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Sample records for potentiates locomotor sensitization

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

    PubMed Central

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

    2010-01-01

    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 ΔFosB in the orbitofrontal cortex (OFC). Mimicking this drug-induced elevation in OFC ΔFosB through viral-mediated gene transfer mimics these behavioural changes: ΔFosB 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 ΔFosB in the OFC also sensitizes animals to the locomotor-stimulant properties of cocaine. Analysis of nucleus accumbens tissue taken from rats over-expressing ΔFosB in the OFC and treated chronically with saline or cocaine does not provide support for the hypothesis that increasing OFC ΔFosB 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. Acute total sleep deprivation potentiates amphetamine-induced locomotor-stimulant effects and behavioral sensitization in mice.

    PubMed

    Saito, Luis P; Fukushiro, Daniela F; Hollais, André W; Mári-Kawamoto, Elisa; Costa, Jacqueline M; Berro, Laís F; Aramini, Tatiana C F; Wuo-Silva, Raphael; Andersen, Monica L; Tufik, Sergio; Frussa-Filho, Roberto

    2014-02-01

    It has been demonstrated that a prolonged period (48 h) of paradoxical sleep deprivation (PSD) potentiates amphetamine (AMP)-induced behavioral sensitization, an animal model of addiction-related neuroadaptations. In the present study, we examined the effects of an acute short-term deprivation of total sleep (TSD) (6h) on AMP-induced behavioral sensitization in mice and compared them to the effects of short-term PSD (6 h). Three-month-old male C57BL/6J mice underwent TSD (experiment 1-gentle handling method) or PSD (experiment 2-multiple platforms method) for 6 h. Immediately after the sleep deprivation period, mice were tested in the open field for 10 min under the effects of saline or 2.0 mg/kg AMP. Seven days later, to assess behavioral sensitization, all of the mice received a challenge injection of 2.0 mg/kg AMP and were tested in the open field for 10 min. Total, peripheral, and central locomotion, and grooming duration were measured. TSD, but not PSD, potentiated the hyperlocomotion induced by an acute injection of AMP and this effect was due to an increased locomotion in the central squares of the apparatus. Similarly, TSD facilitated the development of AMP-induced sensitization, but only in the central locomotion parameter. The data indicate that an acute period of TSD may exacerbate the behavioral effects of AMP in mice. Because sleep architecture is composed of paradoxical and slow wave sleep, and 6-h PSD had no effects on AMP-induced hyperlocomotion or sensitization, our data suggest that the deprivation of slow wave sleep plays a critical role in the mechanisms that underlie the potentiating effects of TSD on both the acute and sensitized addiction-related responses to AMP.

  3. Caffeine and amphetamine produce cross-sensitization to nicotine-induced locomotor activity in mice.

    PubMed

    Celik, Eylem; Uzbay, I Tayfun; Karakas, Sirel

    2006-01-01

    Sensitization development is linked to the addictive potential of the drugs. The same mechanisms might play a role in sensitization development to the different addictive drugs. The aim of the study was to investigate the development of cross-sensitization to caffeine and amphetamine in nicotine-induced locomotor sensitization in mice. Caffeine (2.5-20 mg/kg), amphetamine (1-16 mg/kg) or saline were injected to Swiss-Webster mice and locomotor activity was recorded for 30 min. Nicotine (0.5-2 mg/kg) or saline were injected to mice and locomotor activity was recorded for 30 min. Process was applied for 19 days, every other day (10 sessions). Caffeine (5 mg/kg), amphetamine (4 mg/kg) or saline were challenged to the different groups of nicotine-sensitized mice 2 days later on the last nicotine injection, and locomotor activity was recorded. Repetitive injections of nicotine (0.5-2 mg) produced locomotor sensitization in mice. After caffeine and amphetamine challenge injections, locomotor activity of the nicotine-sensitized mice was found to be significantly higher than saline-pretreated mice. Saline challenge did not produce any significant effect in nicotine- or saline-pretreated mice. Our results suggest that a cross-sensitization developed to both caffeine and amphetamine in nicotine-sensitized mice. In conclusion, similar central mechanisms may be responsible for the development of addiction to these substances.

  4. Effects of salvinorin A on locomotor sensitization to D2/D3 dopamine agonist quinpirole.

    PubMed

    Beerepoot, Pieter; Lam, Vincent; Luu, Alice; Tsoi, Bernice; Siebert, Daniel; Szechtman, Henry

    2008-12-03

    Locomotor sensitization induced by the dopamine agonist quinpirole can be potentiated by co-treatment with the synthetic kappa opioid agonist U69593. The identification of salvinorin A, an active component of the psychotropic sage Salvia divinorum, as a structurally different agonist of kappa-opioid receptors raised the question of whether this compound would similarly potentiate sensitization to quinpirole. Rats were co-treated with 0.5 mg/kg quinpirole and either salvinorin A (0.04, 0.4 or 2.0 mg/kg) or U69593 (0.3 mg/kg). Control groups were co-treated with vehicle and saline, vehicle and quinpirole (0.5 mg/kg), or saline and salvinorin A (0.4 mg/kg). Rats were injected biweekly for a total of 10 injections and locomotor activity measured after each treatment. Results showed that the highest dose of salvinorin A potentiated sensitization to quinpirole as did U69593, the middle salvinorin A dose had no effect on quinpirole sensitization, and the lowest dose of salvinorin A attenuated sensitization to quinpirole. These findings indicate that structural differences between salvinorin A and U69593 do not affect the potentiation of quinpirole sensitization. Moreover, the opposite effects of high and low salvinorin A doses suggest that salvinorin A can produce bidirectional modulation of sensitization to dopamine agonists.

  5. 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.

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

    PubMed

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

    2012-12-01

    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.

  7. Baclofen blocks the development of sensitization to the locomotor stimulant effect of amphetamine.

    PubMed

    Bartoletti, M; Gubellini, C; Ricci, F; Gaiardi, M

    2005-11-01

    The GABAB agonist baclofen (BCF) has recently been reported to block the expression of sensitization to the locomotor effect of amphetamine (AMPH), and to reverse it after repeated administration. The present study was undertaken to investigate whether baclofen could also prevent the development of sensitization to the psychostimulant. Chronic AMPH treatment (1.5 mg/kg i.p. for 10 days) led to an increased locomotor response to AMPH (1.5 mg/kg) when the animals were challenged 3 and 30 days after the end of repeated treatment. Chronic co-administration of BCF (2 mg/kg, i.p.) and AMPH blocked the development of sensitization to the stimulant effect of AMPH. An ancillary experiment excluded that a 'state-dependency' hypothesis could account for the effect of baclofen. Furthermore, a previous repeated treatment with baclofen alone had no influence either on the acute AMPH effect or on the subsequent development of sensitization to AMPH. In conclusion, the results confirm that GABAB receptors play an important role in the acquisition of AMPH behavioural sensitization and further support a potential use of GABAB agonists in the treatment of psychostimulant addiction.

  8. Differential effects of propranolol on conditioned hyperactivity and locomotor sensitization induced by morphine in rats.

    PubMed

    Wei, Shuguang; Li, Xinwang

    2014-01-21

    According to memory reconsolidation theory, when long-term memory is reactivated by relevant clues, the memory traces become labile, which can be altered by pharmacological manipulations. Accumulating evidence reveals that memory related to drug abuse can be erased by disrupting reconsolidation process. We used an animal model that could simultaneously measure conditioned hyperactivity and locomotor sensitization induced by morphine. β-Adrenoceptor antagonist propranolol or saline were administered following conditioned stimuli (CS) or a small dose of morphine reactivation. The results showed that the conditioned hyperactivity could be disrupted by propranolol treatment following CS reactivation. However, the expression of locomotor sensitization could not be disrupted by propranolol administration following CS or morphine reactivation. Furthermore, morphine injection and propranolol intervention enhanced the locomotor sensitization effect. These data suggest that blocking the reconsolidation process can disrupt the conditioned hyperactivity induced by environmental cues associated with morphine treatment, but not morphine-induced locomotor sensitization.

