; Wyse, Bruce D.; Roberts-Thomson, Sarah J.; Zheng, Jie; Monteith, Gregory R.; Cabot, Peter J.

    2008-01-01

    TRPV1 is a nociceptive, Ca2+-selective ion channel involved in the development of several painful conditions. Sensitization of TRPV1 responses by cAMP-dependent PKA crucially contributes to the development of inflammatory hyperalgesia. However, the pathways involved in potentiation of TRPV1 responses by cAMP-dependent PKA remain largely unknown. Using HEK cells stably expressing TRPV1 and the μ opioid receptor, we demonstrated that treatment with the adenylate cyclase activator forskolin significantly increased the multimeric TRPV1 species. Pretreatment with the μ opioid receptor agonist morphine reversed this increased TRPV1 multimerization. FRET analysis revealed that treatment with forskolin did not cause multimerization of pre-existing TRPV1 monomers on the plasma membrane and that intracellular pools of TRPV1 exist mostly as monomers in this model. This suggests that increased TRPV1 multimerization occurred from an intracellular store of inactive TRPV1 monomers. Treatment with forskolin also caused an increase in TRPV1 expression on the plasma membrane not resulting from increased TRPV1 expression, and this rapid TRPV1 translocation was inhibited by treatment with morphine. Thus, potentiation of TRPV1 responses by cAMP-dependent PKA involves plasma membrane insertion of functional TRPV1 multimers formed from an intracellular store of inactive TRPV1 monomers. This potentiation occurs rapidly and can be dynamically modulated by activation of the μ opioid receptor under conditions where cAMP levels are raised, such as with inflammation. Increased translocation and multimerization of TRPV1 channels provide a cellular mechanism for finetuning of nociceptive responses that allow for rapid modulation of TRPV1 responses independent of transcriptional changes. PMID:18482991

  6. Suppression of Locomotor Activity in Female C57Bl/6J Mice Treated with Interleukin-1β: Investigating a Method for the Study of Fatigue in Laboratory Animals

    PubMed Central

    Bonsall, David R.; Kim, Hyunji; Tocci, Catherine; Ndiaye, Awa; Petronzio, Abbey; McKay-Corkum, Grace; Molyneux, Penny C.; Scammell, Thomas E.; Harrington, Mary E.

    2015-01-01

    Fatigue is a disabling symptom in patients with multiple sclerosis and Parkinson’s Disease, and is also common in patients with traumatic brain injury, cancer, and inflammatory disorders. Little is known about the neurobiology of fatigue, in part due to the lack of an approach to induce fatigue in laboratory animals. Fatigue is a common response to systemic challenge by pathogens, a response in part mediated through action of the pro-inflammatory cytokine interleukin-1 beta (IL-1β). We investigated the behavioral responses of mice to IL-1β. Female C57Bl/6J mice of 3 ages were administered IL-1β at various doses i.p. Interleukin-1β reduced locomotor activity, and sensitivity increased with age. Further experiments were conducted with middle-aged females. Centrally administered IL-1β dose-dependently reduced locomotor activity. Using doses of IL-1β that caused suppression of locomotor activity, we measured minimal signs of sickness, such as hyperthermia, pain or anhedonia (as measured with abdominal temperature probes, pre-treatment with the analgesic buprenorphine and through sucrose preference, respectively), all of which are responses commonly reported with higher doses. We found that middle-aged orexin-/- mice showed equivalent effects of IL-1β on locomotor activity as seen in wild-type controls, suggesting that orexins are not necessary for IL-1β -induced reductions in wheel-running. Given that the availability and success of therapeutic treatments for fatigue is currently limited, we examined the effectiveness of two potential clinical treatments, modafinil and methylphenidate. We found that these treatments were variably successful in restoring locomotor activity after IL-1β administration. This provides one step toward development of a satisfactory animal model of the multidimensional experience of fatigue, a model that could allow us to determine possible pathways through which inflammation induces fatigue, and could lead to novel treatments for

  7. Locomotor and pyretic effects of MDMA-ethanol associations in rats.

    PubMed

    Cassel, Jean-Christophe; Jeltsch, Hélène; Koenig, Julie; Jones, Byron C

    2004-01-01

    3,4-Methylenedioxymethamphetamine [(MDMA) or ecstasy] is a popular club drug often used in combination with ethanol. In the current study, we investigated the effects of MDMA and ethanol combinations on locomotor activity and body temperature of rats. For four consecutive days, male Long-Evans rats were treated daily with a 10-mg/kg dose of MDMA with or without a 1.5-g/kg dose of ethanol. 3,4-Methylenedioxymethamphetamine increased spontaneous activity (on average +1,140%), and this increase was potentiated by ethanol on all days (on average +1,710%). Moreover, ethanol inhibited the MDMA-induced hyperthermia (on average -1.3 degrees C) by the first day of treatment, but not on subsequent treatment days, supporting the suggestion that this effect may undergo tolerance. These observations seem to indicate that combined ethanol-MDMA may induce effects on locomotor activity and thermoregulation that involve separate mechanisms, the first one being less sensitive to tolerance than the second one might be. Results of our study have important implications for understanding the motivation and the health risks of polydrug abusers combining ecstasy and ethanol. PMID:15902924

  8. Potential animal model of multiple chemical sensitivity with cholinergic supersensitivity.

    PubMed

    Overstreet, D H; Miller, C S; Janowsky, D S; Russell, R W

    1996-07-17

    Multiple Chemical Sensitivity (MCS) is a clinical phenomenon in which individuals, after acute or intermittent exposure to one or more chemicals, commonly organophosphate pesticides (OPs), become overly sensitive to a wide variety of chemically-unrelated compounds, which can include ethanol, caffeine and other psychotropic drugs. The Flinders Sensitive Line (FSL) rats were selectively bred to be more sensitive to the OP diisopropylfluorophosphate (DFP) compared to their control counterparts, the Flinders Resistant Line (FRL) rats. The present paper will summarize evidence which indicates that the FSL rats exhibit certain similarities to individuals with MCS. In addition to their greater sensitivity to DFP, the FSL rats are more sensitive to nicotine and the muscarinic agonists arecoline and oxotremorine, suggesting that the number of cholinergic receptors may be increased, a conclusion now supported by biochemical evidence. The FSL rats have also been found to exhibit enhanced responses to a variety of other drugs, including the serotonin agonists m-chlorophenylpiperazine and 8-OH-DPAT, the dopamine antagonist raclopride, the benzodiazepine diazepam, and ethanol. MCS patients report enhanced responses to many of these drugs, indicating some parallels between FSL rats and MCS patients. The FSL rats also exhibit reduced activity and appetite and increased REM sleep relative to their FRL controls. Because these behavioral features and the enhanced cholinergic responses are also observed in human depressives, the FSL rats have been proposed as a genetic animal model of depression. It has also been reported that MCS patients have a greater incidence of depression, both before and after onset of their chemical sensitivities, so cholinergic supersensitivity may be a state predisposing individuals to depressive disorders and/or MCS. Further exploration of the commonalities and differences between MCS patients, human depressives, and FSL rats will help to elucidate the

  9. Woodlouse locomotor behavior in the assessment of clean and contaminated field sites

    SciTech Connect

    Bayley, M.; Baatrup, E.; Bjerregaard, P.

    1997-11-01

    Specimens of the woodlouse Oniscus asellus were collected at four clean field sites and from a recently closed iron foundry heavily contaminated with zinc, lead, chromium, and nickel. Each of the 30 woodlice per group was housed individually and acclimatized to laboratory conditions for 2 d on a humid plaster of paris substrate. Thereafter, the locomotor behavior of each animal was measured for 4 h employing automated computer-aided video tracking. Linear discriminant analysis of five locomotor parameters revealed average velocity and path length as the principle components separating the polluted site and control animals. Post hoc analysis of the discriminant variable for animals from all five sites showed that the animals from the polluted site where significantly hyperactive when compared to all controls. Further, control animals collected from sites separated by several hundred kilometers were remarkably similar in their locomotor behavior. This preliminary study highlights the potential utility of quantitative analysis of animal locomotor behavior in environmental monitoring.

  10. Multi-terrain locomotor interactions in flying snakes

    NASA Astrophysics Data System (ADS)

    Yeaton, Isaac; Baumgardner, Grant; Ross, Shane; Socha, John

    Arboreal snakes of the genus Chrysopelea are the only known snakes to glide. To execute aerial locomotion, a snake uses one of several stereotyped jumps from a tree into the air, while simultaneously flattening its body into an aerodynamically favorable shape. Large amplitude traveling waves are propagated posteriorly during the stable glide, while landing involves body wrapping, passive body compression, and energy absorption through compliance in the landing substrate to dissipate the accumulated kinetic energy from the glide. In all of these locomotor events, from interacting with cylindrical branches, falling through the air, grasping compliant tree branches and leaves, to landing on solid ground, snakes appropriate the same body morphology and perhaps the same basic neural mechanisms. Here we discuss our use of computational models and animal experiments to understand how flying snakes interact with and locomote on and through multiple media, potentially providing principles for legless locomotor designs. Supported by NSF 1351322.

  11. Bovine growth hormone transgenic mice display alterations in locomotor activity and brain monoamine neurochemistry.

    PubMed

    Söderpalm, B; Ericson, M; Bohlooly, M; Engel, J A; Törnell, J

    1999-12-01

    Recent clinical and experimental data indicate a role for GH in mechanisms related to anhedonia/hedonia, psychic energy, and reward. In the present study we have investigated whether bovine GH (bGH) transgenic mice and nontransgenic controls differ in spontaneous locomotor activity, a behavioral response related to brain dopamine (DA) and reward mechanisms, as well as in locomotor activity response to drugs of abuse known to interfere with brain DA systems. The animals were tested for locomotor activity once a week for 4 weeks. When first exposed to the test apparatus, bGH transgenic animals displayed significantly more locomotor activity than controls during the entire registration period (1 h). One week later, after acute pretreatment with saline, the two groups did not differ in locomotor activity, whereas at the third test occasion, bGH mice were significantly more stimulated by d-amphetamine (1 mg/kg, ip) than controls. At the fourth test, a tendency for a larger locomotor stimulatory effect of ethanol (2.5 g/kg, ip) was observed in bGH transgenic mice. bGH mice displayed increased tissue levels of serotonin and 5-hydroxyindoleacetic acid in several brain regions, decreased DA levels in the brain stem, and decreased levels of the DA metabolite 3,4-dihydroxyphenylacetic acid in the mesencephalon and diencephalon, compared with controls. In conclusion, bGH mice display more spontaneous locomotor activity than nontransgenic controls in a novel environment and possibly also a disturbed habituation process. The finding that bGH mice were also more sensitive to d-amphetamine-induced locomotor activity may suggest that the behavioral differences observed are related to differences in brain DA systems, indicating a hyperresponsiveness of these systems in bGH transgenic mice. These findings may constitute a neurochemical basis for the reported psychic effects of GH in humans. PMID:10579325

  12. Development of a Countermeasure to Enhance Postflight Locomotor Adaptability

    NASA Technical Reports Server (NTRS)

    Bloomberg, Jacob J.

    2006-01-01

    Astronauts returning from space flight experience locomotor dysfunction following their return to Earth. Our laboratory is currently developing a gait adaptability training program that is designed to facilitate recovery of locomotor function following a return to a gravitational environment. The training program exploits the ability of the sensorimotor system to generalize from exposure to multiple adaptive challenges during training so that the gait control system essentially learns to learn and therefore can reorganize more rapidly when faced with a novel adaptive challenge. We have previously confirmed that subjects participating in adaptive generalization training programs using a variety of visuomotor distortions can enhance their ability to adapt to a novel sensorimotor environment. Importantly, this increased adaptability was retained even one month after completion of the training period. Adaptive generalization has been observed in a variety of other tasks requiring sensorimotor transformations including manual control tasks and reaching (Bock et al., 2001, Seidler, 2003) and obstacle avoidance during walking (Lam and Dietz, 2004). Taken together, the evidence suggests that a training regimen exposing crewmembers to variation in locomotor conditions, with repeated transitions among states, may enhance their ability to learn how to reassemble appropriate locomotor patterns upon return from microgravity. We believe exposure to this type of training will extend crewmembers locomotor behavioral repertoires, facilitating the return of functional mobility after long duration space flight. Our proposed training protocol will compel subjects to develop new behavioral solutions under varying sensorimotor demands. Over time subjects will learn to create appropriate locomotor solution more rapidly enabling acquisition of mobility sooner after long-duration space flight. Our laboratory is currently developing adaptive generalization training procedures and the

  13. Biomarkers of Acute Respiratory Allergen Exposure: Screening For Sensitization Potential

    EPA Science Inventory

    Rationale: An in vitro assay to identify respiratory sensitizers will provide a rapid screen and reduce animal use. The study goal was to identify biomarkers that differentiate allergen versus non-allergen responses following an acute exposure. Methods: Female BALB/c mice rec...

  14. Characterization of a potential radiation-sensitive fragile site

    SciTech Connect

    Jordan, R.; Oroskar, A.A.; Sedita, B.A.

    1995-11-01

    We have been characterizing a Chinese hamster ovary cell line, CHO-K1 10T5, into which a gpt-containing retroviral shuttle vector has been stably integrated. This normally stable locus in CHO-K1 10T5 cells is very sensitive to deletion mutation following ionizing radiation exposure and shows an LET response with an RBE of 3 for {alpha} particles. Almost all of the gpt mutants are total gene deletions. The gpt gene has been localized to chromosome 5q15, within 100-1000 kb of a large region of interstitial telomere repeats. In addition, sequences showing homology to telomere repeat sequences have been identified at the integration site both 5` and 3` to the gpt gene locus. The integration site has been cloned and is presently being sequenced. Preliminary data suggest that there is a hotspot for breakage and/or recombination 5` of the integration site. We hypothesize that (1) the gpt vector has integrated into a region containing telomere repeat sequences, (2) this region of the genome is a radiation-sensitive fragile site, and (3) the radiation sensitivity of this site is due to the telomere sequences, which act by either serving as a site for further telomerase action and chromosome terminilization, or by providing repeat structures to facilitate radiation-induced recombination.

  15. Integrated Computational Solution for Predicting Skin Sensitization Potential of Molecules

    PubMed Central

    Desai, Aarti; Singh, Vivek K.; Jere, Abhay

    2016-01-01

    Introduction Skin sensitization forms a major toxicological endpoint for dermatology and cosmetic products. Recent ban on animal testing for cosmetics demands for alternative methods. We developed an integrated computational solution (SkinSense) that offers a robust solution and addresses the limitations of existing computational tools i.e. high false positive rate and/or limited coverage. Results The key components of our solution include: QSAR models selected from a combinatorial set, similarity information and literature-derived sub-structure patterns of known skin protein reactive groups. Its prediction performance on a challenge set of molecules showed accuracy = 75.32%, CCR = 74.36%, sensitivity = 70.00% and specificity = 78.72%, which is better than several existing tools including VEGA (accuracy = 45.00% and CCR = 54.17% with ‘High’ reliability scoring), DEREK (accuracy = 72.73% and CCR = 71.44%) and TOPKAT (accuracy = 60.00% and CCR = 61.67%). Although, TIMES-SS showed higher predictive power (accuracy = 90.00% and CCR = 92.86%), the coverage was very low (only 10 out of 77 molecules were predicted reliably). Conclusions Owing to improved prediction performance and coverage, our solution can serve as a useful expert system towards Integrated Approaches to Testing and Assessment for skin sensitization. It would be invaluable to cosmetic/ dermatology industry for pre-screening their molecules, and reducing time, cost and animal testing. PMID:27271321

  16. Sigma ligand S14905 and locomotor activity in mice.

    PubMed

    Hascoet, M; Bourin, M; Payeur, R; Lombet, A; Peglion, J L

    1995-12-01

    The binding and locomotor profile of a new sigma ligand, S14905, (isobutyl-N-(1-indan-2yl-piperid-4-yl)N-methyl carbamate, furamate) was studied. The binding data revealed that S14905 has a high affinity for sigma receptors and very low affinity for both dopamine D1 and D2 receptors. We have demonstrated that this sigma ligand prevents the locomotor stimulation induced by morphine (32 and 64 mg/kg), cocaine (16 mg/kg), amphetamine (4 mg/kg) and adrafinil (32 mg/kg) at doses lower than those required to depress spontaneous locomotor activity. The antagonism observed in the present study seems to be more specific of morphine induced hyperlocomotion. The high affinity of this compound for sigma receptors makes it a good choice to study the role of this receptor in the CNS. In addition, S14905 does not directly block dopamine receptors but may modulate them in some manner, and would thus warrant further study as a potential atypical antipsychotic agent, and an antagonist for the hyperactivity induced by opiate drug. PMID:8998401

  17. Locomotor and verbal distance judgments in action and vista space.

    PubMed

    Bergmann, Johanna; Krauss, Elsa; Münch, Agnes; Jungmann, Reiner; Oberfeld, Daniel; Hecht, Heiko

    2011-04-01

    Judging distances is crucial when interacting with the environment. For short distances in action space (up to 30 m), both explicit verbal estimates and locomotor judgments are fairly accurate. For large distances, data have remained scarce. In two laboratory experiments, our observers judged distances to visual targets presented stereoscopically, either by giving a verbal estimate or by walking the distance to the target on a treadmill. While verbal judgments remained linearly scaled over the whole range of distances from 20 to 262 m, locomotor judgments fell short at distances above 100 m, indicating that observers overestimated the distance they had traveled and increasingly did so as a function of actual target distance. This pattern persisted when controlling for the potential confound of fatigue or reluctance to walk. We discuss different approaches to explain our findings and stress the importance of a differential use of distance cues. A model of leaky path integration showed a good fit with our locomotor data. PMID:21365183

  18. Electron beam pattern generator sensitivity to target potentials

    NASA Astrophysics Data System (ADS)

    Ruan, Junru; Hartley, John

    2005-11-01

    Electrostatic chucking is the plan of record for mask clamping in Extreme Ultraviolet (EUV) lithography. In order to minimize mask distortion it is recommended by the EUV lithography community that identical electrostatic chucks be used in the mask patterning and metrology tools. The high voltages used in electrostatic chucking have the potential to establish voltages on the mask surface, which may influence the electron optical characteristics of the pattern generator to the detrimental imaging of the pattern. To understand the relationship between image degradation and mask surface voltages, we are modeling the interaction between mask potential and electron beam columns. The first system modeled consists entirely of electrostatic elements, and the second one is a more traditional electron beam lithography system with electrostatic and magnetic components. All of the working parameters of the systems were fixed to establish optimal imaging on the grounded mask. We then altered the potential on the mask surface and determined the impact on focus and deflection errors. The simulation results establish the relationship between the mask potential, focus and deflection errors. Detailed data of focus deflection error versus mask potential will be presented for these electron beam column configurations. When combined with ITRS roadmap specifications, these results set boundaries on mask and chuck configurations as well as grounding schemes. The results are also applicable to charged particle maskless lithography schemes as well as issues of substrate charging in both pattern generators and metrology tools.

  19. Light sensitivity in a vertebrate mechanoreceptor?

    PubMed Central

    Baker, Gary E.; de Grip, Willem J.; Turton, Michael; Wagner, Hans-Joachim; Foster, Russell G.; Douglas, Ron H.

    2015-01-01

    ABSTRACT Using immunohistochemistry and western blot analysis, we demonstrate that melanopsin is localised in cells around the central pore of lateral line neuromasts in the African clawed frog, Xenopus laevis. Since melanopsin is a known photoreceptor pigment with diverse functions in vertebrates, we suggest that the lateral line of Xenopus laevis, which is primarily a mechanoreceptor, might also be light sensitive. Potential functions of such photosensitivity are discussed, including its role in mediating locomotor responses following dermal illumination. PMID:26206352

  20. Initiation of segmental locomotor-like activities by stimulation of ventrolateral funiculus in the neonatal rat.

    PubMed

    Cheng, Jianguo; Magnuson, David S K

    2011-09-01

    Descending control is critically important for the generation of locomotor activities. Yet, our understanding of the descending control system of locomotion is limited. We hypothesized that stimulation of the ventrolateral funiculus (VLF) induces rhythmic activity in lumbar neurons that is correlated with locomotor-like activity in the neonatal rat. Intracellular recordings were conducted in the L2-L3 lumbar segments, while locomotor-like output was monitored in the L2 and L5 ventral roots. Stimulation of the VLF at thoracic segments induced locomotor-like activity in the L2 and L5 ventral roots in majority of the preparations (26/33). In a few midline split cord preparations (4/13), VLF stimulation induced rhythmic locomotor-like bursts in either L2 or L5 ventral root without alternating pattern between the ventral roots. The response latencies suggest that VLF stimulation induced antidromic activation (<1 ms, 8 cells), monosynaptic activation (1-3 ms, 18 cells), and oligosynaptic activation (3.5-5 ms, 14 cells) of segmental neurons in the lumbar region. VLF stimulation induced rhythmic membrane potential oscillations with or without bursting of action potentials in 9 of 40 putative interneurons. The membrane potential oscillations were in phase with the locomotor-like output of the L2 ventral root in 7 of the 9 cells while the other 2 cells oscillated in phase with the L5 ventral root activity. We have thus demonstrated that descending axons exist in the VLF which make synaptic connections with segmental neurons in the lumbar region that may be a critical element of the locomotor neural network for the initiation of locomotion. PMID:21858680

  1. Initiation of segmental locomotor-like activities by stimulation of ventrolateral funiculus in the neonatal rat

    PubMed Central

    Magnuson, David S. K.

    2011-01-01

    Descending control is critically important for the generation of locomotor activities. Yet, our understanding of the descending control system of locomotion is limited. We hypothesized that stimulation of the ventrolateral funiculus (VLF) induces rhythmic activity in lumbar neurons that is correlated with locomotor-like activity in the neonatal rat. Intracellular recordings were conducted in the L2–L3 lumbar segments, while locomotor-like output was monitored in the L2 and L5 ventral roots. Stimulation of the VLF at thoracic segments induced locomotor-like activity in the L2 and L5 ventral roots in majority of the preparations (26/33). In a few midline split cord preparations (4/13), VLF stimulation induced rhythmic locomotor-like bursts in either L2 or L5 ventral root without alternating pattern between the ventral roots. The response latencies suggest that VLF stimulation induced antidromic activation (<1 ms, 8 cells), monosynaptic activation (1–3 ms, 18 cells), and oligosynaptic activation (3.5–5 ms, 14 cells) of segmental neurons in the lumbar region. VLF stimulation induced rhythmic membrane potential oscillations with or without bursting of action potentials in 9 of 40 putative interneurons. The membrane potential oscillations were in phase with the locomotor-like output of the L2 ventral root in 7 of the 9 cells while the other 2 cells oscillated in phase with the L5 ventral root activity. We have thus demonstrated that descending axons exist in the VLF which make synaptic connections with segmental neurons in the lumbar region that may be a critical element of the locomotor neural network for the initiation of locomotion. PMID:21858680

  2. Nonlinear optical properties of potential sensitive styryl dyes.

    PubMed Central

    Huang, J Y; Lewis, A; Loew, L

    1988-01-01

    The nonlinear optical properties of dyes that alter their optical characteristics rapidly with membrane potential are described. The second harmonic signals from these dyes characterized in this paper are among the largest that have been detected to date. Structural conclusions are drawn from the second harmonic signals generated by the Langmuir Blodgett monolayers used in these measurements. Our results indicate that with appropriate instrumentation second harmonic signals could readily be detected from living cells stained with these dyes. PMID:3390517

  3. High ethanol dose during early adolescence induces locomotor activation and increases subsequent ethanol intake during late adolescence.

    PubMed

    Acevedo, María Belén; Molina, Juan Carlos; Nizhnikov, Michael E; Spear, Norman E; Pautassi, Ricardo Marcos

    2010-07-01

    Adolescent initiation of ethanol consumption is associated with subsequent heightened probability of ethanol use disorders. The present study examined the relationship between motivational sensitivity to ethanol initiation in adolescent rats and later ethanol intake. Experiment 1 determined that ethanol induces locomotor activation shortly after administration but not if tested at a later post-administration interval. In Experiment 2, adolescent rats were assessed for ethanol-induced locomotor activation on postnatal Day 28. These animals were then evaluated for ethanol-mediated conditioned taste aversion and underwent a 16-day-long ethanol intake protocol. Ethanol-mediated aversive effects were unrelated to ethanol locomotor stimulation or subsequent ethanol consumption patterns. Ethanol intake during late adolescence was greatest in animals initiated to ethanol earliest at postnatal Day 28. Females that were more sensitive to ethanol's locomotor-activating effects showed a transient increase in ethanol self-administration. Blood ethanol concentrations during initiation were not related to ethanol-induced locomotor activation. Adolescent rats appeared sensitive to the locomotor-stimulatory effects of ethanol. Even brief ethanol exposure during adolescence may promote later ethanol intake. PMID:20373327

  4. Mephedrone interactions with cocaine: prior exposure to ‘bath salt’ constituent enhances cocaine-induced locomotor activation in rats

    PubMed Central

    Gregg, Ryan A.; Tallarida, Christopher S.; Reitz, Allen B.; Rawls, Scott M.

    2014-01-01

    Concurrent use of mephedrone (4-methylmethcathinone) (MEPH) and established drugs of abuse is now commonplace, but knowledge about interactions between these drugs is sparse. The present study was designed to test the hypothesis that prior MEPH exposure enhances the locomotor-stimulant effects of cocaine and methamphetamine (METH). For cocaine experiments, rats pretreated with saline, cocaine (15 mg/kg), or MEPH (15 mg/kg) for 5 days were injected with cocaine after 10 days of drug absence. For METH experiments, rats pretreated with saline, METH (2 mg/kg), or MEPH (15 mg/kg) were injected with METH after 10 days of drug absence. Cocaine challenge produced greater locomotor activity following pretreatment with cocaine or MEPH than following pretreatment with saline. METH challenge produced greater locomotor activity following METH pretreatment than following saline pretreatment; however, locomotor activity in rats pretreated with MEPH or saline and then challenged with METH was not significantly different. The locomotor response to MEPH (15 mg/kg) was not significantly affected by pretreatment with cocaine (15 mg/kg) or METH (0.5, 2 mg/kg). The present demonstration that cocaine-induced locomotor activation is enhanced by prior MEPH exposure suggests that MEPH cross-sensitizes to cocaine and increases cocaine efficacy. Interestingly, MEPH cross-sensitization was not bi-directional and did not extend to METH, suggesting the phenomenon is sensitive to specific psychostimulants. PMID:24126218

  5. Mephedrone interactions with cocaine: prior exposure to the 'bath salt' constituent enhances cocaine-induced locomotor activation in rats.

    PubMed

    Gregg, Ryan A; Tallarida, Christopher S; Reitz, Allen B; Rawls, Scott M

    2013-12-01

    Concurrent use of mephedrone (4-methylmethcathinone; MEPH) and established drugs of abuse is now commonplace, but knowledge about interactions between these drugs is sparse. The present study was designed to test the hypothesis that prior MEPH exposure enhances the locomotor-stimulant effects of cocaine and methamphetamine (METH). For cocaine experiments, rats pretreated with saline, cocaine (15 mg/kg), or MEPH (15 mg/kg) for 5 days were injected with cocaine after 10 days of drug absence. For METH experiments, rats pretreated with saline, METH (2 mg/kg), or MEPH (15 mg/kg) were injected with METH after 10 days of drug absence. Cocaine challenge produced greater locomotor activity after pretreatment with cocaine or MEPH than after pretreatment with saline. METH challenge produced greater locomotor activity after METH pretreatment than after saline pretreatment; however, locomotor activity in rats pretreated with MEPH or saline and then challenged with METH was not significantly different. The locomotor response to MEPH (15 mg/kg) was not significantly affected by pretreatment with cocaine (15 mg/kg) or METH (0.5, 2 mg/kg). The present demonstration that cocaine-induced locomotor activation is enhanced by prior MEPH exposure suggests that MEPH cross-sensitizes to cocaine and increases cocaine efficacy. Interestingly, MEPH cross-sensitization was not bidirectional and did not extend to METH, suggesting that the phenomenon is sensitive to specific psychostimulants. PMID:24126218

  6. Intestinal microflora as potential modifiers of sensitizer activity in vivo

    SciTech Connect

    Sheldon, P.W.; Clarke, C.; Dawson, K.B.; Simpson, W.; Simmons, D.J.C.

    1984-08-01

    Treatment of mice (some bearing Lewis lung tumors), with penicillin (PEN) at 500 mg/l drinking water for one week prior to treatment with misonidazole (MIS), resulted in: the elimination of their anaerobic cecal flora; a decrease in MIS-induced neurotoxicity; an increase in pharmacological exposure to MIS; a decrease in MIS chemopotentiation; a probable increase in MIS radiosensitization; an increase in MIS induced hypothermia. Assuming no chemical interaction between PEN and MIS, these observations indicate that the intestinal microflora can influence the activity of MIS in vivo. The observed reduction in the neurotoxic but not the radiosensitizing potential of MIS following PEN treatment indicates a therapeutic benefit.

  7. Characteristics of the electrical oscillations evoked by 4-aminopyridine on dorsal root fibers and their relation to fictive locomotor patterns in the rat spinal cord in vitro.

    PubMed

    Taccola, G; Nistri, A

    2005-01-01

    4-Aminopyridine (4-AP) is suggested to improve symptomatology of spinal injury patients because it may facilitate neuromuscular transmission, spinal impulse flow and the operation of the locomotor central pattern generator (CPG). Since 4-AP can also induce repetitive discharges from dorsal root afferents, this phenomenon might interfere with sensory signals necessary to modulate CPG activity. Using electrophysiological recording from dorsal and ventral roots of the rat isolated spinal cord, we investigated 4-AP-evoked discharges and their relation with fictive locomotor patterns. On dorsal roots 4-AP (5-10 microM) induced sustained synchronous oscillations (3.3+/-0.8 s period) smaller than electrically evoked synaptic potentials, persistent after sectioning off the ventral region and preserved in an isolated dorsal quadrant, indicating their dorsal horn origin. 4-AP oscillations were blocked by tetrodotoxin, or 6-cyano-7-nitroquinoxaline-2,3-dione and d-amino-phosphonovalerate, or strychnine and bicuculline, suggesting they were network mediated via glutamatergic, glycinergic and GABAergic transmission. Isolated ventral horn areas could not generated 4-AP oscillations, although their intrinsic disinhibited bursting was accelerated by 4-AP. Thus, ventral horn areas contained 4-AP sensitive sites, yet lacked the network for 4-AP induced oscillations. Activation of fictive locomotion by either application of N-methyl-D-aspartate and serotonin or stimulus trains to a single dorsal root reversibly suppressed dorsal root oscillations induced by 4-AP. This suppression was due to depression of dorsal network activity rather than simple block of root discharges. Since dorsal root oscillations evoked by 4-AP were turned off when the fictive locomotor program was initiated, these discharges are unlikely to interfere with proprioceptive signals during locomotor training in spinal patients. PMID:15857720

  8. Neuronal control of locomotor handedness in Drosophila

    PubMed Central

    Buchanan, Sean M.; Kain, Jamey S.; de Bivort, Benjamin L.