  9. Nicotine-induced locomotor sensitization: pharmacological analyses with candidate smoking cessation aids.

    PubMed

    Goutier, Wouter; Kloeze, Margreet; McCreary, Andrew C

    2016-03-01

    There are a number of approved therapeutics for the management of alcohol dependence, which might also convey the potential as smoking cessation aids. The present study investigated the effect of a few of these therapeutics and potential candidates (non-peptide vasopressin V1b antagonists) on the expression of nicotine-induced behavioral sensitization in Wistar rats. The following compounds were included in this evaluation: rimonabant, bupropion, topiramate, acamprosate, naltrexone, mecamylamine, nelivaptan (SSR-149415, V1b antagonist) and two novel V1b antagonists. Following the development of nicotine-induced locomotor sensitization and a withdrawal period, the expression of sensitization was assessed in the presence of one of the examined agents given 30 minutes prior to the nicotine challenge injection. Acamprosate, naltrexone, rimonabant, mecamylamine, nelivaptan and V1b antagonist 'compound 2' significantly antagonized the expression of nicotine-induced sensitization. Whereas topiramate showed a trend for effects, the V1b antagonist 'compound 1' did not show any significant effects. Bupropion failed to block sensitization but increased activity alone and was therefore tested in development and cross-sensitization studies. Taken together, these findings provide pre-clinical evidence that these molecules attenuated the expression of nicotine-induced sensitization and should be further investigated as putative treatments for nicotine addiction. Moreover, V1b antagonists should be further investigated as a potential novel smoking cessation aid.

  10. 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

  11. 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

  12. Assessment of substance abuse liability in rodents: self-administration, drug discrimination, and locomotor sensitization.

    PubMed

    Paterson, Neil E

    2012-09-01

    Assessing abuse liability is a crucial step in the development of a novel chemical entity (NCE) with central nervous system (CNS) activity or with chemical or pharmacological properties in common with known abused substances. Rodent assessment of abuse liability is highly attractive due to its relatively low cost and high predictive validity. Described in this unit are three rodent assays commonly used to provide data on the potential for abuse liability based on the acute effects of NCEs: specifically, self-administration, drug discrimination, and locomotor sensitization. As these assays provide insight into the potential abuse liability of NCEs as well as in vivo pharmacological mechanism(s) of action, they should form a key part of the development process for novel therapeutics aimed at treating CNS disorders.

  13. Pharmacologic Antagonism of Ghrelin Receptors Attenuates Development of Nicotine Induced Locomotor Sensitization in Rats

    PubMed Central

    Wellman, Paul J.; Clifford, P. Shane; Rodriguez, Juan; Hughes, Samuel; Eitan, Shoshana; Brunel, Luc; Fehrentz, Jean-Alain; Martinez, Jean

    2011-01-01

    Aims Ghrelin (GHR) is an orexigenic gut peptide that interacts with ghrelin receptors (GHR-Rs) to modulate brain reinforcement circuits. Systemic GHR infusions augment cocaine stimulated locomotion and conditioned place preference (CPP) in rats, whereas genetic or pharmacological ablation of GHR-Rs has been shown to attenuate the acute locomotor-enhancing effects of nicotine, cocaine, amphetamine and alcohol and to blunt the CPP induced by food, alcohol, amphetamine and cocaine in mice. The stimulant nicotine can induce CPP and like amphetamine and cocaine, repeated administration of nicotine induces locomotor sensitization in rats. A key issue is whether pharmacological antagonism of GHR-Rs would similarly attenuate nicotine-induced locomotor sensitization. Method To examine the role of GHR-Rs in the behavioral sensitizing effects of nicotine, adult male rats were injected with either 0, 3 or 6 mg/kg of the GHR-R receptor antagonist JMV 2959 (i.p.) and 20 minutes later with either vehicle or 0.4 mg/kg nicotine hydrogen tartrate (s.c.) on each of 7 consecutive days. Results Rats treated with nicotine alone showed robust locomotor sensitization, whereas rats pretreated with JMV 2959 showed significantly attenuated nicotine-induced hyperlocomotion. Conclusions These results suggest that GHR-R activity is required for the induction of locomotor sensitization to nicotine and complement an emerging literature implicating central GHR systems in drug reward/reinforcement. PMID:21903141

  14. A silent synapse-based mechanism for cocaine-induced locomotor sensitization.

    PubMed

    Brown, Travis E; Lee, Brian R; Mu, Ping; Ferguson, Deveroux; Dietz, David; Ohnishi, Yoshinori N; Lin, Ying; Suska, Anna; Ishikawa, Masago; Huang, Yanhua H; Shen, Haowei; Kalivas, Peter W; Sorg, Barbara A; Zukin, R Suzanne; Nestler, Eric J; Dong, Yan; Schlüter, Oliver M

    2011-06-01

    Locomotor sensitization is a common and robust behavioral alteration in rodents whereby following exposure to abused drugs such as cocaine, the animal becomes significantly more hyperactive in response to an acute drug challenge. Here, we further analyzed the role of cocaine-induced silent synapses in the nucleus accumbens (NAc) shell and their contribution to the development of locomotor sensitization. Using a combination of viral vector-mediated genetic manipulations, biochemistry, and electrophysiology in a locomotor sensitization paradigm with repeated, daily, noncontingent cocaine (15 mg/kg) injections, we show that dominant-negative cAMP-element binding protein (CREB) prevents cocaine-induced generation of silent synapses of young (30 d old) rats, whereas constitutively active CREB is sufficient to increase the number of NR2B-containing NMDA receptors (NMDARs) at synapses and to generate silent synapses. We further show that occupancy of CREB at the NR2B promoter increases and is causally related to the increase in synaptic NR2B levels. Blockade of NR2B-containing NMDARs by administration of the NR2B-selective antagonist Ro256981 directly into the NAc, under conditions that inhibit cocaine-induced silent synapses, prevents the development of cocaine-elicited locomotor sensitization. Our data are consistent with a cellular cascade whereby cocaine-induced activation of CREB promotes CREB-dependent transcription of NR2B and synaptic incorporation of NR2B-containing NMDARs, which generates new silent synapses within the NAc. We propose that cocaine-induced activation of CREB and generation of new silent synapses may serve as key cellular events mediating cocaine-induced locomotor sensitization. These findings provide a novel cellular mechanism that may contribute to cocaine-induced behavioral alterations.

  15. 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

  16. Neurotensin receptor antagonist administered during cocaine withdrawal decreases locomotor sensitization and conditioned place preference.

    PubMed

    Felszeghy, Klara; Espinosa, José Manuel; Scarna, Hélène; Bérod, Anne; Rostène, William; Pélaprat, Didier

    2007-12-01

    Chronic use of psychostimulants induces enduringly increased responsiveness to a subsequent psychostimulant injection and sensitivity to drug-associated cues, contributing to drug craving and relapse. Neurotensin (NT), a neuropeptide functionally linked to dopaminergic neurons, was suggested to participate in these phenomena. We and others have reported that SR 48692, an NT receptor antagonist, given in pre- or co-treatments with cocaine or amphetamine, alters some behavioral effects of these drugs in rats. However, its efficacy when applied following repeated cocaine administration remains unknown. We, therefore, evaluated the ability of SR 48692, administered after a cocaine regimen, to interfere with the expression of locomotor sensitization and conditioned place preference (CPP) in rats. We demonstrated that the expression of locomotor sensitization, induced by four cocaine injections (15 mg/kg, i.p.) every other day and a cocaine challenge 1 week later, was attenuated by a subsequent 2-week daily administration of SR 48692 (1 mg/kg, i.p.). Furthermore, the expression of cocaine-induced CPP was suppressed by a 10-day SR 48692 treatment started after the conditioning period (four 15 mg/kg cocaine injections every other day). Taken together, our data show that a chronic SR 48692 treatment given after a cocaine regimen partly reverses the expression of locomotor sensitization and CPP in the rat, suggesting that NT participates in the maintenance of these behaviors. Our results support the hypothesis that targeting neuromodulatory systems, such as the NT systems may offer new strategies in the treatment of drug addiction.

  17. Behavioral cross-sensitization between DOCA-induced sodium appetite and cocaine-induced locomotor behavior.

    PubMed

    Acerbo, Martin J; Johnson, Alan Kim

    2011-05-01

    Behavioral sensitization involves increases in the magnitude of a response to a stimulus after repeated exposures to the same response initiator. Administration of psychomotor stimulants and the induction of appetitive motivational states associated with natural reinforcers like sugar and salt are among experimental manipulations producing behavioral sensitization. In rats, repeated administration of the mineralocorticoid agonist deoxycorticosterone acetate (DOCA) initially induces incremental increases in daily hypertonic saline consumption (i.e., sensitization of sodium appetite) in spite of the retention of sodium. The present studies investigated whether sodium appetite sensitization induced by DOCA shares mechanisms similar to those of psychomotor stimulant-induced sensitization, and whether there is evidence for reciprocal cross-sensitization. In Experiments 1 and 3, rats received control or cocaine treatments to induce locomotor sensitization. A week later DOCA (or vehicle) was administered to generate a sodium appetite. Animals pretreated with cocaine showed a greater sodium appetite. In Experiment 2, the order of the putative sensitizing treatments was reversed. Rats first received either a series of DOCA or vehicle treatments either with or without access to saline and were later tested for sensitization of the locomotor response to cocaine. Animals pretreated with DOCA without access to saline showed greater locomotor responses to cocaine than animals receiving vehicle treatments. Together these experiments indicate that treatments generating a sustained salt appetite and producing cocaine-induced psychomotor responses show reciprocal behavioral cross-sensitization. The underlying mechanisms accounting for this relationship may be the fact that psychostimulants and an unresolved craving for sodium can act as potent stressors.

  18. 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 Central

    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

  19. 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

    2015-07-07

    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.

  20. Insulin-Dependent Activation of MCH Neurons Impairs Locomotor Activity and Insulin Sensitivity in Obesity.

    PubMed

    Hausen, A Christine; Ruud, Johan; Jiang, Hong; Hess, Simon; Varbanov, Hristo; Kloppenburg, Peter; Brüning, Jens C

    2016-12-06

    Melanin-concentrating-hormone (MCH)-expressing neurons (MCH neurons) in the lateral hypothalamus (LH) are critical regulators of energy and glucose homeostasis. Here, we demonstrate that insulin increases the excitability of these neurons in control mice. In vivo, insulin promotes phosphatidylinositol 3-kinase (PI3K) signaling in MCH neurons, and cell-type-specific deletion of the insulin receptor (IR) abrogates this response. While lean mice lacking the IR in MCH neurons (IR(ΔMCH)) exhibit no detectable metabolic phenotype under normal diet feeding, they present with improved locomotor activity and insulin sensitivity under high-fat-diet-fed, obese conditions. Similarly, obesity promotes PI3 kinase signaling in these neurons, and this response is abrogated in IR(ΔMCH) mice. In turn, acute chemogenetic activation of MCH neurons impairs locomotor activity but not insulin sensitivity. Collectively, our experiments reveal an insulin-dependent activation of MCH neurons in obesity, which contributes via distinct mechanisms to the manifestation of impaired locomotor activity and insulin resistance.

  1. 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

    2016-02-04

    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.

  2. Effects of spatial memory on morphine CPP and locomotor sensitization in mice.

    PubMed

    Zhu, Xiaolin; Sun, Wei; Li, Xinwang; Tan, Shuping; Zhang, Xiangyang

    2015-10-01

    Drug addiction is associated with memory processes. We simultaneously measured conditioned place preference (CPP) and locomotor sensitization to investigate the influence of spatial memory retrieval on morphine reward and psychomotor excitement. According to their performance in space probe trial involving the Morris water maze mice were assigned to high (including morphine and saline subgroups, H-Mor and H-Sal) and low spatial memory retrieval ability groups (L-Mor and L-Sal). Morphine (10mg/kg) produced significant CPP in L-Mor and H-Mor mice, although, L-Mor mice showed a significantly greater response to morphine. During the development period of behavior sensitization, no significant group-by-day interaction was found. However, locomotor activities of L-Mor mice were also significantly higher than H-Mor mice during the expression period of behavior sensitization. Our findings suggested that the spatial memory retrieval ability of mice influences morphine CPP, as well as behavioral sensitization. Thus, spatial memory might be implicated in drug addiction.

  3. Attenuation of Cocaine Induced Locomotor Sensitization in Rats Sustaining Genetic or Pharmacologic Antagonism of Ghrelin Receptors

    PubMed Central

    Clifford, P. Shane; Rodriguez, Juan; Schul, Destri; Hughes, Samuel; Kniffin, Tracey; Hart, Nigel; Eitan, Shoshana; Wellman, Paul J.; Brunel, Luc; Fehrentz, Jean-Alain; Martinez, Jean

    2011-01-01

    Systemic infusions of the orexigenic peptide ghrelin (GHR) increase dopamine levels within the nucleus accumbens and augment cocaine stimulated locomotion and conditioned place preference in rats; observations that suggest an important role for ghrelin and GHR receptors (GHR-Rs) in drug reinforcement. In the present studies, we examined the development of cocaine locomotor sensitization in rats sustaining either pharmacologic antagonism or genetic ablation of GHR-Rs. In a pharmacologic study, adult male rats were injected (i.p.) with either 0, 3 or 6 mg/kg JMV 2959 (a GHR-R1 receptor antagonist) and 20 minutes later with either vehicle or 10 mg/kg cocaine HCl on each of 7 consecutive days. Rats pretreated with JMV 2959 showed significantly attenuated cocaine-induced hyperlocomotion. In a second study, adult wild type (WT) or mutant rats sustaining ENU-induced knockout of GHR-R (GHR-R (−/−)) received daily injections (i.p) of vehicle (0.9% saline) or 10.0 mg/kg cocaine HCl for 14 successive days. GHR-R null rats treated repeatedly with cocaine showed diminished development of cocaine locomotor sensitization relative to WT rats treated with cocaine. To verify the lack of GHR-R function in the GHR-R (−/−) rats, a separate feeding experiment was conducted in which WT rats, but not GHR-R (−/−) rats, were noted to eat more after a systemic injection of 15 nmol ghrelin than after vehicle. These results suggest that GHR-R activity is required for the induction of locomotor sensitization to cocaine and complement an emerging literature implicating central GHR systems in drug reward. Ghrelin (GHR) is an orexigenic gut peptide that is transported across the blood brain barrier and interacts with GHR receptors (GHR-R) located on ventral tegmental dopamine neurons. PMID:21790898

  4. Chronic tolerance to ethanol-induced sedation: implication for age-related differences in locomotor sensitization.

    PubMed

    Quoilin, Caroline; Didone, Vincent; Tirelli, Ezio; Quertemont, Etienne

    2013-06-01

    The adolescent brain has been suggested to be particularly sensitive to ethanol-induced neuroadaptations, which in turn could increase the risk of youths for alcohol abuse and dependence. Sensitization to the locomotor stimulant effects of ethanol has often been used as an animal model of ethanol-induced neuroadaptations. Previously, we showed that young mice were more sensitive than adults to the locomotor sensitization induced by high ethanol doses. However, this effect could be due to age-related differences in chronic tolerance to the sedative effects of ethanol. The aim of the present study is to assess chronic tolerance to the sedative effects of ethanol in weaning 21-day-old (P21), adolescent 35-day-old (P35) and adult 63-day-old (P63) female Swiss mice. After a daily injection of saline or 4 g/kg ethanol during 6 consecutive days, all P21, P35 and P63 mice were injected with 4 g/kg ethanol and submitted to the loss of righting reflex procedure. Our results confirm that the sensitivity to the acute sedative effects of ethanol gradually increases with age. Although this schedule of ethanol injections induces significant age-related differences in ethanol sensitization, it did not reveal significant differences between P21, P35 and P63 mice in the development of a chronic ethanol tolerance to its sedative effects. The present results show that age-related differences in the development of ethanol sensitization cannot be explained by differences in chronic ethanol tolerance to its sedative effects. More broadly, they do not support the idea that ethanol-induced sensitization is a by-product of chronic ethanol tolerance.