    2015-01-01

    Genetically identical individuals display variability in their physiology, morphology, and behaviors, even when reared in essentially identical environments, but there is little mechanistic understanding of the basis of such variation. Here, we investigated whether Drosophila melanogaster displays individual-to-individual variation in locomotor behaviors. We developed a new high-throughout platform capable of measuring the exploratory behavior of hundreds of individual flies simultaneously. With this approach, we find that, during exploratory walking, individual flies exhibit significant bias in their left vs. right locomotor choices, with some flies being strongly left biased or right biased. This idiosyncrasy was present in all genotypes examined, including wild-derived populations and inbred isogenic laboratory strains. The biases of individual flies persist for their lifetime and are nonheritable: i.e., mating two left-biased individuals does not yield left-biased progeny. This locomotor handedness is uncorrelated with other asymmetries, such as the handedness of gut twisting, leg-length asymmetry, and wing-folding preference. Using transgenics and mutants, we find that the magnitude of locomotor handedness is under the control of columnar neurons within the central complex, a brain region implicated in motor planning and execution. When these neurons are silenced, exploratory laterality increases, with more extreme leftiness and rightiness. This observation intriguingly implies that the brain may be able to dynamically regulate behavioral individuality. PMID:25953337

  9. Locomotor Experience Affects Self and Emotion

    ERIC Educational Resources Information Center

    Uchiyama, Ichiro; Anderson, David I.; Campos, Joseph J.; Witherington, David; Frankel, Carl B.; Lejeune, Laure; Barbu-Roth, Marianne

    2008-01-01

    Two studies investigated the role of locomotor experience on visual proprioception in 8-month-old infants. "Visual proprioception" refers to the sense of self-motion induced in a static person by patterns of optic flow. A moving room apparatus permitted displacement of an entire enclosure (except for the floor) or the side walls and ceiling. In…

  10. Neuronal control of locomotor handedness in Drosophila.

    PubMed

    Buchanan, Sean M; Kain, Jamey S; de Bivort, Benjamin L

    2015-05-26

    Genetically identical individuals display variability in their physiology, morphology, and behaviors, even when reared in essentially identical environments, but there is little mechanistic understanding of the basis of such variation. Here, we investigated whether Drosophila melanogaster displays individual-to-individual variation in locomotor behaviors. We developed a new high-throughout platform capable of measuring the exploratory behavior of hundreds of individual flies simultaneously. With this approach, we find that, during exploratory walking, individual flies exhibit significant bias in their left vs. right locomotor choices, with some flies being strongly left biased or right biased. This idiosyncrasy was present in all genotypes examined, including wild-derived populations and inbred isogenic laboratory strains. The biases of individual flies persist for their lifetime and are nonheritable: i.e., mating two left-biased individuals does not yield left-biased progeny. This locomotor handedness is uncorrelated with other asymmetries, such as the handedness of gut twisting, leg-length asymmetry, and wing-folding preference. Using transgenics and mutants, we find that the magnitude of locomotor handedness is under the control of columnar neurons within the central complex, a brain region implicated in motor planning and execution. When these neurons are silenced, exploratory laterality increases, with more extreme leftiness and rightiness. This observation intriguingly implies that the brain may be able to dynamically regulate behavioral individuality. PMID:25953337

  11. Water balance and locomotor performance in three species of neotropical toads that differ in geographical distribution.

    PubMed

    Titon, Braz; Navas, Carlos Arturo; Jim, Jorge; Gomes, Fernando Ribeiro

    2010-05-01

    Water availability in the environment is a fundamental factor in determining the limits of geographical distribution and the evolution of the physiological characters associated to water balance in anurans. In this paper, we compare some aspects of water balance and the sensitivity of locomotor performance to dehydration at different temperatures for three species of toads from the genus Rhinella, with different levels of dependence on forested environments. Results show patterns associated to interspecific differences in both geographical distribution and time of seasonal reproduction. Sensitivity of locomotor performance to dehydration was lower at low temperatures for R. icterica, the species that are reproductively active during winter and lower at intermediate temperatures for R. schneideri, the species that reproduces mostly during spring, suggesting a pattern of thermal adaptation of locomotor performance for these species. Otherwise, R. ornata, a species with broader reproductive season, shows high sensitivity of locomotor performance to dehydration at all temperatures tested, suggesting a stronger relation of breeding activity with patterns of rainfall than temperature variation. Furthermore, the low rates of water uptake of R. ornata may pose restrictions on the occupation of open areas by this species. PMID:20096361

  12. A geometric morphometric analysis of acetabular shape of the primate hip joint in relation to locomotor behaviour.

    PubMed

    San Millán, Marta; Kaliontzopoulou, Antigoni; Rissech, Carme; Turbón, Daniel

    2015-06-01

    The description of acetabular shape variation among primates is essential for our understanding of the locomotor behaviour and ecology of both extant and fossil species. In this study, we use two-dimensional geometric morphometrics to examine variation in acetabular shape in human and non-human primates and to determine the degree to which it co-varies with locomotor behaviour, while taking both intra and inter-specific variation into account. To these ends, we examined the acetabulum of 303 left hip bones of 27 extant genera of primates (including humans) with different locomotor behaviours. After accounting for shape variation due to sex, size, and phylogeny, the results confirm that acetabular shape varies significantly across locomotor groups. The two most differentiated locomotor groups are leapers and slow-climbing quadrupeds, which exhibit a unique acetabular shape. Furthermore, the acetabulum of humans differed significantly from all other groups, while no significant differences existed between chimpanzees and gorillas. The most noticeable differences are detected in both cranial and dorsal areas and around the acetabular horns. This variation in acetabular morphology may have biomechanical implications at the level of the hip joint, potentially determining joint range motion and load distribution during locomotion. Given the increasing number of published studies on fossil pelves, our results are widely applicable to fossil analyses, with critical implications for paleoanthropological analyses about the complex locomotor behaviour of fossil specimens and their classification into locomotor groups, which may enhance our understanding of their ecological habits. PMID:25929707

  13. Effects of cocaine on locomotor activity and schedule-controlled behaviors of inbred rat strains.

    PubMed

    Witkin, J M; Goldberg, S R

    1990-10-01

    Effects of cocaine on several behaviors considered to be reflective of psychomotor stimulation were compared in F344/CR1BR and NBR/NIH inbred rat strains. Effects of cocaine on locomotor activity were compared with effects on either bar-press or nose-poke responses maintained under a multiple fixed-interval 3-min, timeout 1-min schedule of food presentation. In locomotor activity experiments, NBR rats were twice as active as F344 rats under baseline conditions and displayed dose-dependent increases in locomotion (5-20 mg/kg). Maximal increases in locomotor activity of F344 rats were only 200% compared to 1000% in NBR rats. In contrast to locomotor activity, no strain differences in the effects of cocaine were observed under the schedules of food delivery. Bar-pressing under the fixed-interval schedule was increased to a maximum of 150% of control in both rat strains. Nose-poke responding under the fixed-interval schedule was not significantly increased, but timeout rates were increased in both strains. These results suggest that NBR and F344 rats do not differ in general sensitivity to stimulant effects of cocaine but exhibit marked differences in responsivity to cocaine that are dependent upon the behavior studied. Further delineation of the behavioral specificity of strain differences in sensitivity to cocaine should help to identify neurobiological substrates underlying unique biologically determined responses to cocaine. PMID:2080195

  14. Dose-dependent changes in the synaptic strength on dopamine neurons and locomotor activity after cocaine exposure

    PubMed Central

    Wanat, M.J.; Bonci, A.

    2016-01-01

    Changes in synaptic strength on ventral tegmental area (VTA) dopamine neurons are thought to play a critical role in the development of addiction-related behaviors. However, it is unknown how a single injection of cocaine at different doses affects locomotor activity, behavioral sensitization, and glutamatergic synaptic strength on VTA dopamine neurons in mice. We observed that behavioral sensitization to a challenge cocaine injection scaled with the dose of cocaine received one day prior. Interestingly, the locomotor activity after the initial exposure to different doses of cocaine corresponded to the changes in glutamatergic strength on VTA dopamine neurons. These results in mice suggest that a single exposure to cocaine dose-dependently affects excitatory synapses on VTA dopamine neurons, and that this acute synaptic alteration is directly associated with the locomotor responses to cocaine and not to behavioral sensitization. PMID:18655120

  15. Development of a Countermeasure to Mitigate Postflight Locomotor Dysfunction

    NASA Technical Reports Server (NTRS)

    Bloomberg, J. J.; Mulavara, A. P.; Peters, B. T.; Cohen, H. S.; Richards, J. T.; Miller, C. A.; Brady, R.; Warren, L. E.; Ruttley, T. M.

    2006-01-01

    Astronauts returning from space flight experience locomotor dysfunction following their return to Earth. Our laboratory is currently developing a gait adaptability training program that is designed to facilitate recovery of locomotor function following a return to a gravitational environment. The training program exploits the ability of the sensorimotor system to generalize from exposure to multiple adaptive challenges during training so that the gait control system essentially learns to learn and therefore can reorganize more rapidly when faced with a novel adaptive challenge. Evidence for the potential efficacy of an adaptive generalization gait training program can be obtained from numerous studies in the motor learning literature which have demonstrated that systematically varying the conditions of training enhances the ability of the performer to learn and retain a novel motor task. These variable practice training approaches have been used in applied contexts to improve motor skills required in a number of different sports. The central nervous system (CNS) can produce voluntary movement in an almost infinite number of ways. For example, locomotion can be achieved with many different combinations of joint angles, muscle activation patterns and forces. The CNS can exploit these degrees of freedom to enhance motor response adaptability during periods of adaptive flux like that encountered during a change in gravitational environment. Ultimately, the functional goal of an adaptive generalization countermeasure is not necessarily to immediately return movement patterns back to normal. Rather the training regimen should facilitate the reorganization of available sensory and motor subsystems to achieve safe and effective locomotion as soon as possible after long duration space flight. Indeed, this approach has been proposed as a basic feature underlying effective neurological rehabilitation. We have previously confirmed that subjects participating in an adaptive

  16. The evolution of locomotor rhythmicity in tetrapods.

    PubMed

    Ross, Callum F; Blob, Richard W; Carrier, David R; Daley, Monica A; Deban, Stephen M; Demes, Brigitte; Gripper, Janaya L; Iriarte-Diaz, Jose; Kilbourne, Brandon M; Landberg, Tobias; Polk, John D; Schilling, Nadja; Vanhooydonck, Bieke

    2013-04-01

    Differences in rhythmicity (relative variance in cycle period) among mammal, fish, and lizard feeding systems have been hypothesized to be associated with differences in their sensorimotor control systems. We tested this hypothesis by examining whether the locomotion of tachymetabolic tetrapods (birds and mammals) is more rhythmic than that of bradymetabolic tetrapods (lizards, alligators, turtles, salamanders). Species averages of intraindividual coefficients of variation in cycle period were compared while controlling for gait and substrate. Variance in locomotor cycle periods is significantly lower in tachymetabolic than in bradymetabolic animals for datasets that include treadmill locomotion, non-treadmill locomotion, or both. When phylogenetic relationships are taken into account the pooled analyses remain significant, whereas the non-treadmill and the treadmill analyses become nonsignificant. The co-occurrence of relatively high rhythmicity in both feeding and locomotor systems of tachymetabolic tetrapods suggests that the anatomical substrate of rhythmicity is in the motor control system, not in the musculoskeletal components. PMID:23550769

  17. Classification of sensitizing and irritative potential in a combined in-vitro assay

    SciTech Connect

    Wanner, Reinhard; Sonnenburg, Anna; Quatchadze, Maria; Schreiner, Maximilian; Peiser, Matthias; Zuberbier, Torsten; Stahlmann, Ralf

    2010-06-01

    We have developed a coculture system which in parallel indicates the sensitizing and irritative potential of xenobiotics. The assay is named loose-fit coculture-based sensitization assay (LCSA) and may be performed within 5 days. The system is composed of human monocytes that differentiate to a kind of dendritic cells by 2-day culturing in the presence of allogenic keratinocytes. The culture medium is enriched by a cocktail of recombinant cytokines. On day 3, concentration series of probes are added. On day 5, cells are harvested and analyzed for expression range of CD86 as a marker of sensitizing potential and for uptake of the viability stain 7-AAD as a marker of irritative potential. Estimation of the concentration required to cause a half-maximal increase in CD86 expression allowed quantification of sensitizing potential, and estimation of the concentration required to reduce viability to 50% allowed quantification of irritative potential. Examination of substances with known potential resulted in categorization of test scores. To evaluate our data, we have compared results with those of the validated animal-based sensitization test, the murine local lymph node assay (LLNA, OECD TG 429). To a large extent, results from LCSA and from LLNA achieved analogous grouping of allergens into categories like weak-moderate-strong. However, the new assay showed an improved capacity to distinguish sensitizers from non-sensitizers and irritants. In conclusion, the LCSA contains potential to fulfil the requirements of the EU's programme for the safety of chemicals 'Registration, Evaluation, Authorisation and Restriction of chemical substances' (REACH, 2006) to replace animal models.

  18. Potential sensitivities in frequency modulation and heterodyne amplitude modulation Kelvin probe force microscopes

    PubMed Central

    2013-01-01

    In this paper, the potential sensitivity in Kelvin probe force microscopy (KPFM) was investigated in frequency modulation (FM) and heterodyne amplitude modulation (AM) modes. We showed theoretically that the minimum detectable contact potential difference (CPD) in FM-KPFM is higher than in heterodyne AM-KPFM. We experimentally confirmed that the signal-to-noise ratio in FM-KPFM is lower than that in heterodyne AM-KPFM, which is due to the higher minimum detectable CPD dependence in FM-KPFM. We also compared the corrugations in the local contact potential difference on the surface of Ge (001), which shows atomic resolution in heterodyne AM-KPFM. In contrast, atomic resolution cannot be obtained in FM-KPFM under the same experimental conditions. The higher potential resolution in heterodyne AM-KPFM was attributed to the lower crosstalk and higher potential sensitivity between topographic and potential measurements. PMID:24350866

  19. Locomotor head movements and semicircular canal morphology in primates

    PubMed Central

    Malinzak, Michael D.; Kay, Richard F.; Hullar, Timothy E.

    2012-01-01

    Animal locomotion causes head rotations, which are detected by the semicircular canals of the inner ear. Morphologic features of the canals influence rotational sensitivity, and so it is hypothesized that locomotion and canal morphology are functionally related. Most prior research has compared subjective assessments of animal “agility” with a single determinant of rotational sensitivity: the mean canal radius of curvature (R). In fact, the paired variables of R and body mass are correlated with agility and have been used to infer locomotion in extinct species. To refine models of canal functional morphology and to improve locomotor inferences for extinct species, we compare 3D vector measurements of head rotation during locomotion with 3D vector measures of canal sensitivity. Contrary to the predictions of conventional models that are based upon R, we find that axes of rapid head rotation are not aligned with axes of either high or low sensitivity. Instead, animals with fast head rotations have similar sensitivities in all directions, which they achieve by orienting the three canals of each ear orthogonally (i.e., along planes at 90° angles to one another). The extent to which the canal configuration approaches orthogonality is correlated with rotational head speed independent of body mass and phylogeny, whereas R is not. PMID:23045679

  20. Evaluation of the skin sensitization potential of chemicals in THP-1/keratinocyte co-cultures.

    PubMed

    Cao, Yu-Ping; Ma, Peng-Cheng; Liu, Wei-Da; Zhou, Wu-Qing; Tao, Yue; Zhang, Meng-Li; Li, Ling-Jun; Chen, Zi-Yi

    2012-04-01

    Many attempts have been made to develop in vitro sensitization tests that employ dendritic cells (DCs), DC-like cell lines or keratinocytes. The aim of the present investigation was to establish a co-culture of THP-1 cells and keratinocytes for evaluation of skin sensitization potential of chemicals. Co-cultures were constructed by THP-1 cells cultured in lower compartments and keratinocytes cultured in upper compartments of cell culture inserts. After 24 h exposure to sensitizers (2, 4-dinitrochlorobenzene, p-phenylenediamine, formaldehyde, nickel sulfate, isoeugenol and eugenol) and non-sensitizers (sodium lauryl sulfate, benzalkonium chloride and lactic acid), the expression of CD86 and CD54 on THP-1 cells were evaluated by flow cytometry, and cell viabilities were determined. The sensitizers induced the augmentation of CD86 and CD54 expression, but the non-sensitizers had no significant effect. Compared with mono-cultures of THP-1 cells, the augmentation of CD86 and CD54 could be detected even at a non-toxic concentration of sensitizers in THP-1 cell/keratinocyte co-cultures. Moreover, isoeugenol was distinguished as a sensitizer in co-cultures, but failed to be identified in mono-cultures. These results revealed that the co-cultures of THP-1 cells and keratinocytes were successfully established and suitable for identifying sensitizers using CD86 and CD54 expression as identification markers. PMID:21721923

  1. AUTS2 in the nucleus accumbens is essential for heroin-induced behavioral sensitization.

    PubMed

    Zhu, Yongsheng; Xing, Bo; Dang, Wei; Ji, Yuanyuan; Yan, Peng; Li, Yunxiao; Qiao, Xiaomeng; Lai, Jianghua

    2016-10-01

    Autism susceptibility candidate 2 (AUTS2) is a gene associated with autism and mental retardation. Recent studies have suggested an association of the AUTS2 gene with heroin dependence, and reduced AUTS2 gene expression may confer increased susceptibility to heroin dependence. However, the functional role of the AUTS2 protein in regulating enduring neuroadaptations in response to heroin exposure has not been established. Here, we investigated the effects of acute and chronic heroin exposure on AUTS2 mRNA and protein expression in the nucleus accumbens (NAc) and caudate-putamen (CPu) to determine whether changes in AUTS2 expression are associated with heroin-induced locomotor sensitization in mice. Moreover, we explored whether AUST2 knockdown affects heroin-induced locomotor sensitization. AUTS2 mRNA and protein expression in the NAc, but not the CPu, was decreased after chronic heroin (1mg/kg) administration. In the NAc, the expression of heroin-induced locomotor sensitization was enhanced through the lentiviral-AUTS2-shRNA-mediated knockdown of AUTS2, while the overexpression of AUTS2 attenuated the locomotor-stimulant effects of heroin. Together, these results indicate that AUTS2 in the NAc, but not the CPu, suppresses the initiation and expression of heroin-induced behavioral sensitization, suggesting that AUST2 may be a potential target for the treatment of heroin dependence. PMID:27423627

  2. Variable Maternal Stress in Rats Alters Locomotor Activity, Social Behavior, and Recognition Memory in the Adult Offspring

    PubMed Central

    Wilson, Christina A.; Terry, Alvin V.

    2013-01-01

    Rats repeatedly exposed to variable prenatal stress (PNS) exhibit behavioral signs that are similar to those manifested in several neuropsychiatric disorders such as deficits in attention and inhibitory control, and impairments in memory-related task performance. The purpose of the study described here was to conduct a comprehensive battery of tests to further characterize the behavioral phenotype of PNS rats as well as to evaluate the sensitivity of the model to therapeutic interventions (i.e., to compounds previously shown to have therapeutic potential in neuropsychiatric disorders). The results of this study indicated that PNS in rats is associated with: 1) increased locomotor activity and stereotypic behaviors, 2) elevated sensitivity to the psychostimulant amphetamine, 3) increased aggressive behaviors toward both adult and juvenile rats and 4) delay-dependent deficits in recognition memory. There was no evidence that PNS rats exhibited deficits in other areas of motor function/learning, sensorimotor gating, spatial learning and memory, social withdrawal, or anhedonia. In addition, the results revealed that the second generation antipsychotic risperidone attenuated amphetamine-related increases in locomotor activity in PNS rats; however, the effect was not sustained over time. Furthermore, deficits in recognition memory in PNS rats were attenuated by the norepinephrine reuptake inhibitor, atomoxetine, but not by the α7 nicotinic acetylcholine receptor partial agonist, GTS-21. This study supports the supposition that important phenomenological similarities exist between rats exposed to PNS and patients afflicted with neuropsychiatric disorders thus further establishing the face validity of the model for evaluating potential therapeutic interventions. PMID:23287801

  3. Differential Effects of Inhaled Toluene on Locomotor Activity in Adolescent and Adult Rats

    PubMed Central

    Batis, Jeffery C.; Hannigan, John H.; Bowen, Scott E.

    2010-01-01

    Inhalant abuse is a world-wide public health concern among adolescents. Most preclinical studies have assessed inhalant effects in adult animals leaving unclear how behavioral effects differ in younger animals. We exposed adolescent (postnatal day [PN] 28) and adult (PN90) male rats to toluene using 1 of 3 exposure patterns. These patterns modeled those reported in toluene abuse in teens and varied concentration, number and length of exposures, as well as the inter-exposure interval. Animals were exposed repeatedly over 12 days to toluene concentrations of 0, 8,000 or 16,000 parts per million (ppm). Locomotor activity was quantified during toluene exposures and for 30 min following completion of the final daily toluene exposure. For each exposure pattern, there were significant toluene concentration-related increases and decreases in locomotor activity compared to the 0-ppm “air” controls at both ages. These changes depended upon when activity was measured – during or following exposure. Compared to adults, adolescents displayed greater locomotor activity on the first day and generally greater increases in activity over days than adults during toluene exposure. Adults displayed greater locomotor activity than adolescents in the “recovery” period following exposure on the first and subsequent days. Age group differences were clearest following the pattern of paced, brief (5-min) repeated binge exposures. The results suggest that locomotor behavior in rats during and following inhalation of high concentrations of toluene depends on age and the pattern of exposure. The results are consistent with dose-dependent shifts in sensitivity and sensitization or tolerance to repeated toluene in the adolescent animals compared to the adult animals. Alternate interpretations are possible and our interpretation is limited by the range of very high concentrations of toluene used. The results imply that both pharmacological and psychosocial factors contribute to the teen

  4. Restraint stress attenuates nicotine’s locomotor stimulant but not discriminative stimulus effects in rats

    PubMed Central

    Harris, Andrew C.; Mattson, Christina; Shelley, David; LeSage, Mark G.

    2014-01-01

    Stress enhances the locomotor stimulant and discriminative stimulus effects of several addictive drugs (e.g., morphine) in rodents, yet interactions between stress and nicotine’s effects in these behavioral models have not been well established. To this end, the current studies examined the effects of restraint stress on nicotine-induced locomotor activity and nicotine discrimination in rats. We used a novel approach in which onset of stress and nicotine administration occurred concurrently (i.e., simultaneous exposure) to simulate effects of stress on ongoing tobacco use, as well as a more traditional approach in which a delay was imposed between stress and nicotine administration (i.e., sequential exposure). Simultaneous exposure to stress reduced the rate of locomotor sensitization induced by daily injections of nicotine (0.4 mg/kg, s.c.). A lower dose of nicotine (0.1 mg/kg, s.c.) produced modest effects on activity that were generally unaffected by simultaneous exposure to stress. Sequential exposure to stress and nicotine (0.4 mg/kg, s.c.) slightly suppressed nicotine-induced activity, but did not influence rate of locomotor sensitization. Neither simultaneous nor sequential exposure to stress influenced the discriminative stimulus effects of nicotine (0.01 – 0.2 mg/kg, s.c.). These data show that restraint stress reduces nicotine’s locomotor stimulant effects, particularly when onset of stress and nicotine exposure occurs simultaneously, but does not influence nicotine discrimination. These findings contrast with the ability of stress to enhance the effects of other drugs in these models. This study also suggests that studying the influence of simultaneous stress exposure on drug effects may be useful for understanding the role of stress in addiction. PMID:24867077

  5. Putting the parts together: combining in vitro methods to test for skin sensitizing potentials.

    PubMed

    Bauch, Caroline; Kolle, Susanne N; Ramirez, Tzutzuy; Eltze, Tobias; Fabian, Eric; Mehling, Annette; Teubner, Wera; van Ravenzwaay, Bennard; Landsiedel, Robert

    2012-08-01

    Allergic contact dermatitis is a common skin disease and is elicited by repeated skin contact with an allergen. In the regulatory context, currently only data from animal experiments are acceptable to assess the skin sensitizing potential of substances. Animal welfare and EU Cosmetic Directive/Regulation call for the implementation of animal-free alternatives for safety assessments. The mechanisms that trigger skin sensitization are complex and various steps are involved. Therefore, a single in vitro method may not be able to accurately assess this endpoint. Non-animal methods are being developed and validated and can be used for testing strategies that ensure a reliable prediction of skin sensitization potentials. In this study, the predictivities of four in vitro assays, one in chemico and one in silico method addressing three different steps in the development of skin sensitization were assessed using 54 test substances of known sensitizing potential. The predictivity of single tests and combinations of these assays were compared. These data were used to develop an in vitro testing scheme and prediction model for the detection of skin sensitizers based on protein reactivity, activation of the Keap-1/Nrf2 signaling pathway and dendritic cell activation. PMID:22659254

  6. Determination of aerodynamic sensitivity coefficients based on the three-dimensional full potential equation

    NASA Technical Reports Server (NTRS)

    Elbanna, Hesham M.; Carlson, Leland A.

    1992-01-01

    The quasi-analytical approach is applied to the three-dimensional full potential equation to compute wing aerodynamic sensitivity coefficients in the transonic regime. Symbolic manipulation is used to reduce the effort associated with obtaining the sensitivity equations, and the large sensitivity system is solved using 'state of the art' routines. Results are compared to those obtained by the direct finite difference approach and both methods are evaluated to determine their computational accuracy and efficiency. The quasi-analytical approach is shown to be accurate and efficient for large aerodynamic systems.

  7. Sensitization and desensitization of burn patients as potential candidates for vascularized composite allotransplantation.

    PubMed

    Klein, H J; Schanz, U; Hivelin, M; Waldner, M; Koljonen, V; Guggenheim, M; Giovanoli, P; Gorantla, V S; Fehr, T; Plock, J A

    2016-03-01

    Sensitization describes the acquired ability of the immune system to react to foreign human leukocyte antigens (HLA) by producing antibodies and developing memory cells. In the field of transplantation, recipient preformed HLA antibodies due to previous sensitization have been identified - beneath ABO incompatibility - as a major factor for acute graft rejection. Several reasons for sensitization have largely been studied, such as previous blood transfusions, pregnancies or former transplants. Recent studies indicate that the use of assist devices (e.g. ECMO) or cadaveric skin allotransplantation providing temporary coverage in burn patients may lead to additional sensitization. As vascularized composite allotransplantation (VCA) has become a rapidly advancing therapeutic option for reconstruction of complex tissue defects in burns, it seems even more important to become familiar with immunological principles and to be cautiously aware of both sources of sensitization and therapeutic concepts in burns avoiding sensitization. This may also include emergency VCAs in burn patients as potential strategy for early definitive reconstruction avoiding procedures triggering HLA antibody formation. We hereby provide an overview on current evidence in the field of pre- and peritransplant sensitization, followed by posttransplant strategies of desensitization and their potential impact on future treatments of burn patients. PMID:26392022

  8. Tonic Pain Experienced during Locomotor Training Impairs Retention Despite Normal Performance during Acquisition

    PubMed Central

    Bouffard, Jason; Bouyer, Laurent J.; Roy, Jean-Sébastien

    2014-01-01

    Many patients are in pain when they receive gait training during rehabilitation. Based on animal studies, it has been proposed that central sensitization associated to nociception (maladaptive plasticity) and plasticity related to the sensorimotor learning (adaptive plasticity) share similar neural mechanisms and compete with each other. The aim of this study was to evaluate whether experimental tonic pain influences motor learning (acquisition and next-day retention) of a new locomotor task. Thirty healthy human subjects performed a locomotor adaptation task (perturbing force field applied to the ankle during swing using a robotized orthosis) on 2 consecutive days. Learning was assessed using kinematic measures (peak and mean absolute plantarflexion errors) and electromyographic (EMG) activity. Half of the participants performed the locomotor adaptation task with pain on Day 1 (capsaicin cream around the ankle), while the task was performed pain-free for all subjects on Day 2 to assess retention. Pain had no significant effect on baseline gait parameters nor on performance during the locomotor adaptation task (for either kinematic or EMG measures) on Day 1. Despite this apparently normal motor acquisition, pain-free Day 2 performance was markedly and significantly impaired in the Pain group, indicating that pain during training had an impact on the retention of motor memories (interfering with consolidation and/or retrieval). These results suggest that the same motor rehabilitation intervention could be less effective if administered in the presence of pain. PMID:25009252

  9. A parallel cholinergic brainstem pathway for enhancing locomotor drive

    PubMed Central

    Smetana, Roy; Juvin, Laurent; Dubuc, Réjean; Alford, Simon

    2010-01-01

    The brainstem locomotor system is believed to be organized serially from the mesencephalic locomotor region (MLR) to reticulospinal neurons, which in turn, project to locomotor neurons in the spinal cord. In contrast, we now identify in lampreys, brainstem muscarinoceptive neurons receiving parallel inputs from the MLR and projecting back to reticulospinal cells to amplify and extend durations of locomotor output. These cells respond to muscarine with extended periods of excitation, receive direct muscarinic excitation from the MLR, and project glutamatergic excitation to reticulospinal neurons. Targeted block of muscarine receptors over these neurons profoundly reduces MLR-induced excitation of reticulospinal neurons and markedly slows MLR-evoked locomotion. Their presence forces us to rethink the organization of supraspinal locomotor control, to include a sustained feedforward loop that boosts locomotor output. PMID:20473293

  10. Development of Testing Methodologies to Evaluate Postflight Locomotor Performance

    NASA Technical Reports Server (NTRS)

    Mulavara, A. P.; Peters, B. T.; Cohen, H. S.; Richards, J. T.; Miller, C. A.; Brady, R.; Warren, L. E.; Bloomberg, J. J.

    2006-01-01

    Crewmembers experience locomotor and postural instabilities during ambulation on Earth following their return from space flight. Gait training programs designed to facilitate recovery of locomotor function following a transition to a gravitational environment need to be accompanied by relevant assessment methodologies to evaluate their efficacy. The goal of this paper is to demonstrate the operational validity of two tests of locomotor function that were used to evaluate performance after long duration space flight missions on the International Space Station (ISS).

  11. Effects of consuming a diet high in fat and/or sugar on the locomotor effects of acute and repeated cocaine in male and female C57BL/6J mice

    PubMed Central

    Collins, Gregory T.; Chen, Yu; Tschumi, Chris; Rush, Elise L.; Mensah, Ayele; Koek, Wouter; France, Charles P.

    2015-01-01

    Drug abuse and obesity are serious public health problems. Dopamine plays a central role in mediating the reinforcing effects of drugs and food. Prolonged use of drugs is known to alter the function and/or sensitivity of many neurotransmitter systems, including dopamine, however, the impact of consuming foods high in fat and/or sugar is less clear. These studies characterized the locomotor effects of acute and repeated cocaine in male and female C57BL/6J mice consuming one of four diets: (1) standard chow + water; (2) standard chow + 10% sucrose solution; (3) high-fat chow + water; or (4) high-fat chow + 10% sucrose solution. The acute locomotor effects of cocaine (3.2–32.0 mg/kg) were evaluated four weeks after initiating dietary conditions; the effects of repeated cocaine administration were evaluated after 5, 6, 7, and 12 weeks. During acute tests, mice consuming a diet high in fat and/or sucrose exhibited greater locomotor responses to cocaine than mice consuming standard chow and water, regardless of sex. Although diet-induced enhancements persisted across repeated cocaine testing, locomotor sensitization developed more rapidly in females drinking sucrose (and consuming either standard or high-fat chow) than in females consuming standard chow and water. In addition to providing evidence that consuming a diet high in fat and/or sugar enhances abuse-related effects of cocaine in ways that might increase vulnerability to abuse cocaine, these studies identified a potentially important sex-related difference in the interaction between nutrition and cocaine effects, with the impacts of sucrose consumption being greater in females than in males. PMID:26237320

  12. Quantitative structure-activity relationships for skin sensitization potential of urushiol analogues.

    PubMed

    Roberts, D W; Benezra, C

    1993-08-01

    The relative alkylation index (RAI), a theoretically derived parameter intended to quantify the relative extent of carrier haptenation resulting from a given dose of a given sensitizer, has previously been successfully applied to the analysis of relative sensitization potential and dose-response data for a variety of contact allergens which are directly electrophilic. Here the RAI concept is applied to analysis of data on compounds related to urushiol (i.e., 3-substituted catechols), the naturally occurring mixture of allergens responsible for contact allergy to poison ivy and poison oak. These allergens are believed to act as pro-electrophiles, being oxidized to electrophilic orthoquinones in vivo. It is found that the various types of urushiol derivatives fit the same sort of RAI-sensitization relationships as expected theoretically and as found previously with direct acting electrophiles. There is evidence that in many cases, the test conditions were such that overload effects, whereby the degree of sensitization induced decreases with increasing carrier haptenation, applied. It is also concluded that the question as to the relative sensitization potencies of the naturally occurring urushiols remains open. The commonly held view that with these materials, sensitization potential increases with increasing unsaturation in the 3-hydrocarbyl chain of the 3-hydrocarbyl catechols, is based on evidence that is capable of alternative interpretation. PMID:8365181

  13. CYTOKINE MRNA PROFILES FOR ISOCYANATES WITH KNOWN AND UNKNOWN POTENTIAL TO INDUCE RESPIRATORY SENSITIZATION

    EPA Science Inventory

    Cytokine mRNA Profiles for Isocyanates with Known and Unknown Potential to Induce Respiratory Sensitization. Plitnick, L.M., Loveless, S.E., Ladics, G.S., Holsapple, M.P., Smialowicz, R.J., Woolhiser, M.R., Anderson, P.K., Smith, C., Sailstad, D.M. and Selgrade, M.J.K (2002) Tox...