  5. Levo-tetrahydropalmatine attenuates the development and expression of methamphetamine-induced locomotor sensitization and the accompanying activation of ERK in the nucleus accumbens and caudate putamen in mice.

    PubMed

    Zhao, N; Chen, Y; Zhu, J; Wang, L; Cao, G; Dang, Y; Yan, C; Wang, J; Chen, T

    2014-01-31

    Levo-tetrahydropalmatine (l-THP) is an alkaloid purified from corydalis and has been used in many traditional Chinese herbal preparations for its analgesic, sedative, and hypnotic properties. Previous studies indicated that l-THP has modest antagonist activity against dopamine receptors and thus it might have potential therapeutic effects on drug addiction. However, whether and how l-THP contributes to methamphetamine (METH)-induced locomotor sensitization remains unclear. Therefore, the current study aims to examine the roles of l-THP in the development and expression of METH-induced locomotor sensitization as well as the accompanying extracellular-regulated kinase (ERK) activation in the nucleus accumbens (NAc), caudate putamen (CPu) and prefrontal cortex (PFc) in mice. We found that moderate doses of METH (0.5 and 2 mg/kg) induced hyper-locomotor activity in mice on all METH injection days whereas high dose of METH (5 mg/kg)-treated mice displayed only acute locomotor response to METH and severe stereotyped behaviors on the first day after drug injection. Interestingly, only 2 mg/kg dose of METH-induced locomotor sensitization which was accompanied by the activation of ERK1/2 in the NAc and CPu in mice. Although l-THP (5 and 10 mg/kg) per se did not induce obvious changes in locomotor activities in mice, its co-administration with METH could significantly attenuate acute METH-induced hyper-locomotor activity, the development and expression of METH-induced locomotor sensitization, and the accompanying ERK1/2 activation in the NAc and CPu. These results suggest that l-THP has potential therapeutic effect on METH-induced locomotor sensitization, and the underlying molecular mechanism might be related to its inhibitory effect on ERK1/2 phosphorylation in the NAc and CPu.

  6. Conditioned place preference and locomotor sensitization after repeated administration of cocaine or methamphetamine in rats treated with epidermal growth factor during the neonatal period.

    PubMed

    Mizuno, Makoto; Malta, Romulo S; Nagano, Tadasato; Nawa, Hiroyuki

    2004-10-01

    Epidermal growth factor (EGF) and its structurally related proteins are involved in the developmental regulation of various brain neurons, including midbrain dopaminergic neurons. We recently reported EGF and EGF-receptor abnormalities in both the brain tissues and blood of schizophrenic patients. Administration of EGF to neonatal rats transiently increases tyrosine hydroxylase expression and subsequently results in behavioral abnormalities in prepulse inhibition of acoustic startle, locomotor activity, and social interaction after development. The enhanced locomotor and stereotypic responses of the neonatally EGF-treated rats are considered to be an animal model for positive schizophrenia symptoms. In the present study, we investigated psychostimulant sensitivity of neonatally EGF-treated rats. At the adult stage, EGF-treated rats were challenged with cocaine (15 mg/kg) or methamphetamine (1 mg/kg), and conditioned place preference and locomotor activity were examined. The rats that received EGF during the neonatal period had significantly higher conditioned place preference for where cocaine or methamphetamine was administered than controls. The neonatal EGF treatment enhanced behavioral response to methamphetamine and behavioral sensitization to cocaine at the adult stage. Drug-naive controls gradually increased locomotor responses to cocaine during their daily injections, whereas EGF-treated rats exhibited a larger increase in cocaine responses. These results indicate that overactivation of the EGF receptors (ErbB1) during the neonatal period influences future sensitivity to psychostimulants. Our findings indicate a potential link between EGF-receptor activation and drug addiction.

  7. Morphine-induced sensitization of locomotor activity in mice: effect of social isolation on plasma corticosterone levels.

    PubMed

    Francès, H; Graulet, A; Debray, M; Coudereau, J P; Guéris, J; Bourre, J M

    2000-03-31

    This study examined the influence of social isolation on behavioural sensitization to the locomotor effect of morphine and the link between this behaviour and plasma corticosterone concentrations. Four weeks isolation induced an increase in the locomotor effect of morphine. In social and isolated mice, repeated administrations (6) of morphine (one injection every 3 or 4 days) followed by 3 h in an actimeter induced behavioural sensitization to the locomotor effect of morphine. No interaction was observed between social isolation and behavioural sensitization to morphine. Resocializing previously isolated mice for 3 weeks reduced the morphine-induced locomotor effect without altering the behavioural sensitization. Corticosterone plasma levels were more increased (416%) in mice isolated 5 weeks than in mice isolated for 2 weeks (243%) and they return to the control levels following 3 weeks of resocialization. Since there was no interaction between the increase in morphine locomotor effect induced by social isolation and the morphine-induced behavioural sensitization, it is suggested that each of these two events acts independently. Whether or not a common mechanism (plasma corticosterone levels?) partly underlies both effects, the result resembles a simple additive effect.

  8. Attenuated methamphetamine-induced locomotor sensitization in serotonin transporter knockout mice is restored by serotonin 1B receptor antagonist treatment.

    PubMed

    Igari, Moe; Shen, Hao-Wei; Hagino, Yoko; Fukushima, Setsu; Kasahara, Yoshiyuki; Lesch, Klaus-Peter; Murphy, Dennis L; Hall, Frank Scott; Uhl, George R; Ikeda, Kazutaka; Yaegashi, Nobuo; Sora, Ichiro

    2015-02-01

    Repeated administration of methamphetamine (METH) enhances acute locomotor responses to METH administered in the same context, a phenomenon termed as 'locomotor sensitization'. Although many of the acute effects of METH are mediated by its influences on the compartmentalization of dopamine, serotonin systems have also been suggested to influence the behavioral effects of METH in ways that are not fully understood. The present experiments examined serotonergic roles in METH-induced locomotor sensitization by assessing: (a) the effect of serotonin transporter (SERT; Slc6A4) knockout (KO) on METH-induced locomotor sensitization; (b) extracellular monoamine levels in METH-treated animals as determined by in-vivo microdialysis; and (c) effects of serotonin (5-HT) receptor antagonists on METH-induced behavioral sensitization, with focus on effects of the 5-HT1B receptor antagonist SB 216641 and a comparison with the 5-HT2 receptor antagonist ketanserin. Repeated METH administration failed to induce behavioral sensitization in homozygous SERT KO (SERT-/-) mice under conditions that produced substantial sensitization in wild-type or heterozygous SERT KO (SERT+/-) mice. The selective 5-HT1B antagonist receptor SB 216641 restored METH-induced locomotor sensitization in SERT-/- mice, whereas ketanserin was ineffective. METH-induced increases in extracellular 5-HT (5-HTex) levels were substantially reduced in SERT-/- mice, although SERT genotype had no effect on METH-induced increases in extracellular dopamine. These experiments demonstrate that 5-HT actions, including those at 5-HT1B receptors, contribute to METH-induced locomotor sensitization. Modulation of 5-HT1B receptors might aid therapeutic approaches to the sequelae of chronic METH use.

  9. 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

  10. Exploring the role of locomotor sensitization in the circadian food entrainment pathway

    PubMed Central

    Opiol, Hanna; de Zavalia, Nuria; Delorme, Tara; Solis, Pavel; Rutherford, Spencer; Shalev, Uri; Amir, Shimon

    2017-01-01

    Food entrainment is the internal mechanism whereby the phase and period of circadian clock genes comes under the control of daily scheduled food availability. Food entrainment allows the body to efficiently realign the internal timing of behavioral and physiological functions such that they anticipate food intake. Food entrainment can occur with or without caloric restriction, as seen with daily schedules of restricted feeding (RF) or restricted treat (RT) that restrict food or treat intake to a single feeding time. However, the extent of clock gene control is more pronounced with caloric restriction, highlighting the role of energy balance in regulating clock genes. Recent studies have implicated dopamine (DA) to be involved in food entrainment and caloric restriction is known to affect dopaminergic pathways to enhance locomotor activity. Since food entrainment results in the development of a distinct behavioral component, called food anticipatory activity (FAA), we examined the role of locomotor sensitization (LS) in food entrainment by 1) observing whether amphetamine (AMPH) sensitization results in enhanced locomotor output of FAA and 2) measuring LS of circadian and non-circadian feeding paradigms to an acute injection of AMPH (AMPH cross-sensitization). Unexpectedly, AMPH sensitization did not show enhancement of FAA. On the contrary, LS did develop with sufficient exposure to RF. LS was present after 2 weeks of RF, but not after 1, 3 or 7 days into RF. When food was returned and rats regain their original body weight at 10–15 days post-RF, LS remained present. LS did not develop to RT, nor to feedings of a non-circadian schedule, e.g. variable restricted feeding (VRF) or variable RT (VRT). Further, when RF was timed to the dark period, LS was observed only when tested at night; RF timed to the light period resulted in LS that was present during day and night. Taken together our results show that LS develops with food entrainment to RF, an effect that is

  11. The 5-HT3 receptor antagonist, ondansetron, blocks the development and expression of ethanol-induced locomotor sensitization in mice.

    PubMed

    Umathe, Sudhir N; Bhutada, Pravinkumar S; Raut, Vivek S; Jain, Nishant S; Mundhada, Yogita R

    2009-02-01

    Manipulation of the serotonergic system has been shown to alter ethanol sensitization. Ondansetron is a 5-HT3 receptor antagonist, reported to attenuate cocaine and methamphetamine-induced behavioral sensitization, but no reports are available on its role in ethanol-induced behavioral sensitization. Therefore, an attempt has been made to assess this issue by using an earlier used animal model of ethanol-induced locomotor sensitization. Results indicated that ondansetron (0.25-1.0 mg/kg, subcutaneously) given before the challenge dose of ethanol (2.4 g/kg, intraperitoneally) injection, significantly and dose dependently attenuated the expression of sensitization. In addition, ondansetron (1.0 mg/kg, subcutaneously) given before ethanol injection on days 1, 4, 7, and 10 significantly blocked the development (days 1, 4, 7, and 10), and expression (day 15) of sensitization to the locomotor stimulant effect of ethanol injection. Ondansetron had no effect per se on locomotor activity and did not affect blood ethanol levels. Therefore, the results raise the possibility that ondansetron blocked the development and expression of ethanol-induced locomotor sensitization by acting on 5-HT3 receptors.

  12. Different locomotor sensitization responses to repeated cocaine injections are associated with differential phosphorylation of GluA1 in the dorsomedial striatum of adult rats.

    PubMed

    Kim, Myonghwan; Kim, Wonju; Baik, Ja-Hyun; Yoon, Bong-June

    2013-11-15

    Behavioral sensitization to psychostimulants reflects neural adaptation, which might share a common mechanism with drug addiction. Outbred male rats show different locomotor sensitization responses to cocaine, and cocaine also produces varied addictive progress in humans. We investigated whether differences in the induction of sensitization would affect the long-term persistence of sensitized locomotor activity, and we sought to determine the molecular basis for the variability in sensitization. Male Sprague-Dawley rats that showed sensitized locomotor responses over 5 consecutive daily cocaine injections (SENS) had significantly lower initial locomotor responses to the 1st cocaine exposure than did rats that did not show locomotor sensitization (NONS). Furthermore, rats that underwent 1 month of cocaine withdrawal after 5 repeated cocaine injections also exhibited sensitized or non-sensitized locomotor responses to a challenge injection of cocaine (SENS-C or NONS-C, respectively). This variability was also related to the initial responsiveness to cocaine. We examined the level of phosphorylation of the GluA1 subunit of α-amino-3-hydroxy-5-methyl-4-isoxazolepropioniate receptor (AMPAR) in the dorsal striatum and found that there were significant differences between the sensitized rats and the non-sensitized rats. pGluA1-Ser831 was increased in the SENS rats during the induction of locomotor sensitization, and pGluA1-Ser845 was increased in the SENS-C rats during the expression of locomotor sensitization. These phosphorylation changes were observed in the dorsomedial striatum (DMS) of adult rats but not in the dorsolateral striatum (DLS) of adults. Our findings suggest that differential phosphorylation of AMPAR might be an important mechanism that contributes to the development of locomotor sensitization to cocaine in adult rats.

  13. Local field potentials in the ventral tegmental area during cocaine-induced locomotor activation: Measurements in freely moving rats.

    PubMed

    Harris Bozer, Amber L; Li, Ai-Ling; Sibi, Jiny E; Bobzean, Samara A M; Peng, Yuan B; Perrotti, Linda I

    2016-03-01

    The ventral tegmental area (VTA) has been established as a critical nucleus for processing behavioral changes that occur during psychostimulant use. Although it is known that cocaine induced locomotor activity is initiated in the VTA, not much is known about the electrical activity in real time. The use of our custom-designed wireless module for recording local field potential (LFP) activity provides an opportunity to confirm and identify changes in neuronal activity within the VTA of freely moving rats. The purpose of this study was to investigate the changes in VTA LFP activity in real time that underlie cocaine induced changes in locomotor behavior. Recording electrodes were implanted in the VTA of rats. Locomotor behavior and LFP activity were simultaneously recorded at baseline, and after saline and cocaine injections. Results indicate that cocaine treatment caused increases in both locomotor behavior and LFP activity in the VTA. Specifically, LFP activity was highest during the first 30 min following the cocaine injection and was most robust in Delta and Theta frequency bands; indicating the role of low frequency VTA activity in the initiation of acute stimulant-induced locomotor behavior. Our results suggest that LFP recording in freely moving animals can be used in the future to provide valuable information pertaining to drug induced changes in neural activity.

  14. 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.

  15. Enhanced cocaine-induced locomotor sensitization and intrinsic excitability of NAc medium spiny neurons in adult but not adolescent rats susceptible to diet-induced obesity

    PubMed Central

    Oginsky, Max F.; Maust, Joel D.; Corthell, John T.; Ferrario, Carrie R.

    2015-01-01

    Rationale Basal and diet-induced differences in mesolimbic function, particularly within the nucleus accumbens (NAc), may contribute to human obesity; these differences may be more pronounced in susceptible populations. Objectives We determined whether there are differences in cocaine-induced behavioral plasticity in rats that are susceptible vs. resistant to diet-induced obesity, and basal differences in the striatal neuron function in adult and adolescent obesity-prone and obesity-resistant rats. Methods Susceptible and resistant outbred rats were identified based on “junk-food” diet-induced obesity. Then, the induction and expression of cocaine-induced locomotor sensitization, which is mediated by enhanced striatal function and is associated with increased motivation for rewards and reward-paired cues, were evaluated. Basal differences in mesolimbic function were examined in selectively bred obesity-prone and obesity-resistant rats (P70-80 and P30-40) using both cocaine induced locomotion and whole-cell patch clamping approaches in NAc core medium spiny neurons (MSNs). Results In rats that became obese after eating “junk-food”, the expression of locomotor sensitization was enhanced compared to non-obese rats, with similarly strong responses to 7.5 and 15 mg/kg cocaine. Without diet manipulation, obesity-prone rats were hyper-responsive to the acute locomotor-activating effects of cocaine, and the intrinsic excitability of NAc core MSNs was enhanced by ~60% at positive and negative potentials. These differences were present in adult, but not adolescent rats. Post-synaptic glutamatergic transmission was similar between groups. Conclusions Mesolimbic systems, particularly NAc MSNs, are hyper-responsive in obesity-prone individuals; and interactions between predisposition and experience influence neurobehavioral plasticity in ways that may promote weight gain and hamper weight loss in susceptible rats. PMID:26612617

  16. 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.

  17. Chronic intermittent heroin produces locomotor sensitization and long-lasting enhancement of conditioned reinforcement.