  14. Sensitivity of the International Skating Union's Mathematical Criteria to Flag Potential Scoring Anomalies

    ERIC Educational Resources Information Center

    Looney, Marilyn A.; Howell, Steven M.

    2015-01-01

    This article describes the "mathematical criteria" employed by the International Skating Union (ISU) to identify potential judging anomalies within competitive figure skating. The mathematical criteria have greater sensitivity to identify scoring anomalies for technical element scores than for the program component scores. This article…

  15. The GALS locomotor screen and disability.

    PubMed Central

    Plant, M J; Linton, S; Dodd, E; Jones, P W; Dawes, P T

    1993-01-01

    OBJECTIVES--Examination of the locomotor system is frequently neglected. Therefore, the GALS locomotor screen (Gait, Arms, Legs, Spine) has been proposed by Doherty et al as a practical method of identifying functionally important problems. This study was designed to test whether this screen reflects functional impairment, as measured by accepted health status measures. METHODS--Two observers performed the GALS screen in a total of 83 patients with a variety of musculoskeletal conditions. The examination components of GALS were rated by a simple 0 to 3 scale. Physical ability was further assessed by Health Activity Questionnaire (HAQ), Barthel index and Steinbrocker's ARA classification. RESULTS--For the total patient group, Spearman correlations between GALS and the three functional indices were good (r = 0.62 to 0.71, p < 0.001). Correlations were equally good for rheumatoid arthritis patients alone (r = 0.65 to 0.70, p < 0.001), but less good although still significant for the other miscellaneous rheumatic conditions (r = 0.31 to 0.46, p < 0.05). Observed proportional agreement between the two observers for the individual scores was > 70%, with a kappa statistic k = 0.49 to 0.74. CONCLUSIONS--The GALS screen is a reliable and valid measure of functional ability, compared with standard accepted indices in a variety of musculoskeletal diseases. This supports the proposal for its use as a screening test by general practitioners and medical students. PMID:8311541

  16. Dynamic Control of Posture Across Locomotor Tasks

    PubMed Central

    Earhart, Gammon M.

    2013-01-01

    Successful locomotion depends on postural control to establish and maintain appropriate postural orientation of body segments relative to one another and to the environment, and to ensure dynamic stability of the moving body. This paper provides a framework for considering dynamic postural control, highlighting the importance of coordination, consistency, and challenges to postural control posed by various locomotor tasks such as turning and backward walking. The impacts of aging and various movement disorders on postural control are discussed broadly in an effort to provide a general overview of the field and recommendations for assessment of dynamic postural control across different populations in both clinical and research settings. Suggestions for future research on dynamic postural control during locomotion are also provided and include discussion of opportunities afforded by new and developing technologies, the need for long-term monitoring of locomotor performance in everyday activities, gaps in our knowledge of how targeted intervention approaches modify dynamic postural control, and the relative paucity of literature regarding dynamic postural control in movement disorder populations other than Parkinson disease. PMID:24132838

  17. Sensitivity analysis of CLIMEX parameters in modeling potential distribution of Phoenix dactylifera L.

    PubMed

    Shabani, Farzin; Kumar, Lalit

    2014-01-01

    Using CLIMEX and the Taguchi Method, a process-based niche model was developed to estimate potential distributions of Phoenix dactylifera L. (date palm), an economically important crop in many counties. Development of the model was based on both its native and invasive distribution and validation was carried out in terms of its extensive distribution in Iran. To identify model parameters having greatest influence on distribution of date palm, a sensitivity analysis was carried out. Changes in suitability were established by mapping of regions where the estimated distribution changed with parameter alterations. This facilitated the assessment of certain areas in Iran where parameter modifications impacted the most, particularly in relation to suitable and highly suitable locations. Parameter sensitivities were also evaluated by the calculation of area changes within the suitable and highly suitable categories. The low temperature limit (DV2), high temperature limit (DV3), upper optimal temperature (SM2) and high soil moisture limit (SM3) had the greatest impact on sensitivity, while other parameters showed relatively less sensitivity or were insensitive to change. For an accurate fit in species distribution models, highly sensitive parameters require more extensive research and data collection methods. Results of this study demonstrate a more cost effective method for developing date palm distribution models, an integral element in species management, and may prove useful for streamlining requirements for data collection in potential distribution modeling for other species as well. PMID:24722140

  18. Sensitivity analysis of potential events affecting the double-shell tank system and fallback actions

    SciTech Connect

    Knutson, B.J.

    1996-09-27

    Sensitivity analyses were performed for fall-back positions (i.e., management actions) to accommodate potential off-normal and programmatic change events overlaid on the waste volume projections and their uncertainties. These sensitivity analyses allowed determining and ranking tank system high-risk parameters and fall- back positions that will accommodate the respective impacts. This quantification of tank system impacts shows periods where tank capacity is sensitive to certain variables that must be carefully managed and/or evaluated. Identifying these sensitive variables and quantifying their impact will allow decision makers to prepare fall-back positions and focus available resources on the highest impact parameters where technical data are needed to reduce waste projection uncertainties. For noncomplexed waste, the period of capacity vulnerability occurs during the years of single-shell tank (SST) retrieval (after approximately 2009) due to the sensitivity to several variables. Ranked by importance these variables include the pretreatment rate and 200-East SST solids transfer volume. For complexed waste, the period of capacity vulnerability occurs during the period after approximately 2005 due to the sensitivity to several variables. Ranked by importance these variables include the pretreatment rate. 200-East SST solids transfer volume. complexed waste reduction factor using evaporation, and 200-west saltwell liquid porosity.

  19. Predicting the potential sensitivity of high elevation wilderness vegetation to changes in atmospheric chemistry -- A strategy

    SciTech Connect

    Schoettle, A.W.

    1995-12-31

    A new strategy to estimate the sensitivity of alpine plant species to atmospheric deposition is presented. This approach utilizes plant physiological and morphological characteristics to estimate pollutant uptake. The plant characteristics can be determined quickly and easily in the field within the constraints of allowable activities in Class 1 wilderness areas. Species in two alpine sites have been sampled and the first potential sensitivity rankings of alpine species have been constructed. While the accuracy of these rankings still needs to be verified, they provide a framework for prioritizing species for future research.

  20. Locomotor Behaviour of Blattella germanica Modified by DEET

    PubMed Central

    Sfara, Valeria; Mougabure-Cueto, Gastón A.; Zerba, Eduardo N.; Alzogaray, Raúl A.

    2013-01-01

    N,N-diethyl-3-methylbenzamide (DEET) is the active principle of most insect repellents used worldwide. However, its toxicity on insects has not been widely studied. The aim of this work is to study the effects of DEET on the locomotor activity of Blattella germanica. DEET has a dose-dependent repellent activity on B. germanica. Locomotor activity was significantly lower when insects were pre-exposed to 700 µg/cm2 of DEET for 20 or 30 minutes, but it did not change when pre-exposure was shorter. Locomotor activity of insects that were pre-exposed to 2.000 µg/cm2 of DEET for 10 minutes was significantly lower than the movement registered in controls. No differences were observed when insects were pre-exposed to lower concentrations of DEET. A 30-minute pre-exposure to 700 µg/cm2 of DEET caused a significant decrease in locomotor activity. Movement was totally recovered 24 h later. The locomotor activity measured during the exposure to different concentrations of DEET remained unchanged. Insects with decreased locomotor activity were repelled to the same extent than control insects by the same concentration of DEET. We demonstrated that the repellency and modification of locomotor activity elicited by DEET are non-associated phenomena. We also suggested that the reduction in locomotor activity indicates toxicity of DEET, probably to insect nervous system. PMID:24376701

  1. Locomotor behaviour of Blattella germanica modified by DEET.

    PubMed

    Sfara, Valeria; Mougabure-Cueto, Gastón A; Zerba, Eduardo N; Alzogaray, Raúl A

    2013-01-01

    N,N-diethyl-3-methylbenzamide (DEET) is the active principle of most insect repellents used worldwide. However, its toxicity on insects has not been widely studied. The aim of this work is to study the effects of DEET on the locomotor activity of Blattella germanica. DEET has a dose-dependent repellent activity on B. germanica. Locomotor activity was significantly lower when insects were pre-exposed to 700 µg/cm(2) of DEET for 20 or 30 minutes, but it did not change when pre-exposure was shorter. Locomotor activity of insects that were pre-exposed to 2.000 µg/cm(2) of DEET for 10 minutes was significantly lower than the movement registered in controls. No differences were observed when insects were pre-exposed to lower concentrations of DEET. A 30-minute pre-exposure to 700 µg/cm(2) of DEET caused a significant decrease in locomotor activity. Movement was totally recovered 24 h later. The locomotor activity measured during the exposure to different concentrations of DEET remained unchanged. Insects with decreased locomotor activity were repelled to the same extent than control insects by the same concentration of DEET. We demonstrated that the repellency and modification of locomotor activity elicited by DEET are non-associated phenomena. We also suggested that the reduction in locomotor activity indicates toxicity of DEET, probably to insect nervous system. PMID:24376701

  2. A Global Sensitivity Analysis Method on Maximum Tsunami Wave Heights to Potential Seismic Source Parameters

    NASA Astrophysics Data System (ADS)

    Ren, Luchuan

    2015-04-01

    A Global Sensitivity Analysis Method on Maximum Tsunami Wave Heights to Potential Seismic Source Parameters Luchuan Ren, Jianwei Tian, Mingli Hong Institute of Disaster Prevention, Sanhe, Heibei Province, 065201, P.R. China It is obvious that the uncertainties of the maximum tsunami wave heights in offshore area are partly from uncertainties of the potential seismic tsunami source parameters. A global sensitivity analysis method on the maximum tsunami wave heights to the potential seismic source parameters is put forward in this paper. The tsunami wave heights are calculated by COMCOT ( the Cornell Multi-grid Coupled Tsunami Model), on the assumption that an earthquake with magnitude MW8.0 occurred at the northern fault segment along the Manila Trench and triggered a tsunami in the South China Sea. We select the simulated results of maximum tsunami wave heights at specific sites in offshore area to verify the validity of the method proposed in this paper. For ranking importance order of the uncertainties of potential seismic source parameters (the earthquake's magnitude, the focal depth, the strike angle, dip angle and slip angle etc..) in generating uncertainties of the maximum tsunami wave heights, we chose Morris method to analyze the sensitivity of the maximum tsunami wave heights to the aforementioned parameters, and give several qualitative descriptions of nonlinear or linear effects of them on the maximum tsunami wave heights. We quantitatively analyze the sensitivity of the maximum tsunami wave heights to these parameters and the interaction effects among these parameters on the maximum tsunami wave heights by means of the extended FAST method afterward. The results shows that the maximum tsunami wave heights are very sensitive to the earthquake magnitude, followed successively by the epicenter location, the strike angle and dip angle, the interactions effect between the sensitive parameters are very obvious at specific site in offshore area, and there

  3. Exploring the potential of context-sensitive CADe in screening mammography

    SciTech Connect

    Tourassi, Georgia D.; Mazurowski, Maciej A.; Harrawood, Brian P.; Krupinski, Elizabeth A.

    2010-11-15

    Purpose: Conventional computer-assisted detection (CADe) systems in screening mammography provide the same decision support to all users. The aim of this study was to investigate the potential of a context-sensitive CADe system which provides decision support guided by each user's focus of attention during visual search and reporting patterns for a specific case. Methods: An observer study for the detection of malignant masses in screening mammograms was conducted in which six radiologists evaluated 20 mammograms while wearing an eye-tracking device. Eye-position data and diagnostic decisions were collected for each radiologist and case they reviewed. These cases were subsequently analyzed with an in-house knowledge-based CADe system using two different modes: Conventional mode with a globally fixed decision threshold and context-sensitive mode with a location-variable decision threshold based on the radiologists' eye dwelling data and reporting information. Results: The CADe system operating in conventional mode had 85.7% per-image malignant mass sensitivity at 3.15 false positives per image (FPsI). The same system operating in context-sensitive mode provided personalized decision support at 85.7%-100% sensitivity and 0.35-0.40 FPsI to all six radiologists. Furthermore, context-sensitive CADe system could improve the radiologists' sensitivity and reduce their performance gap more effectively than conventional CADe. Conclusions: Context-sensitive CADe support shows promise in delineating and reducing the radiologists' perceptual and cognitive errors in the diagnostic interpretation of screening mammograms more effectively than conventional CADe.

  4. Assessing potential impacts associated with contamination events in water distribution systems : a sensitivity analysis.

    SciTech Connect

    Davis, M. J.; Janke, R.; Taxon, T. N.

    2010-11-01

    An understanding of the nature of the adverse effects that could be associated with contamination events in water distribution systems is necessary for carrying out vulnerability analyses and designing contamination warning systems. This study examines the adverse effects of contamination events using models for 12 actual water systems that serve populations ranging from about 104 to over 106 persons. The measure of adverse effects that we use is the number of people who are exposed to a contaminant above some dose level due to ingestion of contaminated tap water. For this study the number of such people defines the impact associated with an event. We consider a wide range of dose levels in order to accommodate a wide range of potential contaminants. For a particular contaminant, dose level can be related to a health effects level. For example, a dose level could correspond to the median lethal dose, i.e., the dose that would be fatal to 50% of the exposed population. Highly toxic contaminants may be associated with a particular response at a very low dose level, whereas contaminants with low toxicity may only be associated with the same response at a much higher dose level. This report focuses on the sensitivity of impacts to five factors that either define the nature of a contamination event or involve assumptions that are used in assessing exposure to the contaminant: (1) duration of contaminant injection, (2) time of contaminant injection, (3) quantity or mass of contaminant injected, (4) population distribution in the water distribution system, and (5) the ingestion pattern of the potentially exposed population. For each of these factors, the sensitivities of impacts to injection location and contaminant toxicity are also examined. For all the factors considered, sensitivity tends to increase with dose level (i.e., decreasing toxicity) of the contaminant, with considerable inter-network variability. With the exception of the population distribution (factor 4

  5. The Potential Utility of High Resolution Ensemble Sensitivities During Weak Flow in Complex Terrain

    NASA Astrophysics Data System (ADS)

    Hacker, J.; Wile, S.

    2013-12-01

    Recent expansion in availability of re-locatable near-surface atmospheric observing sensors introduces the question of where placement maximizes gain in forecast accuracy. Here the potential for ensemble sensitivity analysis (ESA) is examined for high-resolution (Δx=4 km) predictions in complex terrain. The primary objective is to determine whether a mesoscale ESA applied at these scales is useful for identifying potential observing locations in weak flow. ESA can be inaccurate when the underlying assumptions of linear dynamics (and Gaussian statistics) are violated, or when the sensitivity cannot be robustly sampled. A case study of a fog event at the Salt Lake City airport (KSLC) provides a useful period for examining these issues, with the additional influence of complex terrain. A realistic upper-air observing network is used in perfect-model ensemble data assimilation experiments, providing the statistics for ESA. Results show that water vapor mixing ratios over KSLC are sensitive to temperature on the first model layer tens of km away, 6 h prior to verification and prior to the onset of fog. Sensitivity 12 h prior is weaker but leads to qualitatively similar results. Temperatures are shown to be a predictor of inversion strength in the Salt Lake basin; the ESA predicts southerly flow and strengthened inversions with warmer temperatures in a few locations. Simple linearity tests show that small perturbations do not lead to the expected forecast change, but larger perturbations do, suggesting that noise can dominate a small perturbation. Assimilating a perfect observation at the maximum sensitivity location produces forecasts more closely agreeing with the ESA. Sampling error evaluation show that similar conclusions can be reached with ensembles as small as 48 members, but smaller ensembles do not produce accurate sensitivity estimates.

  6. A fluorescence high throughput screening method for the detection of reactive electrophiles as potential skin sensitizers.

    PubMed

    Avonto, Cristina; Chittiboyina, Amar G; Rua, Diego; Khan, Ikhlas A

    2015-12-01

    Skin sensitization is an important toxicological end-point in the risk assessment of chemical allergens. Because of the complexity of the biological mechanisms associated with skin sensitization, integrated approaches combining different chemical, biological and in silico methods are recommended to replace conventional animal tests. Chemical methods are intended to characterize the potential of a sensitizer to induce earlier molecular initiating events. The presence of an electrophilic mechanistic domain is considered one of the essential chemical features to covalently bind to the biological target and induce further haptenation processes. Current in chemico assays rely on the quantification of unreacted model nucleophiles after incubation with the candidate sensitizer. In the current study, a new fluorescence-based method, 'HTS-DCYA assay', is proposed. The assay aims at the identification of reactive electrophiles based on their chemical reactivity toward a model fluorescent thiol. The reaction workflow enabled the development of a High Throughput Screening (HTS) method to directly quantify the reaction adducts. The reaction conditions have been optimized to minimize solubility issues, oxidative side reactions and increase the throughput of the assay while minimizing the reaction time, which are common issues with existing methods. Thirty-six chemicals previously classified with LLNA, DPRA or KeratinoSens™ were tested as a proof of concept. Preliminary results gave an estimated 82% accuracy, 78% sensitivity, 90% specificity, comparable to other in chemico methods such as Cys-DPRA. In addition to validated chemicals, six natural products were analyzed and a prediction of their sensitization potential is presented for the first time. PMID:26455772

  7. Functional Reorganization of the Locomotor Network in Parkinson Patients with Freezing of Gait

    PubMed Central

    Fling, Brett W.; Cohen, Rajal G.; Mancini, Martina; Carpenter, Samuel D.; Fair, Damien A.; Nutt, John G.; Horak, Fay B.

    2014-01-01

    Freezing of gait (FoG) is a transient inability to initiate or maintain stepping that often accompanies advanced Parkinson’s disease (PD) and significantly impairs mobility. The current study uses a multimodal neuroimaging approach to assess differences in the functional and structural locomotor neural network in PD patients with and without FoG and relates these findings to measures of FoG severity. Twenty-six PD patients and fifteen age-matched controls underwent resting-state functional magnetic resonance imaging and diffusion tensor imaging along with self-reported and clinical assessments of FoG. After stringent movement correction, fifteen PD patients and fourteen control participants were available for analysis. We assessed functional connectivity strength between the supplementary motor area (SMA) and the following locomotor hubs: 1) subthalamic nucleus (STN), 2) mesencephalic and 3) cerebellar locomotor region (MLR and CLR, respectively) within each hemisphere. Additionally, we quantified structural connectivity strength between locomotor hubs and assessed relationships with metrics of FoG. FoG+ patients showed greater functional connectivity between the SMA and bilateral MLR and between the SMA and left CLR compared to both FoG− and controls. Importantly, greater functional connectivity between the SMA and MLR was positively correlated with i) clinical, ii) self-reported and iii) objective ratings of freezing severity in FoG+, potentially reflecting a maladaptive neural compensation. The current findings demonstrate a re-organization of functional communication within the locomotor network in FoG+ patients whereby the higher-order motor cortex (SMA) responsible for gait initiation communicates with the MLR and CLR to a greater extent than in FoG− patients and controls. The observed pattern of altered connectivity in FoG+ may indicate a failed attempt by the CNS to compensate for the loss of connectivity between the STN and SMA and may reflect a loss

  8. Evaluation of Phototoxic and Skin Sensitization Potentials of PLA2-Free Bee Venom

    PubMed Central

    Heo, Yunwi; Pyo, Min-Jung; Bae, Seong Kyeong; Lee, Hyunkyoung; Kwon, Young Chul; Kim, Je Hein; Kim, Bokyung; Kim, Choul Goo; Kang, Changkeun; Kim, Euikyung

    2015-01-01

    Bee venom (BV) from honey bee (Apis mellifera L.) has been used in oriental medicine and cosmetic ingredients because of its diverse pharmacological activities. In many studies, among BV components, phospholipase A2 (PLA2) is known as a major player in BV-induced allergic reaction. Therefore, we removed PLA2 from BV using ultrafiltration and then investigated in vitro phototoxicity and in vivo skin sensitization of PLA2-free BV (PBV) in comparison with regular BV. The 3T3 neutral red uptake phototoxicity assay can be appropriated to identify the phototoxic effect of a test substance upon the exposure of ultraviolet A. Chlorpromazine, a positive control, showed high levels of photoirritation factor and mean photo effect values, while BV and PBV had less of these values. Local lymph node assay is an alternative method to evaluate skin sensitization potential of chemicals. BALB/c mice were treated with p-phenylenediamine (PPD, positive control), BV, or PBV. In all of PPD concentrations, stimulation indexes (SI) as sensitizing potential of chemicals were ≥1.6, determined to be sensitizer, while SI levels of BV and PBV were below 1.6. Thus, based on these findings, we propose that both BV and PBV are nonphototoxic compounds and nonsensitizers. PMID:26347784

  9. Potential complex of rhodamine B and copper (II) for dye sensitizer on solar cell

    NASA Astrophysics Data System (ADS)

    Setyawati, Harsasi; Purwaningsih, Aning; Darmokoesoemo, Handoko; Hamami, Rochman, Faidur; Permana, Ahmadi Jaya

    2016-03-01

    A complex from copper(II) and rhodamine B as ligand was synthesized, characterized and applied as potential dye sensitizer on solar cell. A complex was synthesized from the reaction of copper(II) salts and rhodamine B with mole ratio 1:3. A complex showing Metal Ligand Charge Transfer (MLCT) phenomenon at 260 nm. Metal-ligand bonding through carbonyl (CO) groups at 617.22 cm-1 and methoxy (CH3O) groups at 339.47 cm-1. Electrical conductivity analysis confirms that the complex was ionic compound. The complex was applied as potential dye sensitizer with open circuit voltage 0.48775 V, short circuit current 0.01025 mA/cm2 and efficiency 0.0039 %.

  10. Evidence That GABA Mediates Dopaminergic and Serotonergic Pathways Associated with Locomotor Activity in Juvenile Chinook Salmon (Oncorhynchus tshawytscha)

    USGS Publications Warehouse

    Clements, S.; Schreck, C.B.

    2004-01-01

    The authors examined the control of locomotor activity in juvenile salmon (Oncorhynchus tshawytscha) by manipulating 3 neurotransmitter systems-gamma-amino-n-butyric acid (GABA), dopamine, and serotonin-as well as the neuropeptide corticotropin releasing hormone (CRH). Intracerebroventricular (ICV) injections of CRH and the GABAAagonist muscimol stimulated locomotor activity. The effect of muscimol was attenuated by administration of a dopamine receptor antagonist, haloperidol. Conversely, the administration of a dopamine uptake inhibitor (4???,4??? -difluoro-3-alpha-[diphenylmethoxy] tropane hydrochloride [DUI]) potentiated the effect of muscimol. They found no evidence that CRH-induced hyperactivity is mediated by dopaminergic systems following concurrent injections of haloperidol or DUI with CRH. Administration of muscimol either had no effect or attenuated the locomotor response to concurrent injections of CRH and fluoxetine, whereas the GABAA antagonist bicuculline methiodide potentiated the effect of CRH and fluoxetine.

  11. Auditory evoked potentials (AEP) methods for population-level assessment of hearing sensitivity in bottlenose dolphins

    NASA Astrophysics Data System (ADS)

    Houser, Dorian; Finneran, James

    2005-04-01

    A portable system for recording auditory evoked potentials (AEP) was developed to rapidly assess the hearing sensitivity of dolphins in air. The system utilizes a transducer embedded in a silicone suction cup to deliver amplitude modulated tones to the dolphin through the lower jaw. Frequencies tested range from 10-150 kHz and testing of both ears is completed within 90 min. AEP-determined thresholds from one subject were benchmarked against that subject's direct field behavioral audiogram to quantify variation between the two methods. To date, AEP audiograms have been obtained from over 30 bottlenose dolphins. Considerable individual variation in frequency-specific hearing sensitivity was observed. Some high-frequency hearing loss was observed in relatively young (early 20s) and old (35+ years) animals; conversely, age was not necessarily related to hearing loss as several animals greater than 40 years of age had good hearing sensitivity across the range of tested frequencies. Profound hearing loss typically occurred at higher frequencies. Decline in sensitivity was rapid in all cases and began between 50-60 kHz. Increased sample size of hearing sensitivity in dolphins suggest that the use of audiometric functions from single animals as representative of population level audiometry might be misleading.

  12. Microinjection of histone deacetylase inhibitor into the ventrolateral orbital cortex potentiates morphine induced behavioral sensitization.

    PubMed

    Wei, Lai; Zhu, Yuan-Mei; Zhang, Yu-Xiang; Liang, Feng; Barry, Devin M; Gao, Hong-Yu; Li, Tao; Huo, Fu-Quan; Yan, Chun-Xia

    2016-09-01

    Accumulating evidence indicates that epigenetic regulation, such as changes in histone modification in reward-related brain regions, contributes to the memory formation of addiction to opiates and psychostimulants. Our recent results suggested that the ventrolateral orbital cortex (VLO) is involved in the memories of stress and drug addiction. Since addiction and stress memories share some common pathways, the present study was designed to investigate the role of histone deacetylase (HDAC) activity in the VLO during morphine induced-behavioral sensitization. Rats received a single exposure to morphine for establishing the behavioral sensitization model. The effect of HDAC activity in the VLO in morphine induced-behavioral sensitization was examined by microinjection of HDAC inhibitor Trichostatin A (TSA). Furthermore, the protein expression levels of extracellular signal-regulated kinase (ERK) and phosphorylated ERK (p-ERK), histone H3 lysine 9 acetylation (aceH3K9) and brain-derived neurotrophic factor (BDNF) in the VLO in morphine-induced behavioral sensitization were examined. The results showed that the bilateral VLO lesions suppressed the expression phase, but not the developmental phase of morphine-induced behavioral sensitization. Microinjection of TSA into the VLO significantly increased both the development and expression phases. Moreover, the protein levels of p-ERK, aceH3K9 and BDNF except ERK in the VLO were significantly upregulated in morphine-treated rats in the expression phase. These effects were further strengthened by intra-VLO injection of TSA. Our findings suggest that HDAC activity in the VLO could potentiate morphine-induced behavioral sensitization. The upregulated expression of p-ERK, aceH3K9 and BDNF in the VLO might be the underlying mechanism of histone acetylation enhancing the morphine-induced behavioral sensitization. PMID:27312092

  13. Surveys for sensitivity to fibers and potential impacts from fiber induced failures

    NASA Technical Reports Server (NTRS)

    Butterfield, A. J.

    1979-01-01

    The surveys for sensitivities to fibers and potential impacts from fiber induced failures begins with a review of the survey work completed to date and then describes an impact study involving four industrial installations located in Virginia. The observations and results from both the surveys and the study provide guidelines for future efforts. The survey work was done with three broad objectives: (1) identify the pieces of potentially vulnerable equipment as candidates for test; (2) support the transfer function work by gaining an understanding of how fibers could get into a building; and (3) support the economic analysis by understanding what would happen if fibers precipitated a failure in an item of equipment.

  14. Cellular potentials, electrogenic sodium pumping and sensitivity in guinea-pig atria.

    PubMed

    Schulz, J C; Fleming, W W; Westfall, D P; Millecchia, R

    1984-10-01

    Intracellular recording techniques in guinea-pig atrial pacemaker and nonpacemaker cells were used to investigate 1) the role of membrane potential changes in postjunctional supersensitivity, 2) the electrogenicity of the Na+,K+ pump and 3) the role of electrogenic pumping in sensitivity of the atria to agonists. In nonpacemaker cells, ouabain (10(-6) M) had no effect on resting membrane potential (left atria) or maximum diastolic potential (right atria). However, ouabain effectively suppressed the transient hyperpolarization that followed cessation of electrical stimulation. In pacemaker cells, ouabain and chronic treatment with reserpine (0.1 mg/kg/day) produced quite different patterns of changes in intracellular potentials. Chronic treatment with reserpine induced chronotropic supersensitivity to isoproterenol but not to histamine. Ouabain did not alter the chronotropic sensitivity to either agonist. The effects of isoproterenol and histamine on intracellular potentials in pacemaker cells were investigated in the presence and absence of ouabain and in control atria vs. atria from guinea pigs chronically pretreated with reserpine. Analysis of the data indicated that 1) electrophysiological measurements do not provide a discernible explanation for chronotropic supersensitivity, 2) the Na+ pump has the capacity for electrogenic pumping under conditions of Na+ loading, but demonstrates little indication of electrogenicity under basal conditions and 3) chronic treatment with reserpine does suppress the Na+,K+ pump in some areas of the right atrium, but this activity probably does not contribute to chronotropic supersensitivity. Other possible mechanisms of postjunctional supersensitivity in atria are discussed. PMID:6491974

  15. Integrated Locomotor Function Tests for Countermeasure Evaluation

    NASA Technical Reports Server (NTRS)

    Bloomberg, J. J.; Mulavara, A. P.; Peters, B. T.; Cohen, H. S.; Landsness, E. C.; Black, F. O.

    2005-01-01

    Following spaceflight crewmembers experience locomotor dysfunction due to inflight adaptive alterations in sensorimotor function. Countermeasures designed to mitigate these postflight gait alterations need to be assessed with a new generation of tests that evaluate the interaction of various sensorimotor sub-systems central to locomotor control. The goal of the present study was to develop new functional tests of locomotor control that could be used to test the efficacy of countermeasures. These tests were designed to simultaneously examine the function of multiple sensorimotor systems underlying the control of locomotion and be operationally relevant to the astronaut population. Traditionally, gaze stabilization has been studied almost exclusively in seated subjects performing target acquisition tasks requiring only the involvement of coordinated eye-head movements. However, activities like walking involve full-body movement and require coordination between lower limbs and the eye-head-trunk complex to achieve stabilized gaze during locomotion. Therefore the first goal of this study was to determine how the multiple, interdependent, full-body sensorimotor gaze stabilization subsystems are functionally coordinated during locomotion. In an earlier study we investigated how alteration in gaze tasking changes full-body locomotor control strategies. Subjects walked on a treadmill and either focused on a central point target or read numeral characters. We measured: temporal parameters of gait, full body sagittal plane segmental kinematics of the head, trunk, thigh, shank and foot, accelerations along the vertical axis at the head and the shank, and the vertical forces acting on the support surface. In comparison to the point target fixation condition, the results of the number reading task showed that compensatory head pitch movements increased, peak head acceleration was reduced and knee flexion at heel-strike was increased. In a more recent study we investigated the

  16. A case study for evaluating potential soil sensitivity in aridland systems.

    PubMed

    Peterman, Wendy L; Ferschweiler, Ken

    2016-04-01

    Globally, ecosystems are subjected to prolonged droughts and extreme heat events, leading to forest die-offs and dominance shifts in vegetation. Some scientists and managers view soil as the main resource to be considered in monitoring ecosystem responses to aridification. As the medium through which precipitation is received, stored, and redistributed for plant use, soil is an important factor in the sensitivity of ecosystems to a drying climate. This study presents a novel approach to evaluating where on a landscape soils may be most sensitive to drying, making them less resilient to disturbance, and where potential future vegetation changes could lead to such disturbance. The drying and devegetation of arid lands can increase wind erosion, contributing to aerosol and dust emissions. This has implications for air quality, human health, and water resources. This approach combines soil data with vegetation simulations, projecting future vegetation change, to create maps of potential areas of concern for soil sensitivity and dust production in a drying climate. Consistent with recent observations, the projections show shifts from grasslands and woodlands to shrublands in much of the southwestern region. An increase in forested area occurs, but shifts in the dominant types and spatial distribution of the forests also are seen. A net increase in desert ecosystems in the region and some changes in alpine and tundra ecosystems are seen. Approximately 124,000 km(2) of soils flagged as "sensitive" are projected to have vegetation change between 2041 and 2050, and 82,927 km(2) of soils may become sensitive because of future vegetation changes. These maps give managers a way to visualize and identify where soils and vegetation should be investigated and monitored for degradation in a drying climate, so restoration and mitigation strategies can be focused in these areas. PMID:26272449

  17. A numerical analysis of a deep Mediterranean lee cyclone: sensitivity to mesoscale potential vorticity anomalies

    NASA Astrophysics Data System (ADS)

    Horvath, K.; Ivančan-Picek, B.