    PubMed

    Morrison, J; Thornton, V; Ranaldi, R

    2011-09-01

    In a previous study we showed that chronic intermittent heroin in rats enhanced responding with conditioned reinforcement and reversal learning of a conditioned magazine approach task when tested three days after the heroin treatment. Whether or not this enhanced appetitive learning persists after a protracted withdrawal period remains unknown and constitutes the aim of the present study. Forty-eight male Long Evans rats were each exposed to positive pairings of a light stimulus and food for 4 consecutive daily sessions. Then, two groups of rats received saline and two groups received heroin (2 mg/kg) injections before placement in activity monitors for 9 consecutive daily sessions. This was followed by testing in operant conditioning chambers where one lever produced the light stimulus previously paired with food and another no stimulus. For one saline and one heroin group this testing occurred after 2 days of withdrawal while for the other saline and heroin groups it occurred after 30 days of withdrawal. The results indicate that animals treated with heroin displayed progressively and significantly greater locomotor activity across sessions while animals treated with saline displayed locomotor activity that remained low and stable across sessions. In addition, the heroin groups in each withdrawal condition displayed significantly enhanced responding with conditioned reinforcement compared to their respective saline control groups. These results demonstrate that chronic intermittent heroin enhances appetitive learning for natural reinforcers and motivational processes and that this effect persists even after 30-days of withdrawal.

  18. GABAA overactivation potentiates the effects of NMDA blockade during the brain growth spurt in eliciting locomotor hyperactivity in juvenile mice.

    PubMed

    Oliveira-Pinto, Juliana; Paes-Branco, Danielle; Cristina-Rodrigues, Fabiana; Krahe, Thomas E; Manhães, Alex C; Abreu-Villaça, Yael; Filgueiras, Cláudio C

    2015-01-01

    Both NMDA receptor blockade and GABAA receptor overactivation during the brain growth spurt may contribute to the hyperactivity phenotype reminiscent of attention-deficit/hyperactivity disorder. Here, we evaluated the effects of exposure to MK801 (a NMDA antagonist) and/or to muscimol (a GABAA agonist) during the brain growth spurt on locomotor activity of juvenile Swiss mice. This study was carried out in two separate experiments. In the first experiment, pups received a single i.p. injection of either saline solution (SAL), MK801 (MK, 0.1, 0.3 or 0.5 mg/kg) or muscimol (MU, 0.02, 0.1 or 0.5 mg/kg) at the second postnatal day (PND2), and PNDs 4, 6 and 8. In the second experiment, we investigated the effects of a combined injection of MK (0.1 mg/kg) and MU (doses: 0.02, 0.1 or 0.5 mg/kg) following the same injection schedule of the first experiment. In both experiments, locomotor activity was assessed for 15 min at PND25. While MK promoted a dose-dependent increase in locomotor activity, exposure to MU failed to elicit significant effects. The combined exposure to the highest dose of MU and the lowest dose of MK induced marked hyperactivity. Moreover, the combination of the low dose of MK and the high dose of MU resulted in a reduced activity in the center of the open field, suggesting an increased anxiety-like behavior. These findings suggest that, during the brain growth spurt, the blockade of NMDA receptors induces juvenile locomotor hyperactivity whereas hyperactivation of GABAA receptors does not. However, GABAA overactivation during this period potentiates the effects of NMDA blockade in inducing locomotor hyperactivity.

  19. AMN082, a metabotropic glutamate receptor 7 allosteric agonist, attenuates locomotor sensitization and cross-sensitization induced by cocaine and morphine in mice.

    PubMed

    Jenda, M; Gawel, K; Marszalek, M; Komsta, L; Kotlinska, J H

    2015-03-03

    Previous studies have indicated that metabotropic glutamate receptors 7 (mGluR7s) are involved in drug addiction. However, the role of these receptors in drug-induced behavioral sensitization is unknown. The aim of the present study was to determine whether systemic injection of AMN082, a selective mGluR7 allosteric agonist, reduces the cocaine- and morphine-induced hyperactivity and the development and expression of locomotor sensitization, and also affects the reciprocal cross-sensitization to the stimulant effect of cocaine and morphine in mice. AMN082 (1.25-10.0 mg/kg, i.p.) did not have an impact on locomotion of naive mice and did not affect the acute cocaine- or morphine-induced hyperactivity, except the dose of 10 mg/kg that suppressed the locomotor effect of both drugs. Repeated exposure to cocaine or morphine (10 mg/kg, 5× every 3 days) gradually increased locomotion during induction of sensitization and after 4 (cocaine) or 7 day (morphine) withdrawal phase when challenged with cocaine (10 mg/kg, i.p.) or morphine (10 mg/kg, i.p.) on day 17 or 20, respectively. Pretreatment of animals with the lower doses of AMN082 (1.25-5.0 mg/kg, i.p.), 30 min before every cocaine or morphine injection during repeated drug administration or before cocaine or morphine challenge, dose-dependently attenuated the development, as well as the expression of cocaine or morphine locomotor sensitization. AMN082 also inhibited the reciprocal cross-sensitization between these drugs. Prior to administration of MMPIP (10 mg/kg, i.p.), a selective mGluR7 antagonist reversed the inhibitory effect of AMN082 on the development or expression of cocaine or morphine sensitization. These data indicate that AMN082 attenuated the development and expression of cocaine and morphine sensitization, and the reciprocal cross-sensitization via a mechanism that involves mGluR7s. Thus, AMN082 might have therapeutic implications not only in the treatment of cocaine or opioid addiction but also in the

  20. NR2B-deficient mice are more sensitive to the locomotor stimulant and depressant effects of ethanol.

    PubMed

    Badanich, K A; Doremus-Fitzwater, T L; Mulholland, P J; Randall, P K; Delpire, E; Becker, H C

    2011-10-01

    The NR2B subunit of N-methyl d-aspartate glutamate receptors influences pharmacological properties and confers greater sensitivity to the modulatory effects of ethanol. This study examined behavioral responses to acute ethanol in a conditional knockout mouse model that allowed for a delayed genetic deletion of the NR2B subunit to avoid mouse lethality. Mice lacking the NR2B gene (knockout) were produced by mating NR2B[f/f] mice with CAMKIIa-driven tTA transgenic mice and the tetO-CRE transgenic mice. Adult male and female offspring representing each of the resultant genotypes (knockout, CAM, CRE and wildtype mice) were tested for open-field locomotor activity following acute low- and high-dose ethanol challenge as well as loss of righting reflex. Findings indicate that male and female mice lacking the NR2B subunit exhibited greater overall activity in comparison to other genotypes during the baseline locomotor activity test. NR2B knockout mice exhibited an exaggerated stimulant response to 1.5 g/kg (i.p.) and an exaggerated depressant response to 3.0 g/kg (i.p.) ethanol challenge. In addition, NR2B knockout mice slept longer following a high dose of ethanol (4.0 g/kg, i.p.). To evaluate pharmacokinetics, clearance rates of ethanol (1.5, 4.0 g/kg, i.p.) were measured and showed that female NR2B knockouts had a faster rate of metabolism only at the higher ethanol dose. Western blot analyses confirmed significant reduction in NR2B expression in the forebrain of knockout mice. Collectively, these data indicate that the NR2B subunit of the N-methyl d-aspartate glutamate receptor is involved in regulating low-dose stimulant effects of ethanol and the depressant/hypnotic effects of ethanol.

  1. Potentiation of the expression of cocaine-induced sensitization by a conditioned stressor.

    PubMed

    Sasaki, Aya; Sivanathan, Shathveekan; Hussain, Atif; Shanmuganathan, Purathani; Sivakumaran, Archana; Erb, Suzanne

    2015-10-01

    Repeated exposures to physical stressors cross-sensitize to the locomotor activating effects of psychostimulants in rodents. In the present study, we examined the effect of a conditioned stressor on expression of cocaine-induced sensitization in rats. We determined whether a mint odor cue previously paired with footshock stress (FS) would elicit a sensitized locomotor response in cocaine pre-exposed rats. Rats were given once daily injections of cocaine (30 mg/kg, i.p.) or saline for 6 days in activity monitoring chambers. Subsequently, and in a different and distinct context, equal numbers of rats in each drug condition were exposed to 10 min of brief, intermittent FS or no FS, either in the presence or absence of the mint odor cue. Upon re-exposure to the activity chambers (in which cocaine exposures had been given), all rats previously exposed to cocaine showed robust conditioned locomotion. In response to a cocaine challenge (10 mg/kg, i.p.), cocaine relative to saline pre-exposed rats showed a sensitized locomotor response. Finally, in those cocaine pre-exposed rats that had been given prior odor-FS pairings, concurrent delivery of the cocaine challenge and presentation of the odor cue markedly potentiated the expression of sensitization. To our knowledge, this is the first report of a facilitation of cocaine-induced locomotor sensitization by a conditioned stressor.

  2. The expression of MC4Rs in D1R neurons regulates food intake and locomotor sensitization to cocaine

    PubMed Central

    Cui, H.; Lutter, M.

    2013-01-01

    While it is known that mice lacking melanocortin 4 receptor (MC4R) expression develop hyperphagia resulting in early-onset obesity, the specific neural circuits that mediate this process remain unclear. Here, we report that selective restoration of MC4R expression within dopamine-1 receptor-expressing neurons [MC4R/dopamine 1 receptor (D1R) mice] partially blunts the severe obesity seen in MC4R-nullmice by decreasing meal size, but not meal frequency, in the dark cycle. We also report that both acute cocaine-induced anorexia and the development of locomotor sensitization to repeated administration of cocaine are blunted in MC4R-null mice and normalized in MC4R/D1R mice. Neuronal retrograde tracing identifies the lateral hypothalamic area as the primary target ofMC4R-expressing neurons in the nucleus accumbens. Biochemical studies in the ventral striatum show that phosphorylation of DARPP-32Thr-34 and GluR1Ser-845 is diminished in MC4R-null mice after chronic cocaine administration but rescued in MC4R/D1R mice. These findings highlight a physiological role of MC4R-mediated signaling within D1R neurons in the long-term regulation of energy balance and behavioral responses to cocaine. PMID:23786641

  3. Effects of Repeated Ethanol Exposures on NMDA Receptor Expression and Locomotor Sensitization in Mice Expressing Ethanol Resistant NMDA Receptors

    PubMed Central

    den Hartog, Carolina R.; Gilstrap, Meghin; Eaton, Bethany; Lench, Daniel H.; Mulholland, Patrick J.; Homanics, Gregg. E.; Woodward, John J.

    2017-01-01

    ethanol injections and this was associated with differences in NMDAR subunit expression across brain regions thought to be involved in drug sensitization. Overall, while the results of the study suggest that NMDARs with reduced sensitivity to ethanol favor the development of locomotor sensitization, they also show that intrinsic ethanol sensitivity is not the sole determinant underlying changes in NMDAR expression following repeated exposures to ethanol. PMID:28270746

  4. Addictive potential of modafinil and cross-sensitization with cocaine: a pre-clinical study.

    PubMed

    Wuo-Silva, Raphael; Fukushiro, Daniela F; Borçoi, Aline R; Fernandes, Helaine A; Procópio-Souza, Roberta; Hollais, André W; Santos, Renan; Ribeiro, Luciana T C; Corrêa, Jussara M R M; Talhati, Fernanda; Saito, Luis P; Aramini, Tatiana C F; Kameda, Sonia R; Bittencourt, Lia R A; Tufik, Sergio; Frussa-Filho, Roberto

    2011-10-01

    Repeated or even a single exposure to drugs of abuse can lead to persistent locomotor sensitization, which is the result of an abundance of neuroplastic changes occurring within the circuitry involved in motivational behavior and is thought to play a key role in certain aspects of drug addiction. There is substantial controversy about the addictive potential of modafinil, a wake-promoting drug used to treat narcolepsy that is increasingly being used as a cognitive enhancer and has been proposed as a pharmacotherapy for cocaine dependence. Male mice were used to investigate the ability of modafinil to induce locomotor sensitization after repeated or single administration in mice. Bidirectional cross-sensitization with cocaine and modafinil-induced conditioned place preference were also evaluated. Both repeated and single exposure to moderate and high doses of modafinil produced a pronounced locomotor sensitization that cross-sensitized in a bidirectional way with cocaine. Remarkably, when cocaine and modafinil were repeatedly administered sequentially, their behavioral sensitization was additive. Supporting these behavioral sensitization data, modafinil produced a pronounced conditioned place preference in the mouse. Taken together, the present findings provide pre-clinical evidence for the addictive potential of modafinil. Our data also strongly suggest that similar neural substrates are involved in the psychomotor/rewarding effects of modafinil and cocaine.

  5. Neurotensin agonist attenuates nicotine potentiation to cocaine sensitization.

    PubMed

    Fredrickson, Paul; Boules, Mona; Stennett, Bethany; Richelson, Elliott

    2014-03-01

    Tobacco usage typically precedes illicit drug use in adolescent and young adult populations. Several animal studies suggest nicotine increases the risk for subsequent cocaine abuse, and may be a negative prognostic factor for treatment of cocaine addiction; i.e., a "gateway drug". Neurotensin (NT) is a 13-amino acid neuropeptide that modulates dopamine, acetylcholine, glutamate, and GABA neurotransmission in brain reward pathways. NT69L, a NT(8-13) analog, blocks behavioral sensitization (an animal model for psychostimulant addiction) to nicotine, and nicotine self-administration in rats. The present study tested the effect of NT69L on the potentiating effects of nicotine on cocaine-induced locomotor sensitization. Male Wistar rats were injected daily for seven days with nicotine or saline (control) followed by four daily injections of cocaine. NT69L was administered 30 min prior to the last cocaine injection. Behavior was recorded with the use of activity chambers. Subchronic administration of nicotine enhanced cocaine-induced behavioral sensitization in Wistar rats, consistent with an hypothesized gateway effect. These behavioral effects of cocaine were attenuated by pretreatment with NT69L. The effect of the neurotensin agonist on cocaine sensitization in the nicotine treated group indicated a possible therapeutic effect for cocaine addiction, even in the presence of enhanced behavioral sensitization induced by nicotine.

  6. 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.

  7. Methylphenidate enhances the abuse-related behavioral effects of nicotine in rats: intravenous self-administration, drug discrimination, and locomotor cross-sensitization.

    PubMed

    Wooters, Thomas E; Neugebauer, Nichole M; Rush, Craig R; Bardo, Michael T

    2008-04-01

    Stimulant drugs, including D-amphetamine, cocaine, and methylphenidate, increase cigarette smoking in controlled human laboratory experiments. Although the mechanism(s) underlying this effect are unknown, it is possible that stimulants may enhance directly the abuse-related effects of nicotine. In the present study, we characterized the behavioral pharmacological interactions between methylphenidate and nicotine in the intravenous self-administration, drug discrimination, and locomotor cross-sensitization procedures. Adult male Sprague-Dawley rats were trained to respond for intravenous nicotine (0.01 or 0.03 mg/kg/infusion) or sucrose, and the acute effects of methylphenidate (1.25-10 mg/kg) were determined; in addition, separate groups of rats were treated with methylphenidate (2.5 mg/kg) or saline before 12 consecutive nicotine (0.03 mg/kg/infusion) self-administration sessions. Next, the discriminative stimulus effects of nicotine (0.03-0.3 mg/kg) and methylphenidate (1.25-10 mg/kg), alone and in combination with a low nicotine dose (0.056 mg/kg), were tested in nicotine-trained rats. Finally, the locomotor effect of repeated methylphenidate (2.5 mg/kg) was tested in rats previously treated with nicotine (0.2-0.8 mg/kg). Results indicated that acute methylphenidate increased the rate of nicotine self-administration at doses that reduced sucrose-maintained responding; furthermore, tolerance to this effect was not apparent following repeated methylphenidate. Methylphenidate, while not substituting for nicotine alone, dose-dependently enhanced the discriminative stimulus effect of a low nicotine dose. In addition, repeated nicotine exposure promoted the development of locomotor sensitization to methylphenidate. Taken together with recent clinical findings, these results suggest that methylphenidate may enhance the abuse-related behavioral effects of nicotine, perhaps increasing vulnerability to tobacco dependence.