    2009-03-01

    A 12-15 November 2004 cyclone on the lee side of the Atlas Mountains and the related occurrence of severe bora along the eastern Adriatic coast are numerically analyzed using the MM5 mesoscale model. Motivated by the fact that sub-synoptic scales are more sensitive to initialization errors and dominate forecast error growth, this study is designed in order to assess the sensitivity of the mesoscale forecast to the intensity of mesoscale potential vorticity (PV) anomalies. Five sensitivity simulations are performed after subtracting the selected anomalies from the initial conditions, allowing for the analysis of the cyclone intensity and track, and additionally, the associated severe bora in the Adriatic. The results of the ensemble show that the cyclone is highly sensitive to the exact details of the upper-level dynamic forcing. The spread of cyclone intensities is the greatest in the mature phase of the cyclone lifecycle, due to different cyclone advection speeds towards the Mediterranean. However, the cyclone tracks diffluence appears to be the greatest during the cyclone movement out of the Atlas lee, prior to the mature stage of cyclone development, most likely due to the predominant upper-level steering control and its influence on the thermal anomaly creation in the mountain lee. Furthermore, it is quantitatively shown that the southern Adriatic bora is more sensitive to cyclone presence in the Mediterranean then bora in the northern Adriatic, due to unequal influence of the cyclone on the cross-mountain pressure gradient formation. The orographically induced pressure perturbation is strongly correlated with bora in the northern and to a lesser extent in the southern Adriatic, implying the existence of additional controlling mechanisms to bora in the southern part of the basin. In addition, it is shown that the bora intensity in the southern Adriatic is highly sensitive to the precise sub-synoptic pressure distribution in the cyclone itself, indicating a

  18. Phase Sensitivity of Atomic Josephson Junctions with a Bosonic Species Confined by a Double-Well Potential

    NASA Astrophysics Data System (ADS)

    Zhu, Hua-Gui; Huang, Guo-Qiang; Luo, Cui-Lan

    2016-02-01

    We investigate the reciprocal of the mean quantum Fisher information per particle (RMQFIP) and phase sensitivity of atomic Josephson junctions with a bosonic species confined by a double-well potential. Here we are focus on the Rabi oscillation energy's influence on RMQFIP and phase sensitivity. The better quantum entanglement and phase sensitivity may be achieved by decreasing the Rabi oscillation energy.

  19. Application of the KeratinoSens™ assay for assessing the skin sensitization potential of agrochemical active ingredients and formulations.

    PubMed

    Settivari, Raja S; Gehen, Sean C; Amado, Ricardo Acosta; Visconti, Nicolo R; Boverhof, Darrell R; Carney, Edward W

    2015-07-01

    Assessment of skin sensitization potential is an important component of the safety evaluation process for agrochemical products. Recently, non-animal approaches including the KeratinoSens™ assay have been developed for predicting skin sensitization potential. Assessing the utility of the KeratinoSens™ assay for use with multi-component mixtures such as agrochemical formulations has not been previously evaluated and is a significant need. This study was undertaken to evaluate the KeratinoSens™ assay prediction potential for agrochemical formulations. The assay was conducted for 8 agrochemical active ingredients (AIs) including 3 sensitizers (acetochlor, meptyldinocap, triclopyr), 5 non-sensitizers (aminopyralid, clopyralid, florasulam, methoxyfenozide, oxyfluorfen) and 10 formulations for which in vivo sensitization data were available. The KeratinoSens™ correctly predicted the sensitization potential of all the AIs. For agrochemical formulations it was necessary to modify the standard assay procedure whereby the formulation was assumed to have a common molecular weight. The resultant approach correctly predicted the sensitization potential for 3 of 4 sensitizing formulations and all 6 non-sensitizing formulations when compared to in vivo data. Only the meptyldinocap-containing formulation was misclassified, as a result of high cytotoxicity. These results demonstrate the promising utility of the KeratinoSens™ assay for evaluating the skin sensitization potential of agrochemical AIs and formulations. PMID:25981449

  20. Investigation of the dermal sensitization potential of various essential oils in the local lymph node assay.

    PubMed

    Lalko, J; Api, A M

    2006-05-01

    Essential oils are commonly used fragrance ingredients. The oils themselves are complex mixtures, which may contain naturally occurring contact sensitizers. The local lymph node assay was used to evaluate the dermal sensitization potential of basil, citronella, clove leaf, geranium, litsea cubeba, lemongrass, and palmarosa oils. Three of the major components--citral, eugenol, and geraniol--were included to investigate any difference in sensitization potential arising from their exposure in a mixture. Each fragrance material was tested at five concentration ranging from 2.5% to 50% w/v in 1:3 ethanol:diethyl phthalate. The stimulation index (SI) values were calculated for each dose level, an SI > or = 3 was considered a positive response. The estimated concentration (EC3) required to elicit a positive was calculated and taken as a measure of relative potency. The EC3 values and potency classification for basil, clove leaf, litsea cubeba, lemongrass and palmarosa oils were calculated to be <2.5% (> or = moderate), 7.1% (weak), 8.4% (weak), 6.5% (weak) and 9.6% (weak), respectively. Citronella and geranium oils were negative. The individual components citral, eugenol and geraniol resulted in EC3 values of 6.3%, 5.4% and 11.4%, respectively. In general, the potency of each essential oil did not differ significantly from that observed for its main individual component. PMID:16324777

  1. Sensitizing potential of triclosan and triclosan-based skin care products in patients with chronic eczema.

    PubMed

    Schena, Donatella; Papagrigoraki, Anastasia; Girolomoni, Giampiero

    2008-10-01

    Triclosan is a lypophilic chlorophenol biocide with broad-spectrum antibacterial and antifungal activity. Triclosan-based topical products have been shown to be tolerated and beneficial in atopic dermatitis. The aim of this study was to evaluate the sensitizing potential of triclosan and triclosan-based creams in patients affected by eczematous dermatitis. Two hundred and seventy-five patients affected by chronic eczema (allergic contact dermatitis, irritant contact dermatitis, atopic eczema, nummular eczema, stasis dermatitis) were patch tested with standard patch test series as well as triclosan and triclosan-based products. Standard patch test series resulted positive in 164 patients (61%), with nickel sulfate, house dust mites, fragrance mix, propolis, thimerosal, myroxylon pereira, potassium dichromate, wool alcohols, and p-phenylenediamine the most common sensitizing haptens. Only two patients developed positive reactions to triclosan (0.7%) and four (1.4%) to triclosan-based products. The present study's results confirm that triclosan is well tolerated and has a very low sensitizing potential even in high-risk patients affected by eczema. PMID:18837732

  2. Assessment of phototoxicity, skin irritation, and sensitization potential of polystyrene and TiO2 nanoparticles

    NASA Astrophysics Data System (ADS)

    Park, Yoon-Hee; Jeong, Sang Hoon; Yi, Sang Min; Hyeok Choi, Byeong; Kim, Yu-Ri; Kim, In-Kyoung; Kim, Meyoung-Kon; Son, Sang Wook

    2011-07-01

    The human skin equivalent model (HSEM) is well known as an attractive alternative model for evaluation of dermal toxicity. However, only limited data are available on the usefulness of an HSEM for nanotoxicity testing. This study was designed to investigate cutaneous toxicity of polystyrene and TiO2 nanoparticles using cultured keratinocytes, an HSEM, and an animal model. In addition, we also evaluated the skin sensitization potential of nanoparticles using a local lymph node assay with incorporation of BrdU. Findings from the present study indicate that polystyrene and TiO2 nanoparticles do not induce phototoxicity, acute cutaneous irritation, or skin sensitization. Results from evaluation of the HSEMs correspond well with those from animal models. Our findings suggest that the HSEM might be a useful alternative model for evaluation of dermal nanotoxicity.

  3. [The new technologies of kinesiotherapy for the rehabilitation of the patients suffering from the post-stroke locomotor disorders].

    PubMed

    Gusarova, S A; Styazhkina, E M; Gurkina, M V; Chesnikova, E I; Sycheva, A Yu

    2016-01-01

    This paper was designed to report the results of the application of two therapeutic modalities for the rehabilitation of 44 patients presenting with post-stroke locomotor disorders in the form of spastic hemiparesis. The patients allocated to the main group were treated with the use of the new kinesiotherapeutic methods including cryomassage and the Armeo robotic complex. The patients of the control group had to perform traditional therapeutic physical exercises in combination with classical massage and remedial gymnastics. It is concluded that the application of the combination of the modern kinesiotherapeutic factors exerting the positive corrective influence on different aspects of the locomotor deficiency in the upper extremities and the psychoemotional status of the patients has advantages over traditional physical exercise therapy in terms of clinical efficiency because it enhances the rehabilitative potential for these patients with serious locomotor problems. PMID:27213941

  4. Nociceptive-Evoked Potentials Are Sensitive to Behaviorally Relevant Stimulus Displacements in Egocentric Coordinates.

    PubMed

    Moayedi, M; Di Stefano, G; Stubbs, M T; Djeugam, B; Liang, M; Iannetti, G D

    2016-01-01

    Feature selection has been extensively studied in the context of goal-directed behavior, where it is heavily driven by top-down factors. A more primitive version of this function is the detection of bottom-up changes in stimulus features in the environment. Indeed, the nervous system is tuned to detect fast-rising, intense stimuli that are likely to reflect threats, such as nociceptive somatosensory stimuli. These stimuli elicit large brain potentials maximal at the scalp vertex. When elicited by nociceptive laser stimuli, these responses are labeled laser-evoked potentials (LEPs). Although it has been shown that changes in stimulus modality and increases in stimulus intensity evoke large LEPs, it has yet to be determined whether stimulus displacements affect the amplitude of the main LEP waves (N1, N2, and P2). Here, in three experiments, we identified a set of rules that the human nervous system obeys to identify changes in the spatial location of a nociceptive stimulus. We showed that the N2 wave is sensitive to: (1) large displacements between consecutive stimuli in egocentric, but not somatotopic coordinates; and (2) displacements that entail a behaviorally relevant change in the stimulus location. These findings indicate that nociceptive-evoked vertex potentials are sensitive to behaviorally relevant changes in the location of a nociceptive stimulus with respect to the body, and that the hand is a particularly behaviorally important site. PMID:27419217

  5. Nociceptive-Evoked Potentials Are Sensitive to Behaviorally Relevant Stimulus Displacements in Egocentric Coordinates

    PubMed Central

    Di Stefano, G.; Stubbs, M. T.; Djeugam, B.; Liang, M.

    2016-01-01

    Abstract Feature selection has been extensively studied in the context of goal-directed behavior, where it is heavily driven by top-down factors. A more primitive version of this function is the detection of bottom-up changes in stimulus features in the environment. Indeed, the nervous system is tuned to detect fast-rising, intense stimuli that are likely to reflect threats, such as nociceptive somatosensory stimuli. These stimuli elicit large brain potentials maximal at the scalp vertex. When elicited by nociceptive laser stimuli, these responses are labeled laser-evoked potentials (LEPs). Although it has been shown that changes in stimulus modality and increases in stimulus intensity evoke large LEPs, it has yet to be determined whether stimulus displacements affect the amplitude of the main LEP waves (N1, N2, and P2). Here, in three experiments, we identified a set of rules that the human nervous system obeys to identify changes in the spatial location of a nociceptive stimulus. We showed that the N2 wave is sensitive to: (1) large displacements between consecutive stimuli in egocentric, but not somatotopic coordinates; and (2) displacements that entail a behaviorally relevant change in the stimulus location. These findings indicate that nociceptive-evoked vertex potentials are sensitive to behaviorally relevant changes in the location of a nociceptive stimulus with respect to the body, and that the hand is a particularly behaviorally important site. PMID:27419217

  6. Sensitivity of potential evaporation estimates to 100 years of climate variability

    NASA Astrophysics Data System (ADS)

    Bartholomeus, Ruud; Stagge, James; Tallaksen, Lena; Witte, Jan-Philip

    2015-04-01

    Evaporation from the vegetated surface is the largest loss term in many, if not the most, water balance studies on earth. As a consequence, an accurate representation of evaporation fluxes is required for appropriate quantification of surface runoff, the soil moisture budget, transpiration, recharge and groundwater processes. However, despite being a key component of the water balance, evaporation figures are usually associated with large uncertainties, as this term is difficult to measure or estimate by modeling. Many modeling frameworks have used the concept of potential evaporation, often estimated for different vegetation classes by multiplying the evaporation from a reference surface ('reference evaporation') with crop specific scaling factors ('crop factors'). Though this two-step potential evaporation approach undoubtedly has practical advantages, the empirical nature of both reference evaporation methods and crop factors limits its usability in extrapolations under non-stationary climatic conditions. We quantified the sensitivity of potential evaporation estimates for different vegetation classes using the two-step approach when calibrated using a non-stationary climate. We used the past century's time series of observed climate, containing non-stationary signals of multi-decadal atmospheric oscillations, global warming, and global dimming/brightening, to evaluate the sensitivity of potential evaporation estimates to the choice and length of the calibration period. We show that using empirical coefficients outside their calibration range may lead to systematic differences between process-based and empirical reference evaporation methods, and systematic errors in estimated potential evaporation components. Our hydrological models are to varying extent regression models, which limits their general applicability, and the estimation of potential evaporation is closely linked to climate variability. With our analysis, we want to raise awareness and to provide a

  7. Global bioenergy potentials from agricultural land in 2050: Sensitivity to climate change, diets and yields

    PubMed Central

    Haberl, Helmut; Erb, Karl-Heinz; Krausmann, Fridolin; Bondeau, Alberte; Lauk, Christian; Müller, Christoph; Plutzar, Christoph; Steinberger, Julia K.

    2011-01-01

    There is a growing recognition that the interrelations between agriculture, food, bioenergy, and climate change have to be better understood in order to derive more realistic estimates of future bioenergy potentials. This article estimates global bioenergy potentials in the year 2050, following a “food first” approach. It presents integrated food, livestock, agriculture, and bioenergy scenarios for the year 2050 based on a consistent representation of FAO projections of future agricultural development in a global biomass balance model. The model discerns 11 regions, 10 crop aggregates, 2 livestock aggregates, and 10 food aggregates. It incorporates detailed accounts of land use, global net primary production (NPP) and its human appropriation as well as socioeconomic biomass flow balances for the year 2000 that are modified according to a set of scenario assumptions to derive the biomass potential for 2050. We calculate the amount of biomass required to feed humans and livestock, considering losses between biomass supply and provision of final products. Based on this biomass balance as well as on global land-use data, we evaluate the potential to grow bioenergy crops and estimate the residue potentials from cropland (forestry is outside the scope of this study). We assess the sensitivity of the biomass potential to assumptions on diets, agricultural yields, cropland expansion and climate change. We use the dynamic global vegetation model LPJmL to evaluate possible impacts of changes in temperature, precipitation, and elevated CO2 on agricultural yields. We find that the gross (primary) bioenergy potential ranges from 64 to 161 EJ y−1, depending on climate impact, yields and diet, while the dependency on cropland expansion is weak. We conclude that food requirements for a growing world population, in particular feed required for livestock, strongly influence bioenergy potentials, and that integrated approaches are needed to optimize food and bioenergy supply

  8. X-ray phase sensitive imaging methods: basic physical principles and potential medical applications

    PubMed Central

    Chen, Guang-Hong; Zambelli, Joseph; Bevins, Nicholas; Qi, Zhihua; Li, Ke

    2013-01-01

    Phase sensitive imaging theoretically allows for a drastic reduction in x-ray dose while simultaneously achieving comparable or better spatial and contrast resolution compared to traditional x-ray absorption based imaging. Several techniques exist to extract the phase information from an x-ray signal, including x-ray interferometry, diffraction enhanced imaging, in-line holography, coded aperture x-ray imaging, and grating-based interferometry. The physics of each method is reviewed, along with the potential clinical applications. PMID:23970846

  9. Evidence for a Role of Orexin/Hypocretin System in Vestibular Lesion-Induced Locomotor Abnormalities in Rats

    PubMed Central

    Pan, Leilei; Qi, Ruirui; Wang, Junqin; Zhou, Wei; Liu, Jiluo; Cai, Yiling

    2016-01-01

    Vestibular damage can induce locomotor abnormalities in both animals and humans. Rodents with bilateral vestibular loss showed vestibular deficits syndrome such as circling, opisthotonus as well as locomotor and exploratory hyperactivity. Previous studies have investigated the changes in the dopamine system after vestibular loss, but the results are inconsistent and inconclusive. Numerous evidences indicate that the orexin system is implicated in central motor control. We hypothesized that orexin may be potentially involved in vestibular loss-induced motor disorders. In this study, we examined the effects of arsanilate- or 3,3′-iminodipropionitrile (IDPN)-induced vestibular lesion (AVL or IVL) on the orexin-A (OXA) labeling in rat hypothalamus using immunohistochemistry. The vestibular lesion-induced locomotor abnormalities were recorded and verified using a histamine H4 receptor antagonist JNJ7777120 (20 mg/kg, i.p.). The effects of the orexin receptor type 1 antagonist SB334867 (16 μg, i.c.v.) on these behavior responses were also investigated. At 72 h post-AVL and IVL, animals exhibited vestibular deficit syndrome and locomotor hyperactivity in the home cages. These responses were significantly alleviated by JNJ7777120 which also eliminated AVL-induced increases in exploratory behavior in an open field. The numbers of OXA-labeled neurons in the hypothalamus were significantly increased in the AVL animals at 72 h post-AVL and in the IVL animals at 24, 48, and 72 h post-IVL. SB334867 significantly attenuated the vestibular deficit syndrome and locomotor hyperactivity at 72 h post-AVL and IVL. It also decreased exploratory behavior in the AVL animals. These results suggested that the alteration of OXA expression might contribute to locomotor abnormalities after acute vestibular lesion. The orexin receptors might be the potential therapeutic targets for vestibular disorders. PMID:27507932

  10. Evidence for a Role of Orexin/Hypocretin System in Vestibular Lesion-Induced Locomotor Abnormalities in Rats.

    PubMed

    Pan, Leilei; Qi, Ruirui; Wang, Junqin; Zhou, Wei; Liu, Jiluo; Cai, Yiling

    2016-01-01

    Vestibular damage can induce locomotor abnormalities in both animals and humans. Rodents with bilateral vestibular loss showed vestibular deficits syndrome such as circling, opisthotonus as well as locomotor and exploratory hyperactivity. Previous studies have investigated the changes in the dopamine system after vestibular loss, but the results are inconsistent and inconclusive. Numerous evidences indicate that the orexin system is implicated in central motor control. We hypothesized that orexin may be potentially involved in vestibular loss-induced motor disorders. In this study, we examined the effects of arsanilate- or 3,3'-iminodipropionitrile (IDPN)-induced vestibular lesion (AVL or IVL) on the orexin-A (OXA) labeling in rat hypothalamus using immunohistochemistry. The vestibular lesion-induced locomotor abnormalities were recorded and verified using a histamine H4 receptor antagonist JNJ7777120 (20 mg/kg, i.p.). The effects of the orexin receptor type 1 antagonist SB334867 (16 μg, i.c.v.) on these behavior responses were also investigated. At 72 h post-AVL and IVL, animals exhibited vestibular deficit syndrome and locomotor hyperactivity in the home cages. These responses were significantly alleviated by JNJ7777120 which also eliminated AVL-induced increases in exploratory behavior in an open field. The numbers of OXA-labeled neurons in the hypothalamus were significantly increased in the AVL animals at 72 h post-AVL and in the IVL animals at 24, 48, and 72 h post-IVL. SB334867 significantly attenuated the vestibular deficit syndrome and locomotor hyperactivity at 72 h post-AVL and IVL. It also decreased exploratory behavior in the AVL animals. These results suggested that the alteration of OXA expression might contribute to locomotor abnormalities after acute vestibular lesion. The orexin receptors might be the potential therapeutic targets for vestibular disorders. PMID:27507932

  11. Reliability review of the remote tool delivery system locomotor

    SciTech Connect

    Chesser, J.B.

    1999-04-01

    The locomotor being built by RedZone Robotics is designed to serve as a remote tool delivery (RID) system for waste retrieval, tank cleaning, viewing, and inspection inside the high-level waste tanks 8D-1 and 8D-2 at West Valley Nuclear Services (WVNS). The RTD systm is to be deployed through a tank riser. The locomotor portion of the RTD system is designed to be inserted into the tank and is to be capable of moving around the tank by supporting itself and moving on the tank internal structural columns. The locomotor will serve as a mounting platform for a dexterous manipulator arm. The complete RTD system consists of the locomotor, dexterous manipulator arm, cameras, lights, cables, hoses, cable/hose management system, power supply, and operator control station.

  12. Locomotor stereotypy produced by dexbenzetimide and scopolamine is reduced by SKF 83566, not sulpiride.

    PubMed

    Fritts, M E; Mueller, K; Morris, L

    1998-07-01

    Like amphetamine, scopolamine produces locomotor stereotypy (repetitive routes of locomotion) in an open field. To determine whether locomotor stereotypy is a common behavioral effect of anticholingeric agents, several doses of the anticholinergic dexbenzetimide were tested for the ability to produce locomotor stereotypy; like scopolamine, dexbenzetimide produced locomotor stereotypy. To investigate a possible role of dopamine in anticholinergic-induced locomotor stereotypy, we tested the ability of the dopamine D1 antagonist SKF 83566 and the D2 antagonist sulpiride to block the locomotor stereotypy induced by scopolamine as well as dexbenzetimide. SKF 83566 blocked scopolamine- and dexbenzetimide-induced locomotor stereotypy; sulpiride did not reduce dexbenzetimide-induced locomotor stereotypy, but enhanced scopolamine-induced locomotor stereotypy. Hyperlocomotion was reduced by both dopamine antagonists. Results are interpreted in support of the notion that dopamine is the likely candidate mediating locomotor stereotypy. PMID:9678647

  13. Iridium Oxide Nanotube Electrodes for Highly Sensitive and Prolonged Intracellular Measurement of Action Potentials

    PubMed Central

    Lin, Ziliang Carter; Xie, Chong; Osakada, Yasuko; Cui, Yi; Cui, Bianxiao

    2014-01-01

    Intracellular recording of action potentials is important to understand electrically-excitable cells. Recently, vertical nanoelectrodes have been developed to achieve highly sensitive, minimally invasive, and large scale intracellular recording. It has been demonstrated that the vertical geometry is crucial for the enhanced signal detection. Here we develop nanoelectrodes made up of nanotubes of iridium oxide. When cardiomyocytes are cultured upon those nanotubes, the cell membrane not only wraps around the vertical tubes but also protrudes deep into the hollow center. We show that this geometry enhances cell-electrode coupling and results in measuring much larger intracellular action potentials. The nanotube electrodes afford much longer intracellular access and are minimally invasive, making it possible to achieve stable recording up to an hour in a single session and more than 8 days of consecutive daily recording. This study suggests that the electrode performance can be significantly improved by optimizing the electrode geometry. PMID:24487777

  14. Effects of acute and repeated administration of N-methyl-D-aspartate (NMDA) into the ventral tegmental area: locomotor activating effects of NMDA and cocaine.

    PubMed

    Schenk, S; Partridge, B

    1997-09-26

    Repeated, intermittent administration of psychostimulants produces an enhancement of the subsequent behavioral effects of these drugs. This behavioral sensitization has been implicated in maintenance of and relapse to drug-taking. As a result, there has been great interest in elucidating the mechanisms underlying both the development and expression of sensitization. An accumulation of data from studies of stimulant-induced locomotor activity has implicated excitatory amino acids in the development of behavioral sensitization. In the present study, N-methyl-D-aspartate (NMDA) (0.6, 1.25 or 2.5 microg) infused bilaterally into the ventral tegmental area (VTA) produced dose-dependent locomotor activation. The locomotor activating effect of NMDA was increased following repeated NMDA administration (two exposures to intra-VTA NMDA), suggesting sensitization. However, repeated intra-VTA NMDA failed to sensitize rats to the locomotor activating effects of systemically administered cocaine (5.0, 10.0 or 20.0 mg/kg). These findings are consistent with the notion that repeated activation of NMDA receptors is sufficient for the development of behavioral sensitization to NMDA. Other neuroadaptations produced by repeated psychostimulant administration are required in order for the development of sensitization to the behavioral effects of those drugs. PMID:9374190

  15. On understanding the relationship between structure in the potential surface and observables in classical dynamics: A functional sensitivity analysis approach

    NASA Astrophysics Data System (ADS)

    Judson, Richard S.; Rabitz, Herschel

    1987-04-01

    The relationship between structure in the potential surface and classical mechanical observables is examined by means of functional sensitivity analysis. Functional sensitivities provide maps of the potential surface, highlighting those regions that play the greatest role in determining the behavior of observables. A set of differential equations for the sensitivities of the trajectory components are derived. These are then solved using a Green's function method. It is found that the sensitivities become singular at the trajectory turning points with the singularities going as η-3/2, with η being the distance from the nearest turning point. The sensitivities are zero outside of the energetically and dynamically allowed region of phase space. A second set of equations is derived from which the sensitivities of observables can be directly calculated. An adjoint Green's function technique is employed, providing an efficient method for numerically calculating these quantities. Sensitivity maps are presented for a simple collinear atom-diatom inelastic scattering problem and for two Henon-Heiles type Hamiltonians modeling intramolecular processes. It is found that the positions of the trajectory caustics in the bound state problem determine regions of the highest potential surface sensitivities. In the scattering problem (which is impulsive, so that ``sticky'' collisions did not occur), the positions of the turning points of the individual trajectory components determine the regions of high sensitivity. In both cases, these lines of singularities are superimposed on a rich background structure. Most interesting is the appearance of classical interference effects. The interference features in the sensitivity maps occur most noticeably where two or more lines of turning points cross. The important practical motivation for calculating the sensitivities derives from the fact that the potential is a function, implying that any direct attempt to understand how local

  16. Optical coherence tomography is less sensitive than visual evoked potentials in optic neuritis

    PubMed Central

    Naismith, R T.; Tutlam, N T.; Xu, J; Shepherd, J B.; Klawiter, E C.; Song, S -K.; Cross, A H.

    2009-01-01

    Objectives: Determine the utility of optical coherence tomography (OCT) to detect clinical and subclinical remote optic neuritis (ON), its relationship to clinical characteristics of ON and visual function, and whether the retinal nerve fiber layer (RNFL) thickness functions as a surrogate marker of global disease severity. Methods: Cross-sectional study of 65 subjects with at least 1 clinical ON episode at least 6 months prior. Measures included clinical characteristics, visual acuity (VA), contrast sensitivity (CS), OCT, and visual evoked potentials (VEP). Results: Ninety-six clinically affected optic nerves were studied. The sensitivity of OCT RNFL after ON was 60%, decreasing further with mild onset and good recovery. VEP sensitivity was superior at 81% (p = 0.002). Subclinical ON in the unaffected eye was present in 32%. VEP identified 75% of all subclinically affected eyes, and OCT identified <20%. RNFL thickness demonstrated linear correlations with VA (r = 0.65) and CS (r = 0.72) but was unable to distinguish visual categories <20/50. RNFL was thinner with severe onset and disease recurrence but was unaffected by IV glucocorticoids. OCT measurements were not related to overall disability, ethnicity, sex, or age at onset. The greatest predictor for RNFL in the unaffected eye was the RNFL in the fellow affected eye. Conclusions: Visual evoked potentials (VEP) remains the preferred test for detecting clinical and subclinical optic neuritis. Optical coherence tomography (OCT) measures were unrelated to disability and demographic features predicting a worse prognosis in multiple sclerosis. OCT may provide complementary information to VEP in select cases, and remains a valuable research tool for studying optic nerve disease in populations. GLOSSARY ANOVA = analysis of variance; CIS = clinically isolated syndrome; CS = contrast sensitivity; EDSS = Expanded Disability Status Score; logMAR = logarithm of the minimum angle of resolution; MS = multiple sclerosis; MSSS

  17. The GOES-R Advanced Baseline Imager: polarization sensitivity and potential impacts

    NASA Astrophysics Data System (ADS)

    Pearlman, Aaron J.; Cao, Changyong; Wu, Xiangqian

    2015-09-01

    In contrast to the National Oceanic and Atmospheric Administration's (NOAA's) current geostationary imagers for operational weather forecasting, the next generation imager, the Advanced Baseline Imager (ABI) aboard the Geostationary Operational Environmental Satellite R-Series (GOES-R), will have six reflective solar bands - five more than currently available. These bands will be used for applications such as aerosol retrievals, which are influenced by polarization effects. These effects are determined by two factors: instrument polarization sensitivity and the polarization states of the observations. The former is measured as part of the pre-launch testing program performed by the instrument vendor. We analyzed the results of the pre-launch polarization sensitivity measurements of the 0.47 μm and 0.64 μm channels and used them in conjunction with simulated scene polarization states to estimate potential on-orbit radiometric impacts. The pre-launch test setups involved illuminating the ABI with an integrating sphere through either one or two polarizers. The measurement with one (rotating) polarizer yields the degree of linear polarization of ABI, and the measurements using two polarizers (one rotating and one fixed) characterized the non-ideal properties of the polarizer. To estimate the radiometric performance impacts from the instrument polarization sensitivity, we simulated polarized scenes using a radiative transfer code and accounted for the instrument polarization sensitivity over its field of regard. The results show the variation in the polarization impacts over the day and by regions of the full disk can reach up to 3.2% for the 0.47μm channel and 4.8% for the 0.64μm channel. Geostationary orbiters like the ABI give the unique opportunity to show these impacts throughout the day compared to low earth orbiters, which are more limited to certain times of day. This work may enhance the ability to diagnose anomalies on-orbit.

  18. Acute temperature sensitivity in optic nerve axons explained by an electrogenic membrane potential.

    PubMed

    Coates, Tom A; Woolnough, Oscar; Masters, Joseph M; Asadova, Gulsum; Chandrakumar, Charmilie; Baker, Mark D

    2015-11-01

    Classical work in squid axon reports resting membrane potential is independent of temperature, but our findings suggest that this is not the case for axons in mammalian optic nerve. Refractory period duration changes over 10 times between 37 °C and room temperature, and afterpotential polarity is also acutely temperature sensitive, inconsistent with changes in temperature impacting nerve function only through altered rates of ion channel gating kinetics. Our evidence suggests that the membrane potential is enhanced by warming, an effect reduced by exposure to ouabain. The temperature dependence can be explained if axonal Na(+)/K(+) ATPase continuously expels Na(+) ions that enter axons largely electroneutrally, thereby adding a substantial electrogenic component to the membrane potential. Block of the Na(+) transporter NKCC1 with bumetanide increases refractoriness, like depolarization, indicating that this is a probable route by which Na(+) enters, raising the expectation that the rate of electroneutral Na(+) influx increases with temperature and suggesting a temperature-dependent transmembrane Na(+) cycle that contributes to membrane potential. PMID:25724933

  19. Evaluation of Furfuryl Alcohol Sensitization Potential Following Dermal and Pulmonary Exposure: Enhancement of Airway Responsiveness

    PubMed Central

    Franko, Jennifer; Jackson, Laurel G.; Hubbs, Ann; Kashon, Michael; Meade, B. J.; Anderson, Stacey E.

    2015-01-01

    Furfuryl alcohol is considered by the U.S. Environmental Protection Agency to be a high volume production chemical, with over 1 million pounds produced annually. Due to its high production volume and its numerous industrial and consumer uses, there is considerable potential for work-related exposure, as well as exposure to the general population, through pulmonary, oral, and dermal routes of exposure. Human exposure data report a high incidence of asthma in foundry mold workers exposed to furan resins, suggesting potential immunologic effects. Although furfuryl alcohol was nominated and evaluated for its carcinogenic potential by the National Toxicology Program, studies evaluating its immunotoxicity are lacking. The studies presented here evaluated the immunotoxic potential of furfuryl alcohol following exposure by the dermal and pulmonary routes using a murine model. When tested in a combined irritancy local lymph node assay, furfuryl alcohol was identified to be an irritant and mild sensitizer (EC3 = 25.6%). Pulmonary exposure to 2% furfuryl alcohol resulted in enhanced airway hyperreactivity, eosinophilic infiltration into the lungs, and enhanced cytokine production (IL-4, IL-5, and interferon-γ) by ex vivo stimulated lung-associated draining lymphoid cells. Airway hyperreactivity and eosinophilic lung infiltration were augmented by prior dermal exposure to furfuryl alcohol. These results suggest that furfuryl alcohol may play a role in the development of allergic airway disease and encourage the need for additional investigation. PMID:22003193

  20. Sensitivity analysis in multipole-accelerated panel methods for potential flow

    NASA Technical Reports Server (NTRS)

    Leathrum, James F., Jr.

    1995-01-01

    In the design of an airframe, the effect of changing the geometry on resulting computations is necessary for design optimization. The geometry is defined in terms of a series of design variables, including design variables to define the wing planform, tail, canard, pylon, and nacelle. Design optimization in this research is based on how these design variable affect the potential flow. The potential flow is computed as a function of the geometry and location of a series of panels describing the airframe, which are in turn a function of the design variables. Multipole accelerated panel methods improve the computational complexity of the problem and thus are an attractive approach. To utilize the methods in design optimization, it was necessary to define the appropriate sensitivity derivatives. The overhead incurred from finding the sensitivity derivatives in conjunction with the original computation should be small. This research developed the background for multipole-accelerated panel methods and the framework for finding sensitivity derivatives in the methods. Potential flow panel codes are commonly used for powered-lift aerodynamic predictions for three dimensional geometries. Given an airframe which has been discretized into a series of panels to define the airframe geometry, potential is computed as a function of the influence of all panels on all other panels. This is a computationally intensive problem for which efficient solutions are desired to improve the computational time and to allow greater resolution by use of more panels. One such solution is the use of hierarchical multipole methods which entail approximations of the effects of far-field terms. Hierarchical multipole methods have become prevalent in molecular dynamics and gravitational physics, and have been introduced into the fields of capacitance calculations, computational fluid dynamics, and electromagnetics. The methods utilize multipole expansions to describe the effect of bodies (i

  1. Slipping, sliding and stability: locomotor strategies for overcoming low-friction surfaces.

    PubMed

    Clark, Andrew J; Higham, Timothy E

    2011-04-15

    Legged terrestrial animals must avoid falling while negotiating unexpected perturbations inherent to their structurally complex environments. Among humans, fatal and nonfatal injuries frequently result from slip-induced falls precipitated by sudden unexpected encounters with low-friction surfaces. Although studies using walking human models have identified some causes of falls and mechanisms underlying slip prevention, it is unclear whether these apply to various locomotor speeds and other species. We used high-speed video and inverse dynamics to investigate the locomotor biomechanics of helmeted guinea fowl traversing slippery surfaces at variable running speeds (1.3-3.6 m s(-1)). Falls were circumvented when limb contact angles exceeded 70 deg, though lower angles were tolerated at faster running speeds (>3.0 m s(-1)). These prerequisites permitted a forward shift of the body's center of mass over the limb's base of support, which kept slip distances below 10 cm (the threshold distance for falls) and maximized the vertical ground reaction forces, thus facilitating limb retraction and the conclusion of the stance phase. These postural control strategies for slip avoidance parallel those in humans, demonstrating the applicability of these strategies across locomotor gaits and the potential for guinea fowl as an insightful model for invasive approaches to understanding limb neuromuscular control on slippery surfaces. PMID:21430214

  2. An Intensive Locomotor Training Paradigm Improves Neuropathic Pain following Spinal Cord Compression Injury in Rats.

    PubMed

    Dugan, Elizabeth A; Sagen, Jacqueline

    2015-05-01

    Spinal cord injury (SCI) is often associated with both locomotor deficits and sensory dysfunction, including debilitating neuropathic pain. Unfortunately, current conventional pharmacological, physiological, or psychological treatments provide only marginal relief for more than two-thirds of patients, highlighting the need for improved treatment options. Locomotor training is often prescribed as an adjunct therapy for peripheral neuropathic pain but is rarely used to treat central neuropathic pain. The goal of this study was to evaluate the potential anti-nociceptive benefits of intensive locomotor training (ILT) on neuropathic pain consequent to traumatic SCI. Using a rodent SCI model for central neuropathic pain, ILT was initiated either 5 d after injury prior to development of neuropathic pain symptoms (the "prevention" group) or delayed until pain symptoms fully developed (∼3 weeks post-injury, the "reversal" group). The training protocol consisted of 5 d/week of a ramping protocol that started with 11 m/min for 5 min and increased in speed (+1 m/min/week) and time (1-4 minutes/week) to a maximum of two 20-min sessions/d at 15 m/min by the fourth week of training. ILT prevented and reversed the development of heat hyperalgesia and cold allodynia, as well as reversed developed tactile allodynia, suggesting analgesic benefits not seen with moderate levels of locomotor training. Further, the analgesic benefits of ILT persisted for several weeks once training had been stopped. The unique ability of an ILT protocol to produce robust and sustained anti-nociceptive effects, as assessed by three distinct outcome measures for below-level SCI neuropathic pain, suggests that this adjunct therapeutic approach has great promise in a comprehensive treatment strategy for SCI pain. PMID:25539034

  3. The effects of inhaled isoparaffins on locomotor activity and operant performance in mice.

    PubMed

    Bowen, S E; Balster, R L

    1998-11-01

    Very little is known qualitatively or quantitatively about the acute central nervous system effects of isoparaffin solvents that are widely used in household and commercial applications. Four isoparaffinic hydrocarbon solvent products differing in predominant carbon number and volatility (ISOPAR-C, -E -G, -H) were tested for their acute effects on locomotor activity and operant performance after inhalation exposure in mice. For both measures, concentration-effect curves were obtained for 30-min exposures using a within-subject design. The more volatile products, ISOPAR-C and -E, were as easily vaporized under our conditions as vapors such as toluene and TCE, which have acute effects on human behavior and are abused. ISOPAR-G was slowly volatilized and ISOPAR-H could not be completely volatilized within our 30-min exposures, suggesting that acute human exposures may be less likely and that it may be more difficult to abuse them. ISOPAR-C, -E, and -G produced reversible increases in locomotor activity of mice at 4000 and 6000 ppm while ISOPAR-C and -E produced reversible concentration-dependent decreases in rates of schedule-controlled operant behavior in approximately the same concentration range as they affected locomotor activity. The fact that only locomotor activity increases were observed with these isoparaffins provides evidence that they produce a different pattern of effects than those reported for abused solvents such as toluene and TCE. Further research will be needed to determine if this different pattern of effects on animal behavior between isoparaffins and abused solvents is correlated with a different pattern of acute intoxication and abuse potential in humans. PMID:9768561

  4. Sensitivity analysis and parameter estimation for distributed hydrological modeling: potential of variational methods

    NASA Astrophysics Data System (ADS)

    Castaings, W.; Dartus, D.; Le Dimet, F.-X.; Saulnier, G.-M.

    2009-04-01

    Variational methods are widely used for the analysis and control of computationally intensive spatially distributed systems. In particular, the adjoint state method enables a very efficient calculation of the derivatives of an objective function (response function to be analysed or cost function to be optimised) with respect to model inputs. In this contribution, it is shown that the potential of variational methods for distributed catchment scale hydrology should be considered. A distributed flash flood model, coupling kinematic wave overland flow and Green Ampt infiltration, is applied to a small catchment of the Thoré basin and used as a relatively simple (synthetic observations) but didactic application case. It is shown that forward and adjoint sensitivity analysis provide a local but extensive insight on the relation between the assigned model parameters and the simulated hydrological response. Spatially distributed parameter sensitivities can be obtained for a very modest calculation effort (~6 times the computing time of a single model run) and the singular value decomposition (SVD) of the Jacobian matrix provides an interesting perspective for the analysis of the rainfall-runoff relation. For the estimation of model parameters, adjoint-based derivatives were found exceedingly efficient in driving a bound-constrained quasi-Newton algorithm. The reference parameter set is retrieved independently from the optimization initial condition when the very common dimension reduction strategy (i.e. scalar multipliers) is adopted. Furthermore, the sensitivity analysis results suggest that most of the variability in this high-dimensional parameter space can be captured with a few orthogonal directions. A parametrization based on the SVD leading singular vectors was found very promising but should be combined with another regularization strategy in order to prevent overfitting.

  5. Dermal sensitization potential of ja-2 solid propellant in guinea pigs. Report for 4 April-9 May 1986

    SciTech Connect

    Lewis, C.M.; Brown, L.D.; Korte, D.W.

    1989-11-01

    JA-2 Solid Propellant was evaluated for its potential to produce dermal sensitization in male guinea pigs. The Buehler test, which utilizes repeated closed patch inductions with the test compound, was used for this evaluation. No evidence that JA-2 Solid Propellant induced sensitization was obtained in the study.

  6. An apparatus for recording synaptic potentials from neuronal cultures using voltage-sensitive fluorescent dyes.

    PubMed

    Chien, C B; Pine, J

    1991-07-01

    Voltage-sensitive dyes offer the promise of noninvasive multicell recording of electrical activity, and should therefore be useful for studying the synaptic interactions of small networks of cultured neurons. We have designed and built a system for recording from microcultures of 1-15 neurons from the rat superior cervical ganglion (SCG), using voltage-sensitive fluorescent dyes of the styryl class. The apparatus comprises a standard inverted epifluorescence microscope; a mercury arc lamp with an optical feedback regulator; a 256-pixel fiber-optic camera with individual photodiode detectors and very low-noise amplifiers; and a personal computer-based data acquisition system. Its dark noise and illumination fluctuations are low enough that at typical fluorescence levels for these cells, it is limited by shot noise (the inherent physical limit of detection). Recording from SCG neurons, the signal-to-noise ratio is high enough to see large subthreshold synaptic potentials without signal averaging. This apparatus should be useful for studying long-term synaptic plasticity in cultures of vertebrate neurons, and several of its features should apply to optical recording from other preparations. PMID:1784131

  7. Photostability of bacteriochlorophyll a and derivatives: potential sensitizers for photodynamic tumor therapy.

    PubMed

    Limantara, Leenawaty; Koehler, Peter; Wilhelm, Brigitte; Porra, Robert J; Scheer, Hugo

    2006-01-01

    The photostabilities of bacteriochlorophyll a and several of its derivatives, which are of interest as potential sensitizers in photodynamic tumor therapy, were investigated. The pigments were irradiated with light >630 nm in organic solvents (acetone, tetrahydrofuran, pyridine, methanol, ethanol, n-propanol, 2-propanol and toluene) and in aqueous detergent solutions (cetyl-trimethyl-ammonium bromide [CTAB], lauryldimethyl-aminoxide [LDAO] or sodium dodecyl-sulfate [SDS] and Triton X-100 [TX100]). Their stabilities in these different solvents were determined in the presence and absence of an external sensitizer (pyromethyl-pheophorbide a), oxygen, sodium ascorbate and inert gas (Ar) or vacuum. The photodegradation products of bacteriochlorophyll a in acetone solution were isolated, purified by HPLC and analyzed by their absorption spectra and mass spectroscopy. Besides the well-known dehydrogenation products, such as [3-acetyl]-chlorophyll a, which were obtained as by-products, the major products had low absorption in the visible-near infrared spectral range. The spectral signature of the major component of these products was characteristic of linear open-chain tetrapyrroles, but they lacked the characteristic protonation-deprotonation behavior and reactivity of bilins with Zn(++). PMID:16438618

  8. Brain potentials evoked by intraepidermal electrical stimuli reflect the central sensitization of nociceptive pathways

    PubMed Central

    Lee, M. C.; O'Neill, J.; Dickenson, A. H.; Iannetti, G. D.

    2016-01-01

    Central sensitization (CS), the increased sensitivity of the central nervous system to somatosensory inputs, accounts for secondary hyperalgesia, a typical sign of several painful clinical conditions. Brain potentials elicited by mechanical punctate stimulation using flat-tip probes can provide neural correlates of CS, but their signal-to-noise ratio is limited by poor synchronization of the afferent nociceptive input. Additionally, mechanical punctate stimulation does not activate nociceptors exclusively. In contrast, low-intensity intraepidermal electrical stimulation (IES) allows selective activation of type II Aδ-mechano-heat nociceptors (II-AMHs) and elicits reproducible brain potentials. However, it is unclear whether hyperalgesia from IES occurs and coexists with secondary mechanical punctate hyperalgesia, and whether the magnitude of the electroencephalographic (EEG) responses evoked by IES within the hyperalgesic area is increased. To address these questions, we explored the modulation of the psychophysical and EEG responses to IES by intraepidermal injection of capsaicin in healthy human subjects. We obtained three main results. First, the intensity of the sensation elicited by IES was significantly increased in participants who developed robust mechanical punctate hyperalgesia after capsaicin injection (i.e., responders), indicating that hyperalgesia from IES coexists with punctate mechanical hyperalgesia. Second, the N2 peak magnitude of the EEG responses elicited by IES was significantly increased after the intraepidermal injection of capsaicin in responders only. Third, a receiver-operator characteristics analysis showed that the N2 peak amplitude is clearly predictive of the presence of CS. These findings suggest that the EEG responses elicited by IES reflect secondary hyperalgesia and therefore represent an objective correlate of CS. PMID:27098022

  9. Modular diversification of the locomotor system in damselfishes (Pomacentridae).

    PubMed

    Aguilar-Medrano, Rosalía; Frédérich, Bruno; Barber, Paul H

    2016-05-01

    As fish move and interact with their aquatic environment by swimming, small morphological variations of the locomotor system can have profound implications on fitness. Damselfishes (Pomacentridae) have inhabited coral reef ecosystems for more than 50 million years. As such, habitat preferences and behavior could significantly constrain the morphology and evolvability of the locomotor system. To test this hypothesis, we used phylogenetic comparative methods on morphometric, ecological and behavioral data. While body elongation represented the primary source of variation in the locomotor system of damselfishes, results also showed a diverse suite of morphological combinations between extreme morphologies. Results show clear associations between behavior, habitat preferences, and morphology, suggesting ecological constraints on shape diversification of the locomotor system. In addition, results indicate that the three modules of the locomotor system are weakly correlated, resulting in versatile and independent characters. These results suggest that Pomacentridae is shape may result from the interaction between (1) integrated parts of morphological variation that maintain overall swimming ability and (2) relatively independent parts of the morphology that facilitate adaptation and diversification. J. Morphol. 277:603-614, 2016. © 2016 Wiley Periodicals, Inc. PMID:26919129

  10. The ventromedial hypothalamus oxytocin induces locomotor behavior regulated by estrogen.

    PubMed

    Narita, Kazumi; Murata, Takuya; Matsuoka, Satoshi

    2016-10-01

    Our previous studies demonstrated that excitation of neurons in the rat ventromedial hypothalamus (VMH) induced locomotor activity. An oxytocin receptor (Oxtr) exists in the VMH and plays a role in regulating sexual behavior. However, the role of Oxtr in the VMH in locomotor activity is not clear. In this study we examined the roles of oxytocin in the VMH in running behavior, and also investigated the involvement of estrogen in this behavioral change. Microinjection of oxytocin into the VMH induced a dose-dependent increase in the running behavior in male rats. The oxytocin-induced running activity was inhibited by simultaneous injection of Oxtr-antagonist, (d(CH2)5(1), Try(Me)(2), Orn(8))-oxytocin. Oxytocin injection also induced running behavior in ovariectomized (OVX) female rats. Pretreatment of the OVX rats with estrogen augmented the oxytocin-induced running activity twofold, and increased the Oxtr mRNA in the VMH threefold. During the estrus cycle locomotor activity spontaneously increased in the dark period of proestrus. The Oxtr mRNA was up-regulated in the proestrus afternoon. Blockade of oxytocin neurotransmission by its antagonist before the onset of the dark period of proestrus decreased the following nocturnal locomotor activity. These findings demonstrate that Oxtr in the VMH is involved in the induction of running behavior and that estrogen facilitates this effect by means of Oxtr up-regulation, suggesting the involvement of oxytocin in the locomotor activity of proestrus female rats. PMID:27237044

  11. Rotation, locomotor activity and individual differences in voluntary ethanol consumption.

    PubMed

    Nielsen, D M; Crosley, K J; Keller, R W; Glick, S D; Carlson, J N

    1999-03-27

    Spontaneous turning behavior and locomotor activity were evaluated for their ability to predict differences in the voluntary consumption of ethanol in male Long-Evans rats. Animals were assessed for their preferred direction of turning behavior and for high vs. low levels of spontaneous locomotor activity, as determined during nocturnal testing in a rotometer. Subsequently, preference for a 10% ethanol solution vs. water was determined in a 24-h two-bottle home-cage free-choice paradigm. Rats exhibiting a right-turning preference consumed more ethanol than rats showing a left-turning preference. While locomotor activity alone did not predict differences in drinking, turning and locomotor activity together predicted differences in ethanol consumption. Low-activity right-turning rats consumed more ethanol than all the other groups of rats. Previous studies from this laboratory have shown that individual differences in turning behavior are accompanied by different asymmetries in dopamine (DA) function in the medial prefrontal cortex (mPFC). Individual differences in locomotor activity are associated with differences in nucleus accumbens (NAS) DA function. The present data suggest that variations in mPFC DA asymmetry and NAS DA function may underlie differences in the voluntary consumption of ethanol. PMID:10095014

  12. Regionalisation of climate change sensitive forest development types for potential afforestation areas.

    PubMed

    Witt, Anke; Fürst, Christine; Frank, Susanne; Koschke, Lars; Makeschin, Franz

    2013-09-01

    This paper describes how to use sectoral planning information from forestry to predict and up-scale information on Climate Change sensitive forest development types for potential afforestation areas. The method was developed and applied in the frame of the project RegioPower with focus on the case study region 'Oberes Elbtal-Osterzgebirge'. The data for our study was taken from forest management planning at level of the Federal State of Saxony, Germany. Here, a silvicultural system is implemented, which describes best practices to develop our actual forests into Climate Change adapted forest development types. That includes the selection of drought resistant tree species, a broad range of tree species mixtures per eligible forest development type and the tending, harvesting and regeneration strategies to be applied. This information however, exists only for forest areas and not for areas which could be potentially afforested. The eligibility of the forest development types within the actual forest areas depends on site information, such as nutrient potential, exposition and hydrological soil parameters. The regionalisation of the forest development types to landscape scale had to be based on topographical parameters from the digital elevation model and hydrological soil parameters from soil mapping. In result, we could provide maps for regional planning and decision making with spatially explicit information on the eligible forest development types based on forest management planning information. These maps form a valuable input for testing and optimising afforestation areas with regard to improving the ability of our case study region to mitigate Climate Change effects such as water erosion or drought. PMID:22925545

  13. Cross-species sensitivity to a novel androgen receptor agonist of potential environmental concern, spironolactone.

    PubMed

    LaLone, Carlie A; Villeneuve, Daniel L; Cavallin, Jenna E; Kahl, Michael D; Durhan, Elizabeth J; Makynen, Elizabeth A; Jensen, Kathleen M; Stevens, Kyle E; Severson, Megan N; Blanksma, Chad A; Flynn, Kevin M; Hartig, Philip C; Woodard, Jonne S; Berninger, Jason P; Norberg-King, Teresa J; Johnson, Rodney D; Ankley, Gerald T

    2013-11-01

    Spironolactone is a pharmaceutical that in humans is used to treat conditions like hirsutism, various dermatologic afflictions, and female-pattern hair loss through antagonism of the androgen receptor. Although not routinely monitored in the environment, spironolactone has been detected downstream of a pharmaceutical manufacturer, indicating a potential for exposure of aquatic species. Furthermore, spironolactone has been reported to cause masculinization of female western mosquitofish, a response indicative of androgen receptor activation. Predictive methods to identify homologous proteins to the human and western mosquitofish androgen receptor suggest that vertebrates would be more susceptible to adverse effects mediated by chemicals like spironolactone that target the androgen receptor compared with invertebrate species that lack a relevant homolog. In addition, an adverse outcome pathway previously developed for activation of the androgen receptor suggests that androgen mimics can lead to reproductive toxicity in fish. To assess this, 21-d reproduction studies were conducted with 2 fish species, fathead minnow and Japanese medaka, and the invertebrate Daphnia magna. Spironolactone significantly reduced the fecundity of medaka and fathead minnows at 50 μg/L, whereas daphnia reproduction was not affected by concentrations as large as 500 μg/L. Phenotypic masculinization of females of both fish species was observed at 5 μg/L as evidenced by formation of tubercles in fathead minnows and papillary processes in Japanese medaka. Effects in fish occurred at concentrations below those reported in the environment. These results demonstrate how a priori knowledge of an adverse outcome pathway and the conservation of a key molecular target across vertebrates can be utilized to identify potential chemicals of concern in terms of monitoring and highlight potentially sensitive species and endpoints for testing. PMID:23881739

  14. Dose-dependent changes in the locomotor responses to methamphetamine in BALB/c mice: Low doses induce hypolocomotion

    PubMed Central

    Singh, Rana A. K.; Kosten, Therese A.; Kinsey, Berma M.; Shen, Xiaoyun; Lopez, Angel Y.; Kosten, Thomas R.; Orson, Frank M.

    2012-01-01

    The overall goal of the present study was to determine the effects of different doses of (+)-methamphetamine (meth) on locomotor activity of Balb/C mice. Four experiments were designed to test a wide range of meth doses in BALB/c female mice. In Experiment 1, we examined locomotor activity induced by an acute administration of low doses of meth (0.01 and 0.03 mg/kg) in a 90-min session. Experiment 2 was conducted to test higher meth doses (0.3 – 10 mg/kg). In Experiment 3, separate sets of mice were pre-treated with various meth doses once or twice (one injection/week) prior to a locomotor challenge with a low meth dose. Finally, in Experiment 4, we tested whether locomotor activation would be affected by pretreatment with a low or moderate dose of meth one month prior to the low meth dose challenge. Results show that low doses of meth induce hypolocomotion whereas moderate to high doses induce hyperlocomotion. Prior exposure to either one moderate or high dose of meth or to two, low doses of meth attenuated the hypolocomotor effect of a low meth dose one week later. This effect was also attenuated in mice tested one month after administration of a moderate meth dose. These results show that low and high doses of meth can have opposing effects on locomotor activity. Further, prior exposure to the drug leads to tolerance, rather than sensitization, of the hypolocomotor response to low meth doses. PMID:23010423

  15. Evidence for Novel Pharmacological Sensitivities of Transient Receptor Potential (TRP) Channels in Schistosoma mansoni

    PubMed Central

    Bais, Swarna; Churgin, Matthew A.; Fang-Yen, Christopher; Greenberg, Robert M.

    2015-01-01

    Schistosomiasis, caused by parasitic flatworms of the genus Schistosoma, is a neglected tropical disease affecting hundreds of millions globally. Praziquantel (PZQ), the only drug currently available for treatment and control, is largely ineffective against juvenile worms, and reports of PZQ resistance lend added urgency to the need for development of new therapeutics. Ion channels, which underlie electrical excitability in cells, are validated targets for many current anthelmintics. Transient receptor potential (TRP) channels are a large family of non-selective cation channels. TRP channels play key roles in sensory transduction and other critical functions, yet the properties of these channels have remained essentially unexplored in parasitic helminths. TRP channels fall into several (7–8) subfamilies, including TRPA and TRPV. Though schistosomes contain genes predicted to encode representatives of most of the TRP channel subfamilies, they do not appear to have genes for any TRPV channels. Nonetheless, we find that the TRPV1-selective activators capsaicin and resiniferatoxin (RTX) induce dramatic hyperactivity in adult worms; capsaicin also increases motility in schistosomula. SB 366719, a highly-selective TRPV1 antagonist, blocks the capsaicin-induced hyperactivity in adults. Mammalian TRPA1 is not activated by capsaicin, yet knockdown of the single predicted TRPA1-like gene (SmTRPA) in S. mansoni effectively abolishes capsaicin-induced responses in adult worms, suggesting that SmTRPA is required for capsaicin sensitivity in these parasites. Based on these results, we hypothesize that some schistosome TRP channels have novel pharmacological sensitivities that can be targeted to disrupt normal parasite neuromuscular function. These results also have implications for understanding the phylogeny of metazoan TRP channels and may help identify novel targets for new or repurposed therapeutics. PMID:26655809

  16. Sensitive CE-MS analysis of potentially genotoxic alkylation compounds using derivatization and electrokinetic injection.

    PubMed

    van Wijk, A M; Niederländer, H A G; van Ogten, M D; de Jong, G J

    2015-05-18

    A CE-MS method has been developed to detect trace levels of potentially genotoxic alkyl halides. After derivatization of the target components with 4-dimethylaminopyridine (DMAP) or butyl 1-(pyridinyl-4yl) piperidine 4-carboxylate (BPPC), the natively positively charged derivatives are pre-concentrated by applying electrokinetic injection and separated by a highly efficient CZE method using a background electrolyte (BGE) consisting of 100mM of TRIS adjusted to pH 2.5 with phosphoric acid. Using a sheath liquid interface, subsequent MS detection allows highly specific and sensitive analysis of alkyl halides. Conditions for electrokinetic injection were optimized to allow selective and effective injection. Injection of samples with low water content at 10 kV for 150 s using a high concentration of buffer in the BGE resulted in optimum sample stacking during injection and a highly efficient CE separation. At the sample pH applied, neutral and negatively charged components are shown to be selectively discarded, resulting in injection of positively charged ions only. The sample matrix influences the efficiency of the injection, but when using an internal standard, reproducibilities better than 10% RSD are obtained. Relative recoveries of the derivatives spiked to different types of model API between 85 and 115% demonstrate that the method can be applied for quantitative analysis. Detection limits of lower than 1 mg kg(-1) for the tested alkyl halides obtained in CE-MS at least equal the sensitivity obtained in LC-MS. The CE-MS method is a valuable alternative for the LC-MS method used for analysis of alkylation compounds. PMID:25910449

  17. Quaternary naltrexone reverses radiogenic and morphine-induced locomotor hyperactivity

    SciTech Connect

    Mickley, G.A.; Stevens, K.E.; Galbraith, J.A.; White, G.A.; Gibbs, G.L.

    1984-04-01

    The present study attempted to determine the relative role of the peripheral and central nervous system in the production of morphine-induced or radiation-induced locomotor hyperactivity of the mouse. Toward this end, we used a quaternary derivative of an opiate antagonist (naltrexone methobromide), which presumably does not cross the blood-brain barrier. Quaternary naltrexone was used to challenge the stereotypic locomotor response observed in these mice after either an i.p. injection of morphine or exposure to 1500 rads /sup 60/Co. The quaternary derivative of naltrexone reversed the locomotor hyperactivity normally observed in the C57BL/6J mouse after an injection of morphine. It also significantly attenuated radiation-induced locomotion. The data reported here support the hypothesis of endorphin involvement in radiation-induced and radiogenic behaviors. However, these conclusions are contingent upon further research which more fully evaluates naltrexone methobromide's capacity to cross the blood-brain barrier.

  18. Developing Sensorimotor Countermeasures to Mitigate Post-Flight Locomotor Dysfunction

    NASA Technical Reports Server (NTRS)

    Bloomberg, J. J.; Mulavara, A. P.; Cohen, H.; Miller, C. A.; Richards, J. T.; Houser, J.; McDonald, P. V.; Seidler, R. D.; Merkle, L. A.; Stelmach, G. E.

    2001-01-01

    Following spaceflight, crewmembers experience postural and locomotor instability. The magnitude and duration of post-flight sensorimotor disturbances increase with longer duration exposure to microgravity. These post-flight postural and locomotor alterations can pose a risk to crew safety and to mission objectives if nominal or emergency vehicle egress is required immediately following long-duration spaceflight. Gait instabilities could prevent or extend the time required to make an emergency egress from the Orbiter, Crew Return Vehicle or a future Martian lander leading to compromised mission objectives. We propose a countermeasure that aids in maintaining functional locomotor performance. This includes retaining the ability to perform vehicular egress and meet early mission objectives soon after landing on a planetary surface.

  19. Conditioned Place Preference to Acetone Inhalation and the Effects on Locomotor Behavior and 18FDG Uptake

    SciTech Connect

    Pai, J.C.; Dewey, S.L.; Schiffer, W.; Lee, D.