  8. Differential patterns of expression of neuropeptide Y throughout abstinence in outbred Swiss mice classified as susceptible or resistant to ethanol-induced locomotor sensitization.

    PubMed

    de Pauli, Ricardo Fontão; Coelhoso, Cássia Canha; Tesone-Coelho, Carolina; Linardi, Alessandra; Mello, Luiz Eugênio; Silveira, Dartiu Xavier; Santos, Jair Guilherme

    2014-02-01

    Several studies have focused on the negative emotional state associated with drug abstinence. The peptide NPY plays an important role given its involvement in drug addiction, anxiety, and mood disorders. Interestingly, it is well established that outbred Swiss mice exhibit a prominent behavioral variability to ethanol-induced locomotor sensitization. Here, we investigated whether mice that were either susceptible or resistant to ethanol sensitization differed in their NPY expression during abstinence. The mice were treated daily with ethanol (2 g/kg, i.p.) or saline for 21 days. According to the locomotor activity after the last injection, the ethanol group was classified as sensitized (EtOH_High) or non-sensitized (EtOH_Low). To evaluate NPY expression, some of the mice were sacrificed at 18 h or 5 days of abstinence, and others were challenged at the 5th day of abstinence with ethanol (1.4 g/kg) and sacrificed after 1.5 h. At 5 days of abstinence, NPY expression increased in the orbital cortex, dorsomedial striatum, and dentate gyrus in the EtOH_High mice. These changes were counteracted by the ethanol challenge. In the EtOH_Low mice, NPY expression increased in the dentate gyrus only after 18 h of abstinence. Lastly, a decreased level of NPY was found in the prelimbic cortex of the EtOH_Low mice at 5 days of abstinence, and this was reversed by ethanol challenge. Therefore, behavioral variability in ethanol sensitization confers differential neurochemical features during the subsequent abstinence, including distinct patterns of NPY expression.

  9. An Allosteric Potentiator of the Dopamine D1 Receptor Increases Locomotor Activity in Human D1 Knock-In Mice without Causing Stereotypy or Tachyphylaxis

    PubMed Central

    Heinz, Beverly A.; Schaus, John M.; Beck, James P.; Hao, Junliang; Krushinski, Joseph H.; Reinhard, Matthew R.; Cohen, Michael P.; Hellman, Sarah L.; Getman, Brian G.; Wang, Xushan; Menezes, Michelle M.; Maren, Deanna L.; Falcone, Julie F.; Anderson, Wesley H.; Wright, Rebecca A.; Morin, S. Michelle; Knopp, Kelly L.; Adams, Benjamin L.; Rogovoy, Borys; Okun, Ilya; Suter, Todd M.; Statnick, Michael A.; Gehlert, Donald R.; Nelson, David L.; Lucaites, Virginia L.; Emkey, Renee; DeLapp, Neil W.; Wiernicki, Todd R.; Cramer, Jeffrey W.; Yang, Charles R.; Bruns, Robert F.

    2017-01-01

    Allosteric potentiators amplify the sensitivity of physiologic control circuits, a mode of action that could provide therapeutic advantages. This hypothesis was tested with the dopamine D1 receptor potentiator DETQ [2-(2,6-dichlorophenyl)-1-((1S,3R)-3-(hydroxymethyl)-5-(2-hydroxypropan-2-yl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one]. In human embryonic kidney 293 (HEK293) cells expressing the human D1 receptor, DETQ induced a 21-fold leftward shift in the cAMP response to dopamine, with a Kb of 26 nM. The maximum response to DETQ alone was ∼12% of the maximum response to dopamine, suggesting weak allosteric agonist activity. DETQ was ∼30-fold less potent at rat and mouse D1 receptors and was inactive at the human D5 receptor. To enable studies in rodents, an hD1 knock-in mouse was generated. DETQ (3–20 mg/kg orally) caused a robust (∼10-fold) increase in locomotor activity (LMA) in habituated hD1 mice but was inactive in wild-type mice. The LMA response to DETQ was blocked by the D1 antagonist SCH39166 and was dependent on endogenous dopamine. LMA reached a plateau at higher doses (30–240 mg/kg) even though free brain levels of DETQ continued to increase over the entire dose range. In contrast, the D1 agonists SKF 82958, A-77636, and dihydrexidine showed bell-shaped dose-response curves with a profound reduction in LMA at higher doses; video-tracking confirmed that the reduction in LMA caused by SKF 82958 was due to competing stereotyped behaviors. When dosed daily for 4 days, DETQ continued to elicit an increase in LMA, whereas the D1 agonist A-77636 showed complete tachyphylaxis by day 2. These results confirm that allosteric potentiators may have advantages compared with direct-acting agonists. PMID:27811173

  10. Bromocriptine and quinpirole, but not 7-OH-DPAT or SKF 38393, potentiate the inhibitory effect of L-NAME on ethanol-induced locomotor activity in mice.

    PubMed

    Uzbay, I Tayfun; Kayir, Hakan

    2003-04-01

    The effects of N(G)-nitro- l-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor, SKF 38393, bromocriptine (BRM), quinpirole (QPR) and 7-hydroxy-2-dipropylaminotetralin (7-OH-DPAT), dopamine receptor agonists, and combinations of the dopamine agonists and L-NAME on ethanol-induced locomotor activity in adult male Swiss-Webster mice were investigated. The mice were given ethanol (0.5-2 g/kg), L-NAME (15-60 mg/kg), SKF 38393 (5-20 mg/kg), BRM (2.5 and 5 mg/kg), QPR (0.25 and 0.5 mg/kg), 7-OH-DPAT (0.5 and 1.0 mg/kg), a combination of l-arginine (1 g/kg) and L-NAME (60 mg/kg), combinations of SKF 38393, BRM, QPR or 7-OH-DPAT with L-NAME (60 mg/kg) or ethanol (0.5 g/kg) and saline or vehicle by i.p. injection. Triple combinations (dopaminergic agonist, 60 mg/kg L-NAME and 0.5 g/kg ethanol) were also given. Locomotor activity was measured for 30 min immediately following ethanol injections. Ethanol (0.5 g/kg) significantly increased locomotor activity. L-NAME, BRM, QPR and 7-OH-DPAT blocked the ethanol (0.5 g/kg)-induced locomotor hyperactivity dose dependently and at doses that did not affect locomotor activity in naive mice when administered alone. The inhibitory effects of L-NAME (60 mg/kg) were not prevented by pretreatment with l-arginine. BRM and QPR, but not 7-OH-DPAT, significantly and dose-dependently potentiated the inhibitory effect of L-NAME. Our results suggest that L-NAME inhibits ethanol-induced locomotor hyperactivity in mice by a mechanism not involving NO. The inhibitory effect of L-NAME may be related to the activation of presynaptic dopamine D(2) receptors rather than dopamine D(3) receptors.

  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.

  12. The potentiating effect of sertraline and fluoxetine on amphetamine-induced locomotor activity is not mediated by serotonin.

    PubMed

    Sills, T L; Greenshaw, A J; Baker, G B; Fletcher, P J

    1999-04-01

    Sertraline dose-dependently increased the locomotor stimulating effect of amphetamine. At the highest dose, 20 mg/kg sertraline had a biphasic effect on amphetamine-induced hyperactivity, producing an initial reduction in amphetamine-induced hyperactivity that was later followed by an augmentation of amphetamine-induced hyperactivity in the last hour of the 3-h test. Sertraline, at doses of 5 and 10 mg/kg, produced an augmentation of amphetamine-induced hyperactivity over the last 2 h of the 3-h test session. Further, there was an increase in the concentration of amphetamine in the brain in rats pretreated with 5 mg/kg sertraline. Both sertraline (5 mg/kg) and fluoxetine (5 mg/kg) produced an augmentation of amphetamine-induced hyperactivity that was unaltered by a serotonergic lesion of the median and dorsal raphe nuclei that resulted in a greater than 90% depletion of serotonin in hippocampus, striatum, and nucleus accumbens. Further, both sertraline and fluoxetine inhibited spontaneous locomotor activity and this effect was also unaltered by the depletion of serotonin. Thus, serotonergic neurotransmission is not essential