    2006-01-01

    Acetone is a component in many inhalants that have been widely abused. While other solvents have addictive potential, such as toluene, it is unclear whether acetone alone contains addictive properties. The locomotor, relative glucose metabolism and abusive effects of acetone inhalation were studied in animals using the conditioned place preference (CPP) paradigm and [18F]2-fluorodeoxy-D-glucose (18FDG) imaging. The CPP apparatus contains two distinct conditioning chambers and a middle adaptation chamber, each lined with photocells to monitor locomotor activity. Adolescent Sprague-Dawley rats (n=16; 90-110 g) were paired with acetone in least preferred conditioning chamber, determined on the pretest day. The animals were exposed to a 10,000 ppm dose for an hour, alternating days with air. A CPP test was conducted after the 3rd, 6th and 12th pairing. In these same animals, the relative glucose metabolism effects were determined using positron emission tomography (PET) imaging with 18FDG. Following the 3rd pairing, there was a significant aversion to the acetone paired chamber (190.9 ± 13.7 sec and 241.7 ± 16.9 sec, acetone and air, respectively). After the 6th pairing, there was no significant preference observed with equal time spent in each chamber (222 ± 21 sec and 207 ± 20 sec, acetone and air-paired, respectively). A similar trend was observed after the 12th pairing (213 ± 21 sec and 221 ± 22 sec, acetone and air-paired, respectively). Locomotor analysis indicated a significant decrease (p<0.05) from air pairings to acetone pairings on the first and sixth pairings. The observed locomotor activity was characteristic of central nervous system (CNS) depressants, without showing clear abusive effects in this CPP model. In these studies, acetone vapors were not as reinforcing as other solvents, shown by overall lack of preference for the acetone paired side of the chamber. PET imaging indicated a regionally specific distribution of 18FDG uptake following

  20. Association of locomotor complaints and disability in the Rotterdam study.

    PubMed Central

    Odding, E; Valkenburg, H A; Algra, D; Vandenouweland, F A; Grobbee, D E; Hofman, A

    1995-01-01

    OBJECTIVE--To determine the association between joint complaints and locomotor disability. METHODS--During a home interview survey 1901 men and 3135 women aged 55 years and over (the Rotterdam Study) were asked about joint pain and morning stiffness in the past month, and locomotor disability was assessed by six questions from the Health Assessment Questionnaire (HAQ). RESULTS--The prevalence of locomotor disability was 24.5% for men and 40.5% for women. The prevalence of joint pain in men was 0.7% for pain in the hips, knees, and feet simultaneously, 3.7% for pain at two joint sites, 16.0% for pain at one joint site, and 20.4% for pain in the hips and/or knees and/or feet (any joint site); the corresponding estimates for women were 1.9%, 9.0%, 23.7%, and 34.5%, respectively. The prevalence of generalised morning stiffness was 4.9% for men and 10.4% for women. The age adjusted odds ratios for locomotor disability in men ranged from 2.4 of pain at one joint site to 8.8 of pain at all three joint sites; for women these odds ratios varied between 2.5 and 5.7, respectively. The age adjusted odds ratios of generalised morning stiffness were 8.0 for men and 7.3 for women. CONCLUSION--There is a strong and independent association between locomotor disability and age, joint pain, and generalised morning stiffness in people aged 55 years and over. The odds for locomotor disability increase onefold for every year increase in age, while the presence of generalised morning stiffness is of greater influence than the presence of joint pain. PMID:7495342

  1. Potential natural sensitizers extracted from the skin of Canarium odontophyllum fruits for dye-sensitized solar cells

    NASA Astrophysics Data System (ADS)

    Lim, Andery; Kumara, N. T. R. N.; Tan, Ai Ling; Mirza, Aminul Huq; Chandrakanthi, R. L. N.; Petra, Mohammad Iskandar; Ming, Lim Chee; Senadeera, G. K. R.; Ekanayake, Piyasiri

    2015-03-01

    Possibility of use of dye extract from skin samples of a seasonal, indigenous fruit from Borneo, namely Canarium odontophyllum, in dye sensitized solar cells (DSSCs) are explored. Three main groups of flavonoid pigments are detected and these pigments exhibit different UV-vis absorption properties, and hence showing different light harvesting capabilities. When applied in DSSCs. The detected pigment constituents of the extract consist of aurone (maritimein), anthocyanidin (pelargonidin) and anthocyanidin (cyanidin derivatives). When tested in DSSC, the highest conversion efficiency of 1.43% is exhibited by cyanidin derivatives, and this is followed by conversion efficiencies of 0.51% and 0.79% for aurone and pelargonidin, respectively. It is shown that individual pigments, like cyanidin derivatives and pelargonidin, exhibit higher power conversion efficiency when compared to that of C.odontophyllum skin pigment mixture (with a conversion efficiency of only 0.68%). The results indicate a possibility of masking effects of the pigments when used as a mixture. The acidification of C.odontophyllum skin pigments with concentrated hydrochloric acid improves the conversion efficiency of the mixture from 0.68% to 0.99%. The discussion in this paper will draw data and observations from the variation in absorption and adsorption properties, the HOMO-LUMO levels, the energy band gaps and the functional group compositions of the detected flavonoids.

  2. Potential natural sensitizers extracted from the skin of Canarium odontophyllum fruits for dye-sensitized solar cells.

    PubMed

    Lim, Andery; Kumara, N T R N; Tan, Ai Ling; Mirza, Aminul Huq; Chandrakanthi, R L N; Petra, Mohammad Iskandar; Ming, Lim Chee; Senadeera, G K R; Ekanayake, Piyasiri

    2015-03-01

    Possibility of use of dye extract from skin samples of a seasonal, indigenous fruit from Borneo, namely Canarium odontophyllum, in dye sensitized solar cells (DSSCs) are explored. Three main groups of flavonoid pigments are detected and these pigments exhibit different UV-vis absorption properties, and hence showing different light harvesting capabilities. When applied in DSSCs. The detected pigment constituents of the extract consist of aurone (maritimein), anthocyanidin (pelargonidin) and anthocyanidin (cyanidin derivatives). When tested in DSSC, the highest conversion efficiency of 1.43% is exhibited by cyanidin derivatives, and this is followed by conversion efficiencies of 0.51% and 0.79% for aurone and pelargonidin, respectively. It is shown that individual pigments, like cyanidin derivatives and pelargonidin, exhibit higher power conversion efficiency when compared to that of C.odontophyllum skin pigment mixture (with a conversion efficiency of only 0.68%). The results indicate a possibility of masking effects of the pigments when used as a mixture. The acidification of C.odontophyllum skin pigments with concentrated hydrochloric acid improves the conversion efficiency of the mixture from 0.68% to 0.99%. The discussion in this paper will draw data and observations from the variation in absorption and adsorption properties, the HOMO-LUMO levels, the energy band gaps and the functional group compositions of the detected flavonoids. PMID:25541396

  3. Genotypic structure of a Drosophila population for adult locomotor activity

    SciTech Connect

    Grechanyi, G.V.; Korzun, V.M.

    1995-01-01

    Analysis of the variation of adult locomotor activity in four samples taken at different times from a natural population of Drosophila melanogaster showed that the total variation of this trait is relatively stable in time and has a substantial genetic component. Genotypic structure of the population for locomotor activity is characterized by the presence of large groups of genotypes with high and low values of this trait. A possible explanation for the presence of such groups in a population is cyclic density-dependent selection.

  4. Determination of the Spontaneous Locomotor Activity in Drosophila melanogaster

    PubMed Central

    Woods, Jared K.; Kowalski, Suzanne; Rogina, Blanka

    2014-01-01

    Drosophila melanogaster has been used as an excellent model organism to study environmental and genetic manipulations that affect behavior. One such behavior is spontaneous locomotor activity. Here we describe our protocol that utilizes Drosophila population monitors and a tracking system that allows continuous monitoring of the spontaneous locomotor activity of flies for several days at a time. This method is simple, reliable, and objective and can be used to examine the effects of aging, sex, changes in caloric content of food, addition of drugs, or genetic manipulations that mimic human diseases. PMID:24747955

  5. Determination of the spontaneous locomotor activity in Drosophila melanogaster.

    PubMed

    Woods, Jared K; Kowalski, Suzanne; Rogina, Blanka

    2014-01-01

    Drosophila melanogaster has been used as an excellent model organism to study environmental and genetic manipulations that affect behavior. One such behavior is spontaneous locomotor activity. Here we describe our protocol that utilizes Drosophila population monitors and a tracking system that allows continuous monitoring of the spontaneous locomotor activity of flies for several days at a time. This method is simple, reliable, and objective and can be used to examine the effects of aging, sex, changes in caloric content of food, addition of drugs, or genetic manipulations that mimic human diseases. PMID:24747955

  6. Mirtazapine prevents induction and expression of cocaine-induced behavioral sensitization in rats.

    PubMed

    Salazar-Juárez, Alberto; Barbosa-Méndez, Susana; Jurado, Noe; Hernández-Miramontes, Ricardo; Leff, Philippe; Antón, Benito

    2016-07-01

    Cocaine abuse is a major health problem worldwide. Treatment based on both 5-HT2A/C and 5-HT3 receptor antagonists attenuate not only the effects of cocaine abuse but also the incentive/motivational effect related to cocaine-paired cues. Mirtazapine, an antagonist of postsynaptic α2-adrenergic, 5-HT2A/C and 5HT3 receptors and inverse agonist of the 5-HT2C receptor, has been shown to effectively modify, at the preclinical and clinical levels, various behavioral alterations induced by drugs abuse. Therefore, it is important to assess whether chronic dosing of mirtazapine alters locomotor effects of cocaine as well as induction and expression of cocaine sensitization. Our results reveal that a daily mirtazapine regimen administered for 30days effectively induces a significant attenuation of cocaine-dependent locomotor activity and as well as the induction and expression of behavioral sensitization. These results suggest that mirtazapine may be used as a potentially effective therapy to attenuate induction and expression of cocaine-induced locomotor sensitization. PMID:26922897

  7. Chronic methylphenidate alters locomotor activity and dopamine transporters differently from cocaine.

    PubMed

    Izenwasser, S; Coy, A E; Ladenheim, B; Loeloff, R J; Cadet, J L; French, D

    1999-06-01

    Continuous infusion of cocaine produces partial behavioral tolerance to its locomotor activating effects, while daily injections produce sensitization. Methylphenidate binds with a similar affinity to cocaine at the dopamine transporter, but has a much lower affinity for the serotonin transporter than does cocaine. This study was done to compare the effects of chronic methylphenidate with chronic cocaine. The pattern of locomotor activity over a 7 day treatment period was significantly different from cocaine. Methylphenidate elevated activity on each day, compared to saline, yet neither tolerance to a continuous infusion of the drug, nor sensitization to repeated daily injections was produced. We have previously shown that neither of these treatments with cocaine produces significant alterations in dopamine transporter density 1 day after the end of treatment. In contrast, methylphenidate injections significantly decreased dopamine transporters in rostral caudate putamen, with no change in nucleus accumbens. Continuous infusion of methylphenidate had no effect on dopamine transporters in either brain region. These findings provide further evidence that different classes of dopamine uptake inhibitors may interact with the dopamine transporter in qualitatively different manners. Furthermore, it is possible that the inhibition of serotonin uptake by cocaine may contribute to the adaptations in behavioral activity that are seen during chronic treatment. PMID:10414438

  8. Bacterial porin disrupts mitochondrial membrane potential and sensitizes host cells to apoptosis.

    PubMed

    Kozjak-Pavlovic, Vera; Dian-Lothrop, Elke A; Meinecke, Michael; Kepp, Oliver; Ross, Katharina; Rajalingam, Krishnaraj; Harsman, Anke; Hauf, Eva; Brinkmann, Volker; Günther, Dirk; Herrmann, Ines; Hurwitz, Robert; Rassow, Joachim; Wagner, Richard; Rudel, Thomas

    2009-10-01

    The bacterial PorB porin, an ATP-binding beta-barrel protein of pathogenic Neisseria gonorrhoeae, triggers host cell apoptosis by an unknown mechanism. PorB is targeted to and imported by host cell mitochondria, causing the breakdown of the mitochondrial membrane potential (DeltaPsi(m)). Here, we show that PorB induces the condensation of the mitochondrial matrix and the loss of cristae structures, sensitizing cells to the induction of apoptosis via signaling pathways activated by BH3-only proteins. PorB is imported into mitochondria through the general translocase TOM but, unexpectedly, is not recognized by the SAM sorting machinery, usually required for the assembly of beta-barrel proteins in the mitochondrial outer membrane. PorB integrates into the mitochondrial inner membrane, leading to the breakdown of DeltaPsi(m). The PorB channel is regulated by nucleotides and an isogenic PorB mutant defective in ATP-binding failed to induce DeltaPsi(m) loss and apoptosis, demonstrating that dissipation of DeltaPsi(m) is a requirement for cell death caused by neisserial infection. PMID:19851451

  9. An 'Early Warning System' for the prevention of dredging potential impacts on sensitive areas

    NASA Astrophysics Data System (ADS)

    Piermattei, Viviana; Martellucci, Riccardo; Pierattini, Alberto; Bonamano, Simone; Paladini de Mendoza, Francesco; Albani, Marta; Stefanì, Chiara; Madonia, Alice; Fersini, Giorgio; Marcelli, Marco

    2016-04-01

    Coastal marine ecosystems are increasingly subject to multiple pressures and stressors produced by the effects of human activities. Intense and frequent disturbances which affect marine environment can derive from dredging activity, which is a fundamental management for most ports and harbours. The potential environmental effects of dredging procedures are generally due to the excavation of material from the sea bottom and the relocation elsewhere for disposal, overflow from the dredger and loss of material from pipelines during transport. Depending on the location and the intensity of these activities the marine environment, particularly sensitive areas, may be affected by dredging. The main environmental effects can be associated with suspended sediments and increases in turbidity into the water column, which can have adverse effects on marine animals and plants by reducing light penetration and by physical disturbance. For this reason it is fundamental to implement a real time monitoring system to control and prevent negative effects, enabling a rapid response to adverse water quality conditions and a fast activation of mitigation procedures, in agreement with all the reference authorities. In this work we present the development of an innovative 'Early Warning System' based on fixed stations, ad hoc in situ surveys and forecasting models, which was applied to a dredging activity carried out in the Gulf of Gaeta (Latium, Italy). It represents an extension of the C-CEMS (Civitavecchia Coastal Environmental Monitoring System) network, which is operative in the Tyrrhenian sea since 2005.

  10. Immunomodulatory effects of potential probiotics in a mouse peanut sensitization model.

    PubMed

    Meijerink, Marjolein; Wells, Jerry M; Taverne, Nico; de Zeeuw Brouwer, Mary-Lène; Hilhorst, Bianca; Venema, Koen; van Bilsen, Jolanda

    2012-08-01

    Peanut allergy accounts for the majority of severe food-related allergic reactions and there is a need for new prevention and treatment strategies. Probiotics may be considered for treatment on the basis of their immunomodulating properties. Cytokine profiles of probiotic strains were determined by in vitro co-culture with human PBMCs. Three strains were selected to investigate their prophylactic potential in a peanut sensitization model by analysing peanut-specific antibodies, mast cell degranulation and ex vivo cytokine production by splenocytes. The probiotic strains induced highly variable cytokine profiles in PBMCs. L. salivarius HMI001, L. casei Shirota (LCS) and L. plantarum WCFS1 were selected for further investigation owing to their distinct cytokine patterns. Prophylactic treatment with both HMI001 and LCS attenuated the Th2 phenotype (reduced mast cell responses and ex vivo IL-4 and/or IL-5 production). In contrast, WCFS1 augmented the Th2 phenotype (increased mast cell and antibody responses and ex vivo IL-4 production). In vitro PBMC screening was useful in selecting strains with anti-inflammatory and Th1 skewing properties. In case of HMI001 (high IL-10/IL-12 ratio) and LCS (high interferon-γ and IL-12), partial protection was seen in a mouse peanut allergy model. Strikingly, certain strains may worsen the allergic reaction as shown in the case of WCFS1. PMID:22540665

  11. Bone-Targeted Acid-Sensitive Doxorubicin Conjugate Micelles as Potential Osteosarcoma Therapeutics

    PubMed Central

    2015-01-01

    Osteosarcoma is a malignancy of the bone that primarily affects adolescents. Current treatments retain mortality rates, which are higher than average cancer mortality rates for the adolescent age group. We designed a micellar delivery system with the aim to increase drug accumulation in the tumor and potentially reduce side effects associated with chemotherapy. The design features are the use of the hydrophilic d-aspartic acid octapeptide as both the effective targeting agent as well as the hydrophilic micelle corona. Micelle stabilization was accomplished by binding of model drug (doxorubicin) via an acid-sensitive hydrazone bond and incorporating one to four 11-aminoundecanoic acid (AUA) moieties to manipulate the hydrophobic/hydrophilic ratio. Four micelle-forming unimers have been synthesized and their self-assembly into micelles was evaluated. Size of the micelles could be modified by changing the architecture of the unimers from linear to branched. The stability of the micelles increased with increasing content of AUA moieties. Adsorption of all micelles to hydroxyapatite occurred rapidly. Doxorubicin release occurred at pH 5.5, whereas no release was detected at pH 7.4. Cytotoxicity toward human osteosarcoma Saos-2 cells correlated with drug release data. PMID:25291150

  12. Bone-targeted acid-sensitive doxorubicin conjugate micelles as potential osteosarcoma therapeutics.

    PubMed

    Low, Stewart A; Yang, Jiyuan; Kopeček, Jindřich

    2014-11-19

    Osteosarcoma is a malignancy of the bone that primarily affects adolescents. Current treatments retain mortality rates, which are higher than average cancer mortality rates for the adolescent age group. We designed a micellar delivery system with the aim to increase drug accumulation in the tumor and potentially reduce side effects associated with chemotherapy. The design features are the use of the hydrophilic D-aspartic acid octapeptide as both the effective targeting agent as well as the hydrophilic micelle corona. Micelle stabilization was accomplished by binding of model drug (doxorubicin) via an acid-sensitive hydrazone bond and incorporating one to four 11-aminoundecanoic acid (AUA) moieties to manipulate the hydrophobic/hydrophilic ratio. Four micelle-forming unimers have been synthesized and their self-assembly into micelles was evaluated. Size of the micelles could be modified by changing the architecture of the unimers from linear to branched. The stability of the micelles increased with increasing content of AUA moieties. Adsorption of all micelles to hydroxyapatite occurred rapidly. Doxorubicin release occurred at pH 5.5, whereas no release was detected at pH 7.4. Cytotoxicity toward human osteosarcoma Saos-2 cells correlated with drug release data. PMID:25291150

  13. A preliminary investigation of the potential mechanical sensitivity of vertical comb drives

    NASA Astrophysics Data System (ADS)

    Gallagher, E.; Moussa, W.

    2014-10-01

    This article describes a preliminary step taken in investigating the potential of vertical comb drives to be used as force-compensation mechanisms in interfacial force microscopes, by exploring the lower limit of the stiffness of the springs the comb drives can be fabricated with. The stiffness of their springs will affect the sensitivity of the microscope. Six vertical comb drives were fabricated for this study; the dimensions of their spring beams were chosen with the intention of giving them stiffnesses of three different orders of magnitude. During fabrication it was found that etching the tops of some of the teeth down to create the vertical offset between the combs can be done using only photoresist to mask the rest of the teeth. The stiffnesses of the fabricated springs were estimated by applying loads to them and measuring their resulting deflections. Weights were applied to the two comb drives with the stiffest springs. Voltages were also applied to them so as to determine the force-voltage relationship for their comb design. Since the other four comb drives had the same comb design, the stiffnesses of their springs could be estimated from the displacements of their movable combs when voltages were applied to them.

  14. Anxiety sensitivity and the anticipation of predictable and unpredictable threat: Evidence from the startle response and event-related potentials.

    PubMed

    Nelson, Brady D; Hodges, Allie; Hajcak, Greg; Shankman, Stewart A

    2015-06-01

    There is growing evidence that heightened sensitivity to unpredictable threat is a core mechanism of dysfunction in anxiety disorders. However, it is unclear whether anxiety sensitivity is also associated with sensitivity to unpredictable threat. In the present study, 131 participants completed the Anxiety Sensitivity Index-3, which includes physical concerns (PC), social concerns (SC), and cognitive concerns (CC) subscales, and a predictable vs. unpredictable threat-of-shock task. Startle eyeblink and ERP responses (N100, P300) to the acoustic startle probes were measured during the task. PC and CC were associated with heightened and attenuated, respectively, startle for the unpredictable (but not predictable) condition. CC were also associated with attenuated probe N100 for the unpredictable condition only, and PC were associated with increased P300 suppression across the predictable and unpredictable conditions. This study provides novel evidence that the different anxiety sensitivity dimensions demonstrate unique relationships with the RDoC domains "acute" and "potential" threat. PMID:26005838

  15. The role of the serotonergic system in locomotor recovery after spinal cord injury

    PubMed Central

    Ghosh, Mousumi; Pearse, Damien D.

    2015-01-01

    Serotonin (5-HT), a monoamine neurotransmitter synthesized in various populations of brainstem neurons, plays an important role in modulating the activity of spinal networks involved in vertebrate locomotion. Following spinal cord injury (SCI) there is a disruption of descending serotonergic projections to spinal motor areas, which results in a subsequent depletion in 5-HT, the dysregulation of 5-HT transporters as well as the elevated expression, super-sensitivity and/or constitutive auto-activation of specific 5-HT receptors. These changes in the serotonergic system can produce varying degrees of locomotor dysfunction through to paralysis. To date, various approaches targeting the different components of the serotonergic system have been employed to restore limb coordination and improve locomotor function in experimental models of SCI. These strategies have included pharmacological modulation of serotonergic receptors, through the administration of specific 5-HT receptor agonists, or by elevating the 5-HT precursor 5-hydroxytryptophan, which produces a global activation of all classes of 5-HT receptors. Stimulation of these receptors leads to the activation of the locomotor central pattern generator (CPG) below the site of injury to facilitate or improve the quality and frequency of movements, particularly when used in concert with the activation of other monoaminergic systems or coupled with electrical stimulation. Another approach has been to employ cell therapeutics to replace the loss of descending serotonergic input to the CPG, either through transplanted fetal brainstem 5-HT neurons at the site of injury that can supply 5-HT to below the level of the lesion or by other cell types to provide a substrate at the injury site for encouraging serotonergic axon regrowth across the lesion to the caudal spinal cord for restoring locomotion. PMID:25709569

  16. Propofol Restores Transient Receptor Potential Vanilloid Receptor Subtype-1 Sensitivity via Activation of Transient Receptor Potential Ankyrin Receptor Subtype-1 in Sensory Neurons

    PubMed Central

    Zhang, Hongyu; Wickley, Peter J.; Sinha, Sayantani; Bratz, Ian N.; Damron, Derek S.

    2011-01-01

    Background Crosstalk between peripheral nociceptors belonging to the transient receptor potential vanilloid receptor subtype-1 (TRPV1) and ankyrin subtype-1 (TRPA1) family has recently been demonstrated. Moreover, the intravenous anesthetic propofol has been shown to directly activate TRPA1 receptors, and indirectly restore sensitivity of TRPV1 receptors in dorsal root ganglion (DRG) sensory neurons. Our objective was to determine the extent to which TRPA1 activation is involved in mediating the propofol-induced restoration of TRPV1 sensitivity. Methods Mouse DRG neurons were isolated by enzymatic dissociation and grown for 24 h. F-11 cells were transfected with complementary DNA for both TRPV1 and TRPA1 or TRPV1 only. Intracellular Ca2+ concentration was measured in individual cells via fluorescence microscopy. Following TRPV1 de-sensitization with capsaicin (100 nM), cells were treated with propofol (1, 5 and 10 μM) alone, propofol in the presence of the TRPA1 antagonist, HC-030031 (0.5 μM) or the TRPA1 agonist, Allyl isothiocyanate (AITC, 100 μM) and capsaicin was then reapplied. Results In DRG neurons that contain both TRPV1 and TRPA1, propofol and AITC restored TRPV1 sensitivity. However, in DRG neurons containing only TRPV1 receptors, exposure to propofol or AITC following de-sensitization did not restore capsaicin-induced TRPV1 sensitivity. Similarly, in F-11 cells transfected with both TRPV1 and TRPA1, propofol and AITC restored TRPV1 sensitivity. However, in F-11 cells transfected with TRPV1 only, neither propofol nor AITC were capable of restoring TRPV1 sensitivity. Conclusions These data demonstrate that propofol restores TRPV1 sensitivity in primary DRG neurons and in cultured F-11 cells transfected with both the TRPV1 and TRPA1 receptors via a TRPA1-dependent process. Propofol’s effects on sensory neurons may be clinically important and contribute to peripheral sensitization to nociceptive stimuli in traumatized tissue. PMID:21364461

  17. Down-Regulation of Decapping Protein 2 Mediates Chronic Nicotine Exposure-Induced Locomotor Hyperactivity in Drosophila

    PubMed Central

    Ren, Jing; Sun, Jinghan; Zhang, Yunpeng; Liu, Tong; Ren, Qingzhong; Li, Yan; Guo, Aike

    2012-01-01

    Long-term tobacco use causes nicotine dependence via the regulation of a wide range of genes and is accompanied by various health problems. Studies in mammalian systems have revealed some key factors involved in the effects of nicotine, including nicotinic acetylcholine receptors (nAChRs), dopamine and other neurotransmitters. Nevertheless, the signaling pathways that link nicotine-induced molecular and behavioral modifications remain elusive. Utilizing a chronic nicotine administration paradigm, we found that adult male fruit flies exhibited locomotor hyperactivity after three consecutive days of nicotine exposure, while nicotine-naive flies did not. Strikingly, this chronic nicotine-induced locomotor hyperactivity (cNILH) was abolished in Decapping Protein 2 or 1 (Dcp2 or Dcp1) -deficient flies, while only Dcp2-deficient flies exhibited higher basal levels of locomotor activity than controls. These results indicate that Dcp2 plays a critical role in the response to chronic nicotine exposure. Moreover, the messenger RNA (mRNA) level of Dcp2 in the fly head was suppressed by chronic nicotine treatment, and up-regulation of Dcp2 expression in the nervous system blocked cNILH. These results indicate that down-regulation of Dcp2 mediates chronic nicotine-exposure-induced locomotor hyperactivity in Drosophila. The decapping proteins play a major role in mRNA degradation; however, their function in the nervous system has rarely been investigated. Our findings reveal a significant role for the mRNA decapping pathway in developing locomotor hyperactivity in response to chronic nicotine exposure and identify Dcp2 as a potential candidate for future research on nicotine dependence. PMID:23300696

  18. Active Gaze, Visual Look-Ahead, and Locomotor Control

    ERIC Educational Resources Information Center

    Wilkie, Richard M.; Wann, John P.; Allison, Robert S.

    2008-01-01

    The authors examined observers steering through a series of obstacles to determine the role of active gaze in shaping locomotor trajectories. Participants sat on a bicycle trainer integrated with a large field-of-view simulator and steered through a series of slalom gates. Steering behavior was determined by examining the passing distance through…

  19. Acute neuroactive drug exposures alter locomotor activity in larval zebrafish

    EPA Science Inventory

    In an effort to develop a rapid in vivo screen for EPA's prioritization of toxic chemicals, we are characterizing the locomotor activity of zebrafish (Danio rerio) larvae after exposure to prototypic drugs that act on the central nervous system. MPTP (1-methyl-4phenyl- 1 ,2,3,6-...

  20. Modulation of locomotor activation by the rostromedial tegmental nucleus.

    PubMed

    Lavezzi, Heather N; Parsley, Kenneth P; Zahm, Daniel S

    2015-02-01

    The rostromedial tegmental nucleus (RMTg) is a strong inhibitor of dopamine neurons in the ventral tegmental area (VTA) reported to influence neurobiological and behavioral responses to reward omission, aversive and fear-eliciting stimuli, and certain drugs of abuse. Insofar as previous studies implicate ventral mesencephalic dopamine neurons as an essential component of locomotor activation, we hypothesized that the RMTg also should modulate locomotion activation. We observed that bilateral infusions into the RMTg of the gamma-aminobutyric acid A (GABAA) agonist, muscimol, indeed activate locomotion. Alternatively, bilateral RMTg infusions of the GABAA receptor antagonist, bicuculline, suppress robust activations of locomotion elicited in two distinct ways: (1) by disinhibitory stimulation of neurons in the lateral preoptic area and (2) by return of rats to an environment previously paired with amphetamine administration. The possibility that suppressive locomotor effects of RMTg bicuculline infusions were due to unintended spread of drug to the nearby VTA was falsified by a control experiment showing that bilateral infusions of bicuculline into the VTA produce activation rather than suppression of locomotion. These results objectively implicate the RMTg in the regulation of locomotor activation. The effect is important because much evidence reported in the literature suggests that locomotor activation can be an involuntary behavioral expression of expectation and/or want without which the willingness to execute adaptive behaviors is impaired. PMID:25164249

  1. DRUG EFFECTS ON THE LOCOMOTOR ACTIVITY OF LARVAL ZEBRAFISH.

    EPA Science Inventory

    As part of an effort to develop a rapid in vivo screen for EPA’s prioritization of toxic chemicals, we have begun to characterize the locomotor activity of zebrafish (Danio rerio) larvae and the effects of prototype drugs. Zebrafish larvae (6-7 days post-fertilization) were indiv...

  2. Acute Neuroactive Drug Exposures alter Locomotor Activity in Larval Zebrafish

    EPA Science Inventory

    As part of the development of a rapid in vivo screen for prioritization of toxic chemicals, we have begun to characterize the locomotor activity of zebrafish (Danio rerio) larvae by assessing the acute effects of prototypic drugs that act on the central nervous system. Initially,...

  3. A Model of Locomotor-Respiratory Coupling in Quadrupeds

    ERIC Educational Resources Information Center

    Giuliodori,, Mauricio J.; Lujan, Heidi L.; Briggs, Whitney S.; DiCarlo, Stephen E.

    2009-01-01

    Locomotion and respiration are not independent phenomena in running mammals because locomotion and respiration both rely on cyclic movements of the ribs, sternum, and associated musculature. Thus, constraints are imposed on locomotor and respiratory function by virtue of their linkage. Specifically, locomotion imposes mechanical constraints on…

  4. Transgenic APP expression during postnatal development causes persistent locomotor hyperactivity in the adult

    PubMed Central

    2012-01-01

    Background Transgenic mice expressing disease-associated proteins have become standard tools for studying human neurological disorders. Transgenes are often expressed using promoters chosen to drive continuous high-level expression throughout life rather than temporal and spatial fidelity to the endogenous gene. This approach has allowed us to recapitulate diseases of aging within the two-year lifespan of the laboratory mouse, but has the potential for creating aberrant phenotypes by mechanisms unrelated to the human disorder. Results We show that overexpression of the Alzheimer’s-related amyloid precursor protein (APP) during early postnatal development leads to severe locomotor hyperactivity that can be significantly attenuated by delaying transgene onset until adulthood. Our data suggest that exposure to transgenic APP during maturation influences the development of neuronal circuits controlling motor activity. Both when matched for total duration of APP overexpression and when matched for cortical amyloid burden, animals exposed to transgenic APP as juveniles are more active in locomotor assays than animals in which APP overexpression was delayed until adulthood. In contrast to motor activity, the age of APP onset had no effect on thigmotaxis in the open field as a rough measure of anxiety, suggesting that the interaction between APP overexpression and brain development is not unilateral. Conclusions Our findings indicate that locomotor hyperactivity displayed by the tet-off APP transgenic mice and several other transgenic models of Alzheimer’s disease may result from overexpression of mutant APP during postnatal brain development. Our results serve as a reminder of the potential for unexpected interactions between foreign transgenes and brain development to cause long-lasting effects on neuronal function in the adult. The tet-off APP model provides an easy means of avoiding developmental confounds by allowing transgene expression to be delayed until the

  5. Modeling the action-potential-sensitive nonlinear-optical response of myelinated nerve fibers and short-term memory

    NASA Astrophysics Data System (ADS)

    Shneider, M. N.; Voronin, A. A.; Zheltikov, A. M.

    2011-11-01

    The Goldman-Albus treatment of the action-potential dynamics is combined with a phenomenological description of molecular hyperpolarizabilities into a closed-form model of the action-potential-sensitive second-harmonic response of myelinated nerve fibers with nodes of Ranvier. This response is shown to be sensitive to nerve demyelination, thus enabling an optical diagnosis of various demyelinating diseases, including multiple sclerosis. The model is applied to examine the nonlinear-optical response of a three-neuron reverberating circuit—the basic element of short-term memory.

  6. The Use of Germinants to Potentiate the Sensitivity of Bacillus anthracis Spores to Peracetic Acid.

    PubMed

    Celebi, Ozgur; Buyuk, Fatih; Pottage, Tom; Crook, Ant; Hawkey, Suzanna; Cooper, Callum; Bennett, Allan; Sahin, Mitat; Baillie, Leslie

    2016-01-01

    Elimination of Bacillus anthracis spores from the environment is a difficult and costly process due in part to the toxicity of current sporicidal agents. For this reason we investigated the ability of the spore germinants L-alanine (100 mM) and inosine (5 mM) to reduce the concentration of peracetic acid (PAA) required to inactivate B. anthracis spores. While L-alanine significantly enhanced (p = 0.0085) the bactericidal activity of 500 ppm PAA the same was not true for inosine suggesting some form of negative interaction. In contrast the germinant combination proved most effective at 100 ppm PAA (p = 0.0009). To determine if we could achieve similar results in soil we treated soil collected from the burial site of an anthrax infected animal which had been supplemented with spores of the Sterne strain of B. anthracis to increase the level of contamination to 10(4) spores/g. Treatment with germinants followed 1 h later by 5000 ppm PAA eliminated all of the spores. In contrast direct treatment of the animal burial site using this approach delivered using a back pack sprayer had no detectable effect on the level of B. anthracis contamination or on total culturable bacterial numbers over the course of the experiment. It did trigger a significant, but temporary, reduction (p < 0.0001) in the total spore count suggesting that germination had been triggered under real world conditions. In conclusion, we have shown that the application of germinants increase the sensitivity of bacterial spores to PAA. While the results of the single field trial were inconclusive, the study highlighted the potential of this approach and the challenges faced when attempting to perform real world studies on B. anthracis spores contaminated sites. PMID:26858699

  7. The Use of Germinants to Potentiate the Sensitivity of Bacillus anthracis Spores to Peracetic Acid

    PubMed Central

    Celebi, Ozgur; Buyuk, Fatih; Pottage, Tom; Crook, Ant; Hawkey, Suzanna; Cooper, Callum; Bennett, Allan; Sahin, Mitat; Baillie, Leslie

    2016-01-01

    Elimination of Bacillus anthracis spores from the environment is a difficult and costly process due in part to the toxicity of current sporicidal agents. For this reason we investigated the ability of the spore germinants L-alanine (100 mM) and inosine (5 mM) to reduce the concentration of peracetic acid (PAA) required to inactivate B. anthracis spores. While L-alanine significantly enhanced (p = 0.0085) the bactericidal activity of 500 ppm PAA the same was not true for inosine suggesting some form of negative interaction. In contrast the germinant combination proved most effective at 100 ppm PAA (p = 0.0009). To determine if we could achieve similar results in soil we treated soil collected from the burial site of an anthrax infected animal which had been supplemented with spores of the Sterne strain of B. anthracis to increase the level of contamination to 104 spores/g. Treatment with germinants followed 1 h later by 5000 ppm PAA eliminated all of the spores. In contrast direct treatment of the animal burial site using this approach delivered using a back pack sprayer had no detectable effect on the level of B. anthracis contamination or on total culturable bacterial numbers over the course of the experiment. It did trigger a significant, but temporary, reduction (p < 0.0001) in the total spore count suggesting that germination had been triggered under real world conditions. In conclusion, we have shown that the application of germinants increase the sensitivity of bacterial spores to PAA. While the results of the single field trial were inconclusive, the study highlighted the potential of this approach and the challenges faced when attempting to perform real world studies on B. anthracis spores contaminated sites. PMID:26858699

  8. Sensitive bioassay for detection of PPARα potentially hazardous ligands with gold nanoparticle probe.

    PubMed

    Xia, Wei; Wan, Yan-Jian; Wang, Xianliang; Li, Yuan-Yuan; Yang, Wen-Jie; Wang, Chun-Xiang; Xu, Shun-qing

    2011-09-15

    There are so many kinds of peroxisome proliferator-activated receptor α (PPARα) ligands with hazardous effect for human health in the environment, such as certain herbicides, plasticizers and drugs. Among these agonists, perfluorooctane sulfonate (PFOS), perfluorooctanoic acid (PFOA), and mono-(2-ethylhexyl) phthalate (MEHP) are mostly investigated due to their persistence and accumulation in environment and their potential toxicity via PPARα. This investigation aims at developing a bioassay method to detect PPARα ligands based on the ligand-receptor interaction on microplate. PPARα, which formed heterodimers with retinoid X receptor-α (RXRα), were activated by PPARα ligands to form ligands-PPARα-RXRα complexes. Then the complexes were transferred into a microplate and captured via monoclonal anti-PPARα antibody. The PPARα responsive elements (PPRE) modified-gold nanoparticle probes were captured by the ligand-PPARα-RXRα complexes immobilized on the microplate, and then could be quantified through measuring the optical density after silver enhancement. The results showed that PFOS was quantified with a linear range from 100 pM to 1 μM and the detection limit was 10 pM. In addition to PFOS, PFOA and MEHP were also quantified within a proper range through the proposed bioassay. This bioassay was compared with that of liquid chromatography tandem-mass spectrometry (LC-MS) for water spiked samples with a significant correlation (r = 0.9893). This study provides a high-throughput detection method for PPARα ligands in microplate with high sensitivity and wide linear range. It may serve as an assistant of LC-MS for prescreening of PPARα ligands like PFOS. PMID:21726938

  9. Mercury-sensitive water channels as possible sensors of water potentials in pollen

    PubMed Central

    Hill, Adrian E.

    2013-01-01

    The growing pollen tube is central to plant reproduction and is a long-standing model for cellular tip growth in biology. Rapid osmotically driven growth is maintained under variable conditions, which requires osmosensing and regulation. This study explores the mechanism of water entry and the potential role of osmosensory regulation in maintaining pollen growth. The osmotic permeability of the plasmalemma of Lilium pollen tubes was measured from plasmolysis rates to be 1.32±0.31×10–3 cm s–1. Mercuric ions reduce this permeability by 65%. Simulations using an osmotic model of pollen tube growth predict that an osmosensor at the cell membrane controls pectin deposition at the cell tip; inhibiting the sensor is predicted to cause tip bursting due to cell wall thinning. It was found that adding mercury to growing pollen tubes caused such a bursting of the tips. The model indicates that lowering the osmotic permeability per se does not lead to bursting but rather to thickening of the tip. The time course of induced bursting showed no time lag and was independent of mercury concentration, compatible with a surface site of action. The submaximal bursting response to intermediate mercuric ion concentration was independent of the concentration of calcium ions, showing that bursting is not due to a competitive inhibition of calcium binding or entry. Bursting with the same time course was also shown by cells growing on potassium-free media, indicating that potassium channels (implicated in mechanosensing) are not involved in the bursting response. The possible involvement of mercury-sensitive water channels as osmosensors and current knowledge of these in pollen cells are discussed. PMID:24098048

  10. Mercury-sensitive water channels as possible sensors of water potentials in pollen.

    PubMed

    Shachar-Hill, Bruria; Hill, Adrian E; Powell, Janet; Skepper, Jeremy N; Shachar-Hill, Yair

    2013-11-01

    The growing pollen tube is central to plant reproduction and is a long-standing model for cellular tip growth in biology. Rapid osmotically driven growth is maintained under variable conditions, which requires osmosensing and regulation. This study explores the mechanism of water entry and the potential role of osmosensory regulation in maintaining pollen growth. The osmotic permeability of the plasmalemma of Lilium pollen tubes was measured from plasmolysis rates to be 1.32±0.31×10(-3) cm s(-1). Mercuric ions reduce this permeability by 65%. Simulations using an osmotic model of pollen tube growth predict that an osmosensor at the cell membrane controls pectin deposition at the cell tip; inhibiting the sensor is predicted to cause tip bursting due to cell wall thinning. It was found that adding mercury to growing pollen tubes caused such a bursting of the tips. The model indicates that lowering the osmotic permeability per se does not lead to bursting but rather to thickening of the tip. The time course of induced bursting showed no time lag and was independent of mercury concentration, compatible with a surface site of action. The submaximal bursting response to intermediate mercuric ion concentration was independent of the concentration of calcium ions, showing that bursting is not due to a competitive inhibition of calcium binding or entry. Bursting with the same time course was also shown by cells growing on potassium-free media, indicating that potassium channels (implicated in mechanosensing) are not involved in the bursting response. The possible involvement of mercury-sensitive water channels as osmosensors and current knowledge of these in pollen cells are discussed. PMID:24098048

  11. Transforming potential and matrix stiffness co-regulate confinement sensitivity of tumor cell migration.

    PubMed

    Pathak, Amit; Kumar, Sanjay

    2013-08-01

    It is now well established that tumor cell invasion through tissue is strongly regulated by the microstructural and mechanical properties of the extracellular matrix (ECM). However, it remains unclear how these physical microenvironmental inputs are jointly processed with oncogenic lesions to drive invasion. In this study, we address this open question by combining a microfabricated polyacrylamide channel (μPAC) platform that enables independent control of ECM stiffness and confinement with an isogenically-matched breast tumor progression series in which the oncogenes ErbB2 and 14-3-3ζ are overexpressed independently or in tandem. We find that increasing channel confinement and overexpressing ErbB2 both promote cell migration to a similar degree when other parameters are kept constant. In contrast, 14-3-3ζ overexpression slows migration speed, and does so in a fashion that dwarfs effects of ECM confinement and stiffness. We also find that ECM stiffness dramatically enhances cell motility when combined with ErbB2 overexpression, demonstrating that biophysical cues and cell-intrinsic parameters promote cell invasion in an integrative manner. Morphometric analysis of cells inside the μPAC platform reveals that the rapid cell migration induced by narrow channels and ErbB2 overexpression are both accompanied by increased cell polarization. Disruption of this polarization occurs by pharmacological inhibition of Rac GTPase phenocopies 14-3-3ζ overexpression by reducing cell polarization and slowing migration. By systematically measuring migration speed as a function of matrix stiffness and confinement, we also quantify for the first time the sensitivity of migration speed to microchannel properties and transforming potential. These results demonstrate that oncogenic lesions and ECM biophysical properties can synergistically interact to drive invasive migration, and that both inputs may act through common molecular mechanisms to enhance migration speed. PMID:23832051

  12. Effects of cocaine on norepinephrine stimulated phosphoinositide hydrolysis and locomotor activity in rat

    SciTech Connect

    Mosaddeghi, M.

    1989-01-01

    The function of {alpha}{sub 1}-adrenoceptors was determined by stimulating cortical tissue slices, which were pre-labeled with ({sup 3}H)inositol, with norepinephrine (NE) in the presence of 8 mM LiCl. Results of in vitro studies showed that cocaine 10 {mu}M potentiated maximal NE-stimulated PI hydrolysis by 30%. In addition, the EC{sub 50} was decreased from 3.93 {plus minus} 0.42 to 1.91 {plus minus} 0.31 {mu}M NE. Concentrations of 0.1-100 {mu}M and 0.1-10 {mu}M cocaine enhanced PI hydrolysis stimulated by 0.3 and 3 {mu}M NE, respectively. The concentration-effect curves for NE-stimulated PI hydrolysis were shifted to the right 100-fold in the presence of 0.1 {mu}M prazosin. Cocaine (10 {mu}M) did not potentiate NE-stimulated PI hydrolysis in the presence of 0.1 {mu}M prazosin. ({sup 3}H)Prazosin saturation and NE ({sup 3}H)prazosin competition binding studies using crude membrane preparations showed that 10 {mu}M cocaine did not alter binding parameters B{sub max}, K{sub d}, Hill slope, and IC{sub 50}. Together, these results implied that cocaine in vitro potentiated NE-stimulated PI hydrolysis by blocking NE reuptake. For in vivo studies, the locomotor activity was determined after an acute or chronic injections of either cocaine or saline. Cocaine or saline-treated rats were killed after measurement of the locomotor activity, and NE-stimulated PI hydrolysis was measured. Acute administration of cocaine 3.2-42 mg/kg (i.p.) produced an inverted U shaped dose-response curve on locomotor activity. The peak increase in locomotor activity was at 32 mg/kg cocaine. A dose of 42 mg/kg cocaine produced a significant depression of maximal NE-stimulated PI hydrolysis.

  13. Leuco-crystal-violet micelle gel dosimeters: I. Influence of recipe components and potential sensitizers.

    PubMed

    Nasr, A T; Alexander, K; Schreiner, L J; McAuley, K B

    2015-06-21

    Radiochromic leuco crystal violet (LCV) micelle gel dosimeters are promising three-dimensional radiation dosimeters because of their spatial stability and suitability for optical readout. The effects of surfactant type and surfactant concentration on dose sensitivity of LCV micelle gels are tested, demonstrating that dose sensitivity and initial colour of the gel increases with increasing Triton x-100 (Tx100) concentration. Using Cetyl Trimethyl Ammonium Bromide (CTAB) in place of Tx100 produces gels that are nearly colourless prior to irradiation, but reduces the dose sensitivity. The separate effects of Tri-chloro acetic acid concentration and pH are investigated, revealing that controlling the pH near 3.6 is crucial for achieving high dose sensitivity. The sensitizing effect of chlorinated species on dose sensitivity is tested using 2,2,2-trichloroethanol (TCE), chloroform, and 1,1,1-trichloro-2-methyl-2-propanol hemihydrate. TCE gives the largest improvement in dose sensitivity and is recommended for use in micelle gel dosimeters because it is less volatile and safer to use than chloroform. Preliminary experiments on a new gel containing CTAB as the surfactant and TCE show that this new gel gives a dose sensitivity that is 24% higher than that of previous LCV micelle gels and is nearly colourless prior to irradiation. PMID:26020840

  14. A fluorescence high throughput screening method for the detection of reactive electrophiles as potential skin sensitizers

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Skin sensitization is an important toxicological end-point in the risk assessment of chemical allergens. Because of the complexity of the biological mechanisms associated with skin sensitization integrated approaches combining different chemical, biological and in silico methods are recommended to r...

  15. Leuco-crystal-violet micelle gel dosimeters: I. Influence of recipe components and potential sensitizers

    NASA Astrophysics Data System (ADS)

    Nasr, A. T.; Alexander, K.; Schreiner, L. J.; McAuley, K. B.

    2015-06-01

    Radiochromic leuco crystal violet (LCV) micelle gel dosimeters are promising three-dimensional radiation dosimeters because of their spatial stability and suitability for optical readout. The effects of surfactant type and surfactant concentration on dose sensitivity of LCV micelle gels are tested, demonstrating that dose sensitivity and initial colour of the gel increases with increasing Triton x-100 (Tx100) concentration. Using Cetyl Trimethyl Ammonium Bromide (CTAB) in place of Tx100 produces gels that are nearly colourless prior to irradiation, but reduces the dose sensitivity. The separate effects of Tri-chloro acetic acid concentration and pH are investigated, revealing that controlling the pH near 3.6 is crucial for achieving high dose sensitivity. The sensitizing effect of chlorinated species on dose sensitivity is tested using 2,2,2-trichloroethanol (TCE), chloroform, and 1,1,1-trichloro-2-methyl-2-propanol hemihydrate. TCE gives the largest improvement in dose sensitivity and is recommended for use in micelle gel dosimeters because it is less volatile and safer to use than chloroform. Preliminary experiments on a new gel containing CTAB as the surfactant and TCE show that this new gel gives a dose sensitivity that is 24% higher than that of previous LCV micelle gels and is nearly colourless prior to irradiation.

  16. The thermal plasticity of locomotor performance has diverged between northern and southern populations of the eastern newt (Notophthalmus viridescens).

    PubMed

    Mineo, Patrick M; Schaeffer, Paul J

    2015-01-01

    Many temperate ectotherms undergo thermal acclimation to remain functional over a wide range of body temperatures, but few studies have investigated whether populations of a single species have evolved differences in the thermal plasticity of locomotor performance. Therefore, we asked whether the thermal plasticity of locomotor performance has diverged between northern and southern populations of eastern newts (Notophthalmus viridescens). We acclimated eastern newts from Florida and Maine to cold (6 °C) or warm (28 °C) conditions for 12 weeks. Following acclimation, we measured the burst speed of newts at 6, 11.5, 17, 22.5, 28, and 33.5 °C. We also measured the activities of creatine kinase (CK) and lactate dehydrogenase (LDH) in skeletal muscle of newts. The newts from Maine were better able to acclimate to low temperature compared to newts from Florida. Regardless of acclimation, the thermal sensitivity of burst speed was higher in the Florida compared to the Maine population. In general, newts from Maine performed better at low temperatures, whereas newts from Florida performed better at high temperatures. The activities of CK and LDH were lower in cold compared to warm-acclimated newts in the Florida population, but acclimation did not affect the activities of these enzymes in the Maine population. The activities of CK and LDH do not explain differences in the thermal plasticity of locomotor performance between populations. Our results demonstrate that the thermal sensitivity and plasticity of locomotor performance differ between northern and southern populations of eastern newts, suggesting that these traits readily adapt to the thermal environment. PMID:25388211

  17. Activation of neurotensin receptor type 1 attenuates locomotor activity.

    PubMed

    Vadnie, Chelsea A; Hinton, David J; Choi, Sun; Choi, YuBin; Ruby, Christina L; Oliveros, Alfredo; Prieto, Miguel L; Park, Jun Hyun; Choi, Doo-Sup

    2014-10-01

    Intracerebroventricular administration of neurotensin (NT) suppresses locomotor activity. However, the brain regions that mediate the locomotor depressant effect of NT and receptor subtype-specific mechanisms involved are unclear. Using a brain-penetrating, selective NT receptor type 1 (NTS1) agonist PD149163, we investigated the effect of systemic and brain region-specific NTS1 activation on locomotor activity. Systemic administration of PD149163 attenuated the locomotor activity of C57BL/6J mice both in a novel environment and in their homecage. However, mice developed tolerance to the hypolocomotor effect of PD149163 (0.1 mg/kg, i.p.). Since NTS1 is known to modulate dopaminergic signaling, we examined whether PD149163 blocks dopamine receptor-mediated hyperactivity. Pretreatment with PD149163 (0.1 or 0.05 mg/kg, i.p.) inhibited D2R agonist bromocriptine (8 mg/kg, i.p.)-mediated hyperactivity. D1R agonist SKF-81297 (8 mg/kg, i.p.)-induced hyperlocomotion was only inhibited by 0.1 mg/kg of PD149163. Since the nucleus accumbens (NAc) and medial prefrontal cortex (mPFC) have been implicated in the behavioral effects of NT, we examined whether microinjection of PD149163 into these regions reduces locomotion. Microinjection of PD149163 (2 pmol) into the NAc, but not the mPFC suppressed locomotor activity. In summary, our results indicate that systemic and intra-NAc activation of NTS1 is sufficient to reduce locomotion and NTS1 activation inhibits D2R-mediated hyperactivity. Our study will be helpful to identify pharmacological factors and a possible therapeutic window for NTS1-targeted therapies for movement disorders. PMID:24929110

  18. Highly Sensitive Measurement of Bio-Electric Potentials by Boron-Doped Diamond (BDD) Electrodes for Plant Monitoring

    PubMed Central

    Ochiai, Tsuyoshi; Tago, Shoko; Hayashi, Mio; Fujishima, Akira

    2015-01-01

    We describe a sensitive plant monitoring system by the detection of the bioelectric potentials in plants with boron-doped diamond (BDD) electrodes. For sensor electrodes, we used commercially available BDD, Ag, and Pt plate electrodes. We tested this approach on a hybrid species in the genus Opuntia (potted) and three different trees (ground-planted) at different places in Japan. For the Opuntia, we artificially induced bioelectric potential changes by the surface potential using the fingers. We detected substantial changes in bioelectric potentials through all electrodes during finger touches on the surface of potted Opuntia hybrid plants, although the BDD electrodes were several times more sensitive to bioelectric potential change compared to the other electrodes. Similarly for ground-planted trees, we found that both BDD and Pt electrodes detected bioelectric potential change induced by changing environmental factors (temperature and humidity) for months without replacing/removing/changing electrodes, BDD electrodes were 5–10 times more sensitive in this detection than Pt electrodes. Given these results, we conclude that BDD electrodes on live plant tissue were able to consistently detect bioelectrical potential changes in plants. PMID:26512663

  19. Highly Sensitive Measurement of Bio-Electric Potentials by Boron-Doped Diamond (BDD) Electrodes for Plant Monitoring.

    PubMed

    Ochiai, Tsuyoshi; Tago, Shoko; Hayashi, Mio; Fujishima, Akira

    2015-01-01

    We describe a sensitive plant monitoring system by the detection of the bioelectric potentials in plants with boron-doped diamond (BDD) electrodes. For sensor electrodes, we used commercially available BDD, Ag, and Pt plate electrodes. We tested this approach on a hybrid species in the genus Opuntia (potted) and three different trees (ground-planted) at different places in Japan. For the Opuntia, we artificially induced bioelectric potential changes by the surface potential using the fingers. We detected substantial changes in bioelectric potentials through all electrodes during finger touches on the surface of potted Opuntia hybrid plants, although the BDD electrodes were several times more sensitive to bioelectric potential change compared to the other electrodes. Similarly for ground-planted trees, we found that both BDD and Pt electrodes detected bioelectric potential change induced by changing environmental factors (temperature and humidity) for months without replacing/removing/changing electrodes, BDD electrodes were 5-10 times more sensitive in this detection than Pt electrodes. Given these results, we conclude that BDD electrodes on live plant tissue were able to consistently detect bioelectrical potential changes in plants. PMID:26512663

  20. The novel recreational drug 3,4-methylenedioxypyrovalerone (MDPV) is a potent psychomotor stimulant: self-administration and locomotor activity in rats.

    PubMed

    Aarde, S M; Huang, P K; Creehan, K M; Dickerson, T J; Taffe, M A

    2013-08-01

    Recreational use of the cathinone derivative 3,4-methylenedioxypyrovalerone (MDPV; "bath salts") has increased worldwide in past years, accompanied by accounts of health and legal problems in the popular media and efforts to criminalize possession in numerous jurisdictions. Minimal information exists on the effects of MDPV in laboratory models. This study determined the effects of MDPV, alongside those of the better studied stimulant d-methamphetamine (METH), using rodent models of intravenous self-administration (IVSA), thermoregulation and locomotor activity. Male Wistar rats were trained to self-administer MDPV or METH (0.05 mg/kg/infusion, i.v.) or were prepared with radiotelemetry implants for the assessment of body temperature and activity responses to MDPV or METH (0-5.6 mg/kg s.c.). METH and MDPV were consistently self-administered within 10 training sessions (mg/kg/h; METH Mean = 0.4 and Max = 1.15; MDPV Mean = 0.9 and Max = 5.8). Dose-substitution studies demonstrated that behavior was sensitive to dose for both drugs, but MDPV (0.01-0.50 mg/kg/inf) showed greater potency and efficacy than METH (0.1-0.25 mg/kg/inf). In addition, both MDPV and METH increased locomotor activity at lower doses (0.5-1.0 mg/kg, s.c.) and transiently decreased activity at the highest dose (5.6 mg/kg, s.c.). Body temperature increased monotonically with increasing doses of METH but MDPV had a negligible effect on temperature. Stereotypy was associated with relatively high self-administered cumulative doses of MDPV (∼1.5 mg/kg/h) as well as with non-contingent MDPV administration wherein the intensity and duration of stereotypy increased as MDPV dose increased. Thus, MDPV poses a substantial threat for compulsive use that is potentially greater than that for METH. PMID:23597511

  1. Do group responses mask the effects of air pollutants on potentially sensitive individuals in controlled human exposure studies?

    PubMed

    Goodman, Julie E; Seeley, Mara; Mattuck, Rosemary; Thakali, Sagar

    2015-04-01

    To establish primary National Ambient Air Quality Standards (NAAQS) for criteria air pollutants such as nitrogen dioxide (NO2), ozone (O3), and sulfur dioxide (SO2), US EPA relies in part on controlled human exposure studies. It has been suggested that evaluating average responses for all participants in these studies may not reflect the responses of sensitive participants in these studies. To evaluate this, we identified controlled exposure studies with multiple exposure concentrations or durations that provided individual-level lung function data. Based on individual lung function responses at specific exposure concentrations and the slope of individual concentration-response curves, we identified 12 participants out of a total of 208 participants in 12 studies who were potentially sensitive to O3, SO2, or sulfuric acid (H2SO4). We did not identify any participants sensitive to NO2. All of these participants were found to be potentially sensitive only at concentrations that were well above the NAAQS (SO2), above likely ambient concentrations (H2SO4), or at concentrations at which the study reported significant lung function effects for all participants (O3). Based on our analysis, average responses for all participants combined adequately reflect lung function responses for potentially sensitive study participants at concentrations in the range of the current NAAQS. PMID:25667955

  2. Establishment of a novel experimental protocol for drug-induced seizure liability screening based on a locomotor activity assay in zebrafish.

    PubMed

    Koseki, Naoteru; Deguchi, Jiro; Yamashita, Akihito; Miyawaki, Izuru; Funabashi, Hitoshi

    2014-08-01

    As drug-induced seizures have severe impact on drug development, evaluating seizure induction potential of candidate drugs at the early stages of drug discovery is important. A novel assay system using zebrafish has attracted interest as a high throughput toxicological in vivo assay system, and we tried to establish an experimental method for drug-induced seizure liability on the basis of locomotor activity in zebrafish. We monitored locomotor activity at high-speed movement (> 20 mm/sec) for 60 min immediately after exposure, and assessed seizure liability potential in some drugs using locomotor activity. However this experimental procedure was not sufficient for predicting seizures because the potential of several drugs with demonstrated seizure potential in mammals was not detected. We, therefore, added other parameters for locomotor activity such as extending exposure time or conducting flashlight stimulation (10 Hz) which is a known seizure induction stimulus, and these additional parameters improved seizure potential detection in some drugs. The validation study using the improved methodology was used to assess 52 commercially available drugs, and the prediction rate was approximately 70%. The experimental protocol established in this present study is considered useful for seizure potential screening during early stages of drug discovery. PMID:25056783

  3. Climbing on the cage lid, a regular component of locomotor activity in the mouse.

    PubMed

    Büttner, D

    1991-01-01

    The aim of the study was to obtain base values of climbing behaviour in mice maintained under standardized conditions in Makrolon-cages. Therefore three adult male mice each of the inbred strains BALB/cJ and C57BL/6J were kept separately and two C57BL/6J females as a group in Makrolon-cages type III. In addition, the same BALB/c mice were later kept in a cage with an eightfold floor area. Behavioural observations were carried out by video technique using a light-sensitive camera and a time-lapse recorder. Locomotor activity on the cage floor and climbing on the top of the cage were measured over a period of 48 h for each animal. The duration of locomotion on the ground ranged from 24-65 min/day, climbing between 49-122 (males) and 159 min/day (females) respectively. Climbing showed a more pronounced daily periodicity than locomotion, especially in the case of the BALB/cJ strain, where the average duration of climbing was about 28 min/h during the first hour after light off. In the mouse, climbing is obviously a regular component of activity, which deserves not only attention in the discussion concerning the needs of laboratory animals, but also in measurements of locomotor activity. PMID:1814462

  4. Differentiating Event-Related Potential Components Sensitive to Emotion in Middle Childhood: Evidence from Temporal-Spatial PCA

    PubMed Central

    Kujawa, Autumn; Weinberg, Anna; Hajcak, Greg; Klein, Daniel N.

    2012-01-01

    Event-related potentials (ERPs) may be particularly useful for examining emotional processing across development. Though a number of ERP components are sensitive to emotional content in adults, previous studies have yet to systematically examine the components sensitive to emotion in children. The current study used temporal-spatial principal components analysis (PCA) to identify ERP components in response to complex emotional images in nine-year-old children. Three components were modulated by emotional content and were similar to those previously observed in adults, including: the early posterior negativity, the P300, and a sustained relative positivity similar to the late positive potential (LPP). Compared to those previously observed in adults, the components sensitive to emotion in children were maximal over more occipital regions and the LPP component appeared to be less protracted in time, perhaps indicative of less elaborative processing of emotional stimuli. PMID:22692816

  5. Assessment of the Sensitizing Potential of Processed Peanut Proteins in Brown Norway Rats: Roasting Does Not Enhance Allergenicity

    PubMed Central

    Kroghsbo, Stine; Rigby, Neil M.; Johnson, Philip E.; Adel-Patient, Karine; Bøgh, Katrine L.; Salt, Louise J.; Mills, E. N. Clare; Madsen, Charlotte B.

    2014-01-01

    Background IgE-binding of process-modified foods or proteins is the most common method for examination of how food processing affects allergenicity of food allergens. How processing affects sensitization capacity is generally studied by administration of purified food proteins or food extracts and not allergens present in their natural food matrix. Objectives The aim was to investigate if thermal processing increases sensitization potential of whole peanuts via the oral route. In parallel, the effect of heating on sensitization potential of the major peanut allergen Ara h 1 was assessed via the intraperitoneal route. Methods Sensitization potential of processed peanut products and Ara h 1 was examined in Brown Norway (BN) rats by oral administration of blanched or oil-roasted peanuts or peanut butter or by intraperitoneal immunization of purified native (N-), heated (H-) or heat glycated (G-)Ara h 1. Levels of specific IgG and IgE were determined by ELISA and IgE functionality was examined by rat basophilic leukemia (RBL) cell assay. Results In rats dosed orally, roasted peanuts induced significant higher levels of specific IgE to NAra h 1 and 2 than blanched peanuts or peanut butter but with the lowest level of RBL degranulation. However, extract from roasted peanuts was found to be a superior elicitor of RBL degranulation. Process-modified Ara h 1 had similar sensitizing capacity as NAra h 1 but specific IgE reacted more readily with process-modified Ara h 1 than with native. Conclusions Peanut products induce functional specific IgE when dosed orally to BN rats. Roasted peanuts do not have a higher sensitizing capacity than blanched peanuts. In spite of this, extract from roasted peanuts is a superior elicitor of RBL cell degranulation irrespectively of the peanut product used for sensitization. The results also suggest that new epitopes are formed or disclosed by heating Ara h 1 without glucose. PMID:24805813

  6. Conditioned place preference and locomotor activity in response to methylphenidate, amphetamine and cocaine in mice lacking dopamine D4 receptors

    SciTech Connect

    Thanos, P.K.; Thanos, P.K.; Bermeo, C.; Rubinstein, M.; Suchland, K.L.; Wang, G.-J.; Grandy, D.K.; Volkow, N.D.

    2010-05-01

    Methylphenidate (MP) and amphetamine (AMPH) are the most frequently prescribed medications for the treatment of attention-deficit/hyperactivity disorder (ADHD). Both drugs are believed to derive their therapeutic benefit by virtue of their dopamine (DA)-enhancing effects, yet an explanation for the observation that some patients with ADHD respond well to one medication but not to the other remains elusive. The dopaminergic effects of MP and AMPH are also thought to underlie their reinforcing properties and ultimately their abuse. Polymorphisms in the human gene that codes for the DA D4 receptor (D4R) have been repeatedly associated with ADHD and may correlate with the therapeutic as well as the reinforcing effects of responses to these psychostimulant medications. Conditioned place preference (CPP) for MP, AMPH and cocaine were evaluated in wild-type (WT) mice and their genetically engineered littermates, congenic on the C57Bl/6J background, that completely lack D4Rs (knockout or KO). In addition, the locomotor activity in these mice during the conditioning phase of CPP was tested in the CPP chambers. D4 receptor KO and WT mice showed CPP and increased locomotor activity in response to each of the three psychostimulants tested. D4R differentially modulates the CPP responses to MP, AMPH and cocaine. While the D4R genotype affected CPP responses to MP (high dose only) and AMPH (low dose only) it had no effects on cocaine. Inasmuch as CPP is considered an indicator of sensitivity to reinforcing responses to drugs these data suggest a significant but limited role of D4Rs in modulating conditioning responses to MP and AMPH. In the locomotor test, D4 receptor KO mice displayed attenuated increases in AMPH-induced locomotor activity whereas responses to cocaine and MP did not differ. These results suggest distinct mechanisms for D4 receptor modulation of the reinforcing (perhaps via attenuating dopaminergic signalling) and locomotor properties of these stimulant drugs

  7. Right Hemisphere Sensitivity to Word- and Sentence-Level Context: Evidence From Event-Related Brain Potentials

    ERIC Educational Resources Information Center

    Coulson, Seana; Federmeier, Kara D.; Van Petten, Cyma; Kutas, Marta

    2005-01-01

    Researchers using lateralized stimuli have suggested that the left hemisphere is sensitive to sentence-level context, whereas the right hemisphere (RH) primarily processes word-level meaning. The authors investigated this message-blind RH model by measuring associative priming with event-related brain potentials (ERPs). For word pairs in…

  8. Growth Differentiation Factor-15 (GDF-15) is a potential marker of radiation response and radiation sensitivity.

    PubMed

    Sándor, Nikolett; Schilling-Tóth, Boglárka; Kis, Enikő; Benedek, Anett; Lumniczky, Katalin; Sáfrány, Géza; Hegyesi, Hargita

    2015-11-01

    We have investigated the importance of GDF-15 (secreted cytokine belonging to the TGF-β superfamily) in low and high dose radiation-induced cellular responses. A telomerase immortalized human fibroblast cell line (F11hT) was used in the experiments. A lentiviral system encoding small hairpin RNAs (shRNA) was used to establish GDF-15 silenced cells. Secreted GDF-15 levels were measured in culture medium by ELISA. Cell cycle analysis was performed by flow cytometry. The experiments demonstrated that in irradiated human fibroblasts GDF-15 expression increased with dose starting from 100mGy. Elevated GDF-15 expression was not detected in bystander cells. The potential role of GDF-15 in radiation response was investigated by silencing GDF-15 in immortalized human fibroblasts with five different shRNA encoded in lentiviral vectors. Cell lines with considerably reduced GDF-15 levels presented increased radiation sensitivity, while a cell line with elevated GDF-15 was more radiation resistant than wild type cells. We have investigated how the reduced GDF-15 levels alter the response of several known radiation inducible genes. In F11hT-shGDF-15 cells the basal expression level of CDKN1A was unaltered relative to F11hT cells, while GADD45A and TGF-β1 mRNA levels were slightly higher, and TP53INP1 was considerably reduced. The radiation-induced expression of TP53INP1 was lower in the silenced than in wild type fibroblast cells. Cell cycle analysis indicated that radiation-induced early G2/M arrest was abrogated in GDF-15 silenced cells. Moreover, radiation-induced bystander effect was less pronounced in GDF-15 silenced fibroblasts. In conclusion, the results suggest that GDF-15 works as a radiation inducible radiation resistance increasing factor in normal human fibroblast cells, acts by regulating the radiation-induced transcription of several genes and might serve as a radiation-induced early biomarker in exposed cells. PMID:26520384

  9. Enhanced locomotor adaptation aftereffect in the “broken escalator” phenomenon using anodal tDCS

    PubMed Central

    Kaski, D.; Quadir, S.; Patel, M.; Yousif, N.

    2012-01-01

    The everyday experience of stepping onto a stationary escalator causes a stumble, despite our full awareness that the escalator is broken. In the laboratory, this “broken escalator” phenomenon is reproduced when subjects step onto an obviously stationary platform (AFTER trials) that was previously experienced as moving (MOVING trials) and attests to a process of motor adaptation. Given the critical role of M1 in upper limb motor adaptation and the potential for transcranial direct current stimulation (tDCS) to increase cortical excitability, we hypothesized that anodal tDCS over leg M1 and premotor cortices would increase the size and duration of the locomotor aftereffect. Thirty healthy volunteers received either sham or real tDCS (anodal bihemispheric tDCS; 2 mA for 15 min at rest) to induce excitatory effects over the primary motor and premotor cortex before walking onto the moving platform. The real tDCS group, compared with sham, displayed larger trunk sway and increased gait velocity in the first AFTER trial and a persistence of the trunk sway aftereffect into the second AFTER trial. We also used transcranial magnetic stimulation to probe changes in cortical leg excitability using different electrode montages and eyeblink conditioning, before and after tDCS, as well as simulating the current flow of tDCS on the human brain using a computational model of these different tDCS montages. Our data show that anodal tDCS induces excitability changes in lower limb motor cortex with resultant enhancement of locomotor adaptation aftereffects. These findings might encourage the use of tDCS over leg motor and premotor regions to improve locomotor control in patients with neurological gait disorders. PMID:22323638

  10. An innovative spinal cord injury model for the study of locomotor networks.

    PubMed

    Nistri, A

    2012-03-01

    An acute lesion to the spinal cord triggers complex mechanisms responsible for amplification of the initial damage and its chronicity. In vitro preparations of the rodent spinal cord retain the intrinsic ability to produce locomotor-like discharges from lumbar ventral roots and, thus, offer the opportunity to study the still unclear process of lesion progression in relation to cell number and topography. In addition, these models enable a detailed approach to the molecular mechanisms of damage and to pharmacological tools to counteract them. Using the rat spinal cord in vitro, our laboratory has shown how to reliably produce discrete lesions by applying the glutamate agonist kainate that evokes delayed neuronal loss via a non-apoptotic cell death mechanism termed parthanatos. Parthanatos is believed to be due to mitochondrial damage and exhaustion of cell energy stores caused by hyperactivation of enzymatic systems initially set to repair DNA damage. Locomotor network activity is irreversibly destroyed by kainate in a virtually all-or-none manner, suggesting destruction of a highly-vulnerable cell population crucial for the expression of locomotion. Hypoxic challenge to the spinal cord together with toxic radicals primarily damages white matter cells with deficit (without full suppression) of locomotor network function, while neurons are less vulnerable. Pharmacological agents to inhibit different targets involved in the early pathophysiology of spinal injury provided limited success, indicating that novel approaches based on newly identified steps in the biochemical cascade leading to cell death should be investigated for their potential to improve the outcome of spinal cord injury. PMID:22407008

  11. Cross-sensitization between cocaine and acute restraint stress is associated with sensitized dopamine but not glutamate release in the nucleus accumbens.

    PubMed

    Garcia-Keller, C; Martinez, S A; Esparza, M A; Bollati, F; Kalivas, P W; Cancela, L M

    2013-03-01

    Repeated administration of psychostimulant drugs or stress can elicit a sensitized response to the stimulating and reinforcing properties of the drug. Here we explore the mechanisms in the nucleus accumbens (NAc) whereby an acute restraint stress augments the acute locomotor response to cocaine. This was accomplished by a combination of behavioral pharmacology, microdialysis measures of extracellular dopamine and glutamate, and Western blotting for GluR1 subunit of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor (AMPAR). A single exposure to restraint stress 3 weeks before testing revealed that enduring locomotor sensitization to cocaine was paralleled by an increase in extracellular dopamine in the core, but not the shell subcompartment, of the NAc. Wistar rats pre-exposed to acute stress showed increased basal levels of glutamate in the core, but the increase in glutamate by acute cocaine was blunted. The alterations in extracellular glutamate seem to be relevant, as blocking AMPAR by 6-cyano-7-nitroquinoxaline-2,3-dione microinjection into the core prevented both the behavioral cross-sensitization and the augmented increase in cocaine-induced extracellular dopamine. Further implicating glutamate, the locomotor response to AMPAR stimulation in the core was potentiated, but not in the shell of pre-stressed animals, and this was accompanied by an increase in NAc GluR1 surface expression. This study provides evidence that the long-term expression of restraint stress-induced behavioral cross-sensitization to cocaine recapitulates some mechanisms thought to underpin the sensitization induced by daily cocaine administration, and shows that long-term neurobiological changes induced in the NAc by acute stress are consequential in the expression of cross-sensitization to cocaine. PMID:23360446

  12. Low and high cocaine locomotor responding male Sprague-Dawley rats differ in rapid cocaine-induced regulation of striatal dopamine transporter function.

    PubMed

    Mandt, Bruce H; Zahniser, Nancy R

    2010-03-01

    Adult outbred Sprague-Dawley rats can be classified as either low or high cocaine responders (LCRs or HCRs, respectively). Importantly, LCRs and HCRs are distinguished by their differential responsiveness to acute cocaine-induced (but not baseline) locomotor activity, inhibition of the dopamine transporter (DAT) and resulting extracellular DA (HCR > LCR), as well as by repeated cocaine-induced locomotor sensitization and measures of cocaine's rewarding and reinforcing effects (LCR > HCR). Curiously, 30 min after acute cocaine HCRs exhibit greater DAT-mediated [(3)H]DA uptake into striatal synaptosomes than LCRs. To investigate this finding further, we measured locomotor activity, striatal [(3)H]DA uptake kinetics and DAT cell surface expression in LCRs and HCRs over an extended period (25-180 min) after a single relatively low-dose of cocaine (10 mg/kg, i.p.). HCRs exhibited the "predicted" locomotor response: a marked initial activation that returned to baseline by 120 min post-injection. While LCRs exhibited a >50% lower maximal locomotor response, this increase was sustained, lasting approximately 33% longer than in HCRs. At 25 min post-cocaine, maximal velocity (V(max)) of [(3)H]DA uptake was significantly higher by 25% in HCRs than LCRs, with no difference in affinity (K(m)). Despite the DAT V(max) difference, however, DAT surface expression did not differ between LCRs and HCRs. There was a similar trend (HCR > LCR) for DAT V(max) at 40 min, but not at 150 or 180 min. These findings suggest that, compared to LCRs, HCRs have an enhanced ability to rapidly up-regulate DAT function in response to acute cocaine, which may contribute to their more "normal" cocaine-induced locomotor activation. PMID:19951714

  13. Direct and Indirect 5-HT receptor agonists produce gender-specific effects on locomotor and vertical activity in C57 BL/6J mice

    PubMed Central

    Brookshire, Bethany R.; Jones, Sara R.

    2009-01-01

    It is well established that the dopamine (DA) and serotonin (5-HT) systems have extensive and complex interactions. However, the effects of specific 5-HT receptor agonists on traditionally DA-related behaviors remain unclear. Our goal in these studies was to characterize the effects of 5-HT receptor agonists on measures of locomotor activity and vertical rearing. The SSRIs fluoxetine and citalopram produced significant decreases in locomotor activity and vertical rearing at the highest doses used with females significant more sensitive to citalopram. The 5-HT1A agonist 8-OH-DPAT and the 5-HT2C agonist MK 212 significantly decreased activity in both male and female mice, with females more sensitive to 8-OH-DPAT. In contrast, the 5-HT1B agonist RU 24969 and the 5-HT2A agonist DOI both increased activity, with DOI exhibiting differential effects with regard to sex. Finally, the 5-HT3 agonist SR 57227 produced significant locomotor increases only in female mice at the lowest dose. The results of these experiments define locomotor profiles of several 5-HT agonists in male and female C57BL/6J mice, providing a foundation for further explorations of 5-HT receptor effects on activity. PMID:19698737

  14. Neurotransmitter systems of the medial prefrontal cortex: potential role in sensitization to psychostimulants.

    PubMed

    Steketee, Jeffery D

    2003-03-01

    The mesocorticolimbic dopamine system, which arises in the ventral tegmental area and innervates the nucleus accumbens, among numerous other regions, has been implicated in processes associated with drug addiction, including behavioral sensitization. Behavioral sensitization is the enhanced motor-stimulant response that occurs with repeated exposure to psychostimulants. The medial prefrontal cortex (mPFC), defined as the cortical region that has a reciprocal innervation with the mediodorsal nucleus of the thalamus, is also a terminal region of the mesocorticolimbic dopamine system. The mPFC contains pyramidal glutamatergic neurons that serve as the primary output of this region. These pyramidal neurons are modulated by numerous neurotransmitter systems, including gamma-aminobutyric acidergic interneurons and dopaminergic, noradrenergic, serotonergic, glutamatergic, cholinergic and peptidergic afferents. Changes in interactions between these various neurotransmitter systems in the mPFC may lead to alterations in behavioral responses. For example, recent studies have demonstrated a role for decreased mPFC dopaminergic transmission in the development of psychostimulant-induced behavioral sensitization. The present review will discuss the anatomical organization of the mPFC including descriptions of innervation patterns and receptor localization of the various neurotransmitter systems of this region. Data supporting or suggesting a role for each of these mPFC transmitter systems in the development of behavioral sensitization to cocaine and amphetamine will be presented. Finally a model of the mPFC that may be useful in directing future research efforts on the cortical mechanisms involved in the development of sensitization will be proposed. PMID:12663081

  15. Heteromeric Heat-sensitive Transient Receptor Potential Channels Exhibit Distinct Temperature and Chemical Response*

    PubMed Central

    Cheng, Wei; Yang, Fan; Liu, Shuang; Colton, Craig K.; Wang, Chunbo; Cui, Yuanyuan; Cao, Xu; Zhu, Michael X.; Sun, Changsen; Wang, KeWei; Zheng, Jie

    2012-01-01

    TRPV1 and TRPV3 are two heat-sensitive ion channels activated at distinct temperature ranges perceived by human as hot and warm, respectively. Compounds eliciting human sensations of heat or warmth can also potently activate these channels. In rodents, TRPV3 is expressed predominantly in skin keratinocytes, whereas in humans TRPV1 and TRPV3 are co-expressed in sensory neurons of dorsal root ganglia and trigeminal ganglion and are known to form heteromeric channels with distinct single channel conductances as well as sensitivities to TRPV1 activator capsaicin and inhibitor capsazepine. However, how heteromeric TRPV1/TRPV3 channels respond to heat and other stimuli remains unknown. In this study, we examined the behavior of heteromeric TRPV1/TRPV3 channels activated by heat, capsaicin, and voltage. Our results demonstrate that the heteromeric channels exhibit distinct temperature sensitivity, activation threshold, and heat-induced sensitization. Changes in gating properties apparently originate from interactions between TRPV1 and TRPV3 subunits. Our results suggest that heteromeric TRPV1/TRPV3 channels are unique heat sensors that may contribute to the fine-tuning of sensitivity to sensory inputs. PMID:22184123

  16. The skin sensitization potential of resorcinol: experience with the local lymph node assay.

    PubMed

    Basketter, David A; Sanders, David; Jowsey, Ian R

    2007-04-01

    Resorcinol is a simple aromatic chemical (1,3-benzenediol) that has found widespread use, particularly as a coupler in hair dyes. Clinical experience clearly shows that resorcinol is a (albeit uncommon) skin sensitizer. By contrast, predictive methods, both animal and human, have previously failed to identify resorcinol as such. Here, we describe the outcome of a recent local lymph node assay performed in accordance with Organisation for Economic Co-operation and Development guideline 429, which correctly identified resorcinol as a skin sensitizer. Clear evidence of a dose response was apparent, and an EC3 value of approximately 6% was calculated. This suggests that the skin-sensitizing potency of resorcinol is approximately 2 orders of magnitude lower than that of p-phenylenediamine but similar to that of hexyl cinnamic aldehyde. These data show the importance of adherence to test guidelines and aligns the clinical experience with resorcinol with that obtained in predictive animal methods. PMID:17343618

  17. Gluten Sensitivity – A Potentially Reversible Cause of Progressive Cerebellar Ataxia and Myoclonus - A Case Report

    PubMed Central

    Bohra, Vikram; Duggal, Ashish; Ghuge, Vijay V; Chaudhary, Neera

    2015-01-01

    Gluten sensitivity is an umbrella term used for diverse clinical manifestations occurring as a result of abnormal immunological reactivity to dietary gluten in genetically susceptible individuals. Celiac disease is the most well-known but not the only manifestation of gluten sensitivity. Myoclonus with Ataxia is a rare manifestation of gluten sensitivity and should be considered in the differential diagnosis of all patients with idiopathic sporadic ataxia. The presence of gluten-related immune markers in normal population however complicates the reliable diagnosis of gluten related neurological disorders and clinical improvement on gluten free diet can serve as a diagnostic tool for this disease. We report a case of sporadic progressive cerebellar ataxia with myoclonus with positive antigliadin antibodies, which improved with a trial of gluten free diet. This case highlights an important diagnostic and therapeutic principle in management of late onset idiopathic ataxia. PMID:26673942

  18. Potential Roles of Amiloride-Sensitive Sodium Channels in Cancer Development

    PubMed Central

    Xu, Siguang; Liu, Cui; Ma, Yana; Ji, Hong-Long; Li, Xiumin

    2016-01-01

    The ENaC/degenerin ion channel superfamily includes the amiloride-sensitive epithelial sodium channel (ENaC) and acid sensitive ionic channel (ASIC). ENaC is a multimeric ion channel formed by heteromultimeric membrane glycoproteins, which participate in a multitude of biological processes by mediating the transport of sodium (Na+) across epithelial tissues such as the kidney, lungs, bladder, and gut. Aberrant ENaC functions contribute to several human disease states including pseudohypoaldosteronism, Liddle syndrome, cystic fibrosis, and salt-sensitive hypertension. Increasing evidence suggests that ion channels not only regulate ion homeostasis and electric signaling in excitable cells but also play important roles in cancer cell behaviors such as proliferation, apoptosis, invasion, and migration. Indeed, ENaCs/ASICs had been reported to be associated with cancer characteristics. Given their cell surface localization and pharmacology, pharmacological strategies to target ENaC/ASIC family members may be promising cancer therapeutics. PMID:27403419

  19. Potential Roles of Amiloride-Sensitive Sodium Channels in Cancer Development.

    PubMed

    Xu, Siguang; Liu, Cui; Ma, Yana; Ji, Hong-Long; Li, Xiumin

    2016-01-01

    The ENaC/degenerin ion channel superfamily includes the amiloride-sensitive epithelial sodium channel (ENaC) and acid sensitive ionic channel (ASIC). ENaC is a multimeric ion channel formed by heteromultimeric membrane glycoproteins, which participate in a multitude of biological processes by mediating the transport of sodium (Na(+)) across epithelial tissues such as the kidney, lungs, bladder, and gut. Aberrant ENaC functions contribute to several human disease states including pseudohypoaldosteronism, Liddle syndrome, cystic fibrosis, and salt-sensitive hypertension. Increasing evidence suggests that ion channels not only regulate ion homeostasis and electric signaling in excitable cells but also play important roles in cancer cell behaviors such as proliferation, apoptosis, invasion, and migration. Indeed, ENaCs/ASICs had been reported to be associated with cancer characteristics. Given their cell surface localization and pharmacology, pharmacological strategies to target ENaC/ASIC family members may be promising cancer therapeutics. PMID:27403419

  20. Locomotor, discriminative stimulus, and place conditioning effects of MDAI in rodents.

    PubMed

    Gatch, Michael B; Dolan, Sean B; Forster, Michael J

    2016-09-01

    5,6-Methylenedioxy-2-aminoindane (MDAI) has become a common substitute for (±)-3,4-methylenedioxymethamphetamine (MDMA) in Ecstasy. MDAI is known to produce MDMA-like discriminative stimulus effects, but it is not known whether MDAI has psychostimulant or hallucinogen-like effects. MDAI was tested for locomotor stimulant effects in mice and subsequently for discriminative stimulus effects in rats trained to discriminate cocaine (10 mg/kg, intraperitoneally), methamphetamine (1 mg/kg, intraperitoneally), ±MDMA (1.5 mg/kg, intraperitoneally), or (-)-2,5-dimethoxy-4-methylamphetamine hydrochloride (0.5 mg/kg, intraperitoneally) from saline. The ability of MDAI to produce conditioned place preference was also tested in mice. MDAI (3 to 30 mg/kg) depressed locomotor activity from 10 to 60 min. A rebound stimulant effect was observed at 1 to 3.5 h following 30 mg/kg. Lethality occurred in 8/8 mice following 100 mg/kg MDAI. Similarly, MDMA depressed locomotor activity immediately following the administration of 0.25 mg/kg and stimulant effects were observed 50-70 min following the administration of 0.5 and 1 mg/kg. MDAI fully substituted for the discriminative stimulus effects of MDMA (2.5 mg/kg), (-)-2,5-dimethoxy-4-methylamphetamine hydrochloride (5 mg/kg), and cocaine (7.5 mg/kg), but produced only 73% methamphetamine-appropriate responding at a dose that suppressed responding (7.5 mg/kg). MDAI produced tremors at 10 mg/kg in one methamphetamine-trained rat. MDAI produced conditioned place preference from 0.3 to 10 mg/kg. The effects of MDAI on locomotor activity and drug discrimination were similar to those produced by MDMA, having both psychostimulant-like and hallucinogen-like effects; thus, MDAI may have similar abuse potential as MDMA. PMID:27028902

  1. Contact sensitizing potential of pyrogallol and 5-amino-o-cresol in female BALB/c mice.

    PubMed

    Guo, T L; Germolec, D R; Zhang, Ling X; Auttachoat, W; Smith, M J; White, K L

    2013-12-15

    Hair dye components such as pyrogallol and cresol have been shown previously to promote allergic reactions such as rashes, dermal inflammation, irritation and dermatitis. The objective of this study was to determine the contact sensitization potential of pyrogallol (PYR) and 5-amino-o-cresol (AOC) when applied dermally to female BALB/c mice. Measurement of the contact hypersensitivity response was initially accomplished using the local lymph node assay. For PYR, significant increases in the proliferation of lymph node cells were observed at concentrations of 0.5% (w/v) and higher. For AOC, borderline increases, albeit significant, in auricular lymph node cell proliferation were observed at 5% and 10%. Results from the irritancy assay suggested that PYR, but not AOC, was an irritant. To further delineate whether PYR was primarily an irritant or a contact sensitizer, the mouse ear swelling test (MEST) was conducted. A significant increase in mouse ear thickness was observed at 72h following challenge with 0.5% PYR in mice that had been sensitized with 5% PYR. In contrast, no effects were observed in the MEST in mice sensitized and challenged with the highest achievable concentration of AOC (10%). Additional studies examining lymph node subpopulations and CD86 (B7.2) expression by B cells further support the indication that PYR was a sensitizer in BALB/c mice. The results demonstrate that PYR is both a sensitizer and an irritant in female BALB/c mice. However, the contact sensitization potential of AOC is minimal in this strain of mouse. PMID:24172597

  2. Determination of the interatomic potential from elastic differential cross sections at fixed energy: Functional sensitivity analysis approach

    SciTech Connect

    Ho, T.; Rabitz, H.

    1989-02-01

    Elastic differential cross sections in atomic crossed beam experiments contain detailed information about the underlying interatomic potentials. The functional sensitivity density of the cross sections with respect to the potential deltasigma(theta)/deltaV(R) reveals such information and has been implemented in an iterative inversion procedure, analogous to that of the Newton--Raphson technique. The stability of the inversion is achieved with the use of the regularization method of Tikhonov and Miller. It is shown that given a set of well resolved and noise-free differential cross section data within a limited angular range and given a reasonable starting reference potential, the recovered potential accurately resembles the desired one in the important region, i.e., the region to which the scattering data are sensitive. The region of importance depends upon the collision energy relative to the well depth of the potential under study; usually a higher collision energy penetrates deeper into the repulsive part of the potential and thus accordingly yields a more accurate potential in that part. The inversion procedure produces also a quality function indicating the well determined radial region. Moreover, the extracted potential is quite independent of the functional form of the reference potential in contrast to curve fitting approaches. As illustrations, the model inert gas systems He--Ne and Ne--Ar have been considered. For collision energies within an order of magnitude of the associated potential well depth, the attractive part of the potential can be determined to high precision provided that scattering data at small enough angles are available.

  3. Anti-HLA sensitization in extensively burned patients: extent, associated factors, and reduction in potential access to vascularized composite allotransplantation.

    PubMed

    Duhamel, Patrick; Suberbielle, Caroline; Grimbert, Philippe; Leclerc, Thomas; Jacquelinet, Christian; Audry, Benoit; Bargues, Laurent; Charron, Dominique; Bey, Eric; Lantieri, Laurent; Hivelin, Mikael

    2015-05-01

    Extensively burned patients receive iterative blood transfusions and skin allografts that often lead to HLA sensitization, and potentially impede access to vascularized composite allotransplantation (VCA). In this retrospective, single-center study, anti-HLA sensitization was measured by single-antigen-flow bead analysis in patients with deep, second- and third-degree burns over ≥40% total body surface area (TBSA). Association of HLA sensitization with blood transfusions, skin allografts, and pregnancies was analyzed by bivariate analysis. The eligibility for transplantation was assessed using calculated panel reactive antibodies (cPRA). Twenty-nine patients aged 32 ± 14 years, including 11 women, presented with a mean burned TBSA of 54 ± 11%. Fifteen patients received skin allografts, comprising those who received cryopreserved (n = 3) or glycerol-preserved (n = 7) allografts, or both (n = 5). An average 36 ± 13 packed red blood cell (PRBC) units were transfused per patient. In sera samples collected 38 ± 13 months after the burns, all patients except one presented with anti-HLA antibodies, of which 13 patients (45%) had complement-fixing antibodies. Eighteen patients (62%) were considered highly sensitized (cPRA≥85%). Cryopreserved, but not glycerol-preserved skin allografts, history of pregnancy, and number of PRBC units were associated with HLA sensitization. Extensively burned patients may become highly HLA sensitized during acute care and hence not qualify for VCA. Alternatives to skin allografts might help preserve their later access to VCA. PMID:25683513

  4. Force wave transmission through the human locomotor system.

    PubMed

    Voloshin, A; Wosk, J; Brull, M

    1981-02-01

    A method to measure the capability of the human shock absorber system to attenuate input dynamic loading during the gait is presented. The experiments were carried out with two groups: healthy subjects and subjects with various pathological conditions. The results of the experiments show a considerable difference in the capability of each group's shock absorbers to attenuate force transmitted through the locomotor system. Comparison shows that healthy subjects definitely possess a more efficient shock-absorbing capacity than do those subjects with joint disorders. Presented results show that degenerative changes in joints reduce their shock absorbing capacity, which leads to overloading of the next shock absorber in the locomotor system. So, the development of osteoarthritis may be expected to result from overloading of a shock absorber's functional capacity. PMID:7253613

  5. Direction-dependent spectral sensitivity and interaural spectral difference in a dolphin: evoked potential study.

    PubMed

    Supin AYa; Popov, V V

    1993-06-01

    Sensitivity and interaural intensity difference (IID) dependence on sound frequency and direction was measured in an Amazon river dolphin Inia geoffrensis by recording the auditory nerve evoked response from the body surface. The maximal sensitivity in the horizontal plane was found when the sound direction was 5 degrees to 10 degrees ipsilateral to the recorded ear; the direction dependence of sensitivity was more pronounced at higher frequencies than at lower ones. The IID reached its peak at small azimuthal angles (7.5 degrees to 15 degrees) and higher sound frequencies (100 kHz), or at large azimuthal angles (30 degrees to 45 degrees) and lower sound frequencies (20 to 30 kHz). Each sound direction featured its specific pattern of spectral sensitivity and of interaural spectral difference. The interaural spectral difference fluctuated within a range of more than 20 dB depending on sound direction. The data indicate that interaural intensity as well as spectral difference may be cues for binaural localization of sound direction by dolphins. PMID:8326074

  6. Structural and effective connectivity reveals potential network-based influences on category-sensitive visual areas

    PubMed Central

    Furl, Nicholas

    2015-01-01

    Visual category perception is thought to depend on brain areas that respond specifically when certain categories are viewed. These category-sensitive areas are often assumed to be “modules” (with some degree of processing autonomy) and to act predominantly on feedforward visual input. This modular view can be complemented by a view that treats brain areas as elements within more complex networks and as influenced by network properties. This network-oriented viewpoint is emerging from studies using either diffusion tensor imaging to map structural connections or effective connectivity analyses to measure how their functional responses influence each other. This literature motivates several hypotheses that predict category-sensitive activity based on network properties. Large, long-range fiber bundles such as inferior fronto-occipital, arcuate and inferior longitudinal fasciculi are associated with behavioral recognition and could play crucial roles in conveying backward influences on visual cortex from anterior temporal and frontal areas. Such backward influences could support top-down functions such as visual search and emotion-based visual modulation. Within visual cortex itself, areas sensitive to different categories appear well-connected (e.g., face areas connect to object- and motion sensitive areas) and their responses can be predicted by backward modulation. Evidence supporting these propositions remains incomplete and underscores the need for better integration of DTI and functional imaging. PMID:25999841

  7. The ratios of partition functions at different temperatures - Sensitivity to potential energy shape II

    NASA Astrophysics Data System (ADS)

    Buchowiecki, Marcin

    2016-05-01

    The ratios of partition functions at different temperatures are calculated and its dependence on potential energy shape is analyzed. The role of anharmonicity and non-rigidity of rotations is discussed in the context of the angular frequency and the shape of potential energy curve. A role of inflection point of potential energy curve for the quality of rigid rotor harmonic oscillator and rigid rotor Morse oscillator is elucidated.

  8. Locomotor adaptation to a soleus EMG-controlled antagonistic exoskeleton.

    PubMed

    Gordon, Keith E; Kinnaird, Catherine R; Ferris, Daniel P

    2013-04-01

    Locomotor adaptation in humans is not well understood. To provide insight into the neural reorganization that occurs following a significant disruption to one's learned neuromuscular map relating a given motor command to its resulting muscular action, we tied the mechanical action of a robotic exoskeleton to the electromyography (EMG) profile of the soleus muscle during walking. The powered exoskeleton produced an ankle dorsiflexion torque proportional to soleus muscle recruitment thus limiting the soleus' plantar flexion torque capability. We hypothesized that neurologically intact subjects would alter muscle activation patterns in response to the antagonistic exoskeleton by decreasing soleus recruitment. Subjects practiced walking with the exoskeleton for two 30-min sessions. The initial response to the perturbation was to "fight" the resistive exoskeleton by increasing soleus activation. By the end of training, subjects had significantly reduced soleus recruitment resulting in a gait pattern with almost no ankle push-off. In addition, there was a trend for subjects to reduce gastrocnemius recruitment in proportion to the soleus even though only the soleus EMG was used to control the exoskeleton. The results from this study demonstrate the ability of the nervous system to recalibrate locomotor output in response to substantial changes in the mechanical output of the soleus muscle and associated sensory feedback. This study provides further evidence that the human locomotor system of intact individuals is highly flexible and able to adapt to achieve effective locomotion in response to a broad range of neuromuscular perturbations. PMID:23307949

  9. Fluctuation-Driven Neural Dynamics Reproduce Drosophila Locomotor Patterns

    PubMed Central

    Cruchet, Steeve; Gustafson, Kyle; Benton, Richard; Floreano, Dario

    2015-01-01

    The neural mechanisms determining the timing of even simple actions, such as when to walk or rest, are largely mysterious. One intriguing, but untested, hypothesis posits a role for ongoing activity fluctuations in neurons of central action selection circuits that drive animal behavior from moment to moment. To examine how fluctuating activity can contribute to action timing, we paired high-resolution measurements of freely walking Drosophila melanogaster with data-driven neural network modeling and dynamical systems analysis. We generated fluctuation-driven network models whose outputs—locomotor bouts—matched those measured from sensory-deprived Drosophila. From these models, we identified those that could also reproduce a second, unrelated dataset: the complex time-course of odor-evoked walking for genetically diverse Drosophila strains. Dynamical models that best reproduced both Drosophila basal and odor-evoked locomotor patterns exhibited specific characteristics. First, ongoing fluctuations were required. In a stochastic resonance-like manner, these fluctuations allowed neural activity to escape stable equilibria and to exceed a threshold for locomotion. Second, odor-induced shifts of equilibria in these models caused a depression in locomotor frequency following olfactory stimulation. Our models predict that activity fluctuations in action selection circuits cause behavioral output to more closely match sensory drive and may therefore enhance navigation in complex sensory environments. Together these data reveal how simple neural dynamics, when coupled with activity fluctuations, can give rise to complex patterns of animal behavior. PMID:26600381

  10. The fungicide imazalil induces developmental abnormalities and alters locomotor activity during early developmental stages in zebrafish.

    PubMed

    Jin, Yuanxiang; Zhu, Zhihong; Wang, Yueyi; Yang, Enlu; Feng, Xiayan; Fu, Zhengwei

    2016-06-01

    The fungicide imazalil (IMZ) is used extensively to protect vegetable fields, fruit plantations and post-harvest crops from rot. Likely due to its wide-spread use, IMZ is frequently detected in vegetable, fruit, soil and even surface water samples. Even though several previous studies have reported on the neurotoxicity of IMZ, its effects on the neurobehavior of zebrafish have received little attention to date. In this study, we show that the heartbeat and hatchability of zebrafish were significantly influenced by IMZ concentrations of 300 μg L(-1) or higher. Moreover, in zebrafish larvae, locomotor behaviors such as average swimming speed and swimming distance were significantly decreased after exposure to 300 μg L(-1) IMZ for 96 h, and acetylcholinesterase (AChE) expression and activity were consistently inhibited in IMZ-treated fish. Our results further suggest that IMZ could act as a neuroendocrine disruptor by decreasing the expression of neurotoxicity-related genes such as Glial fibrillary acidic protein (Gfap), Myelin basic protein (Mbp) and Sonic hedgehog a (Shha) during early developmental stages of zebrafish. In conclusion, we show that exposure to IMZ has the potential to induce developmental toxicity and locomotor behavior abnormalities during zebrafish development. PMID:27035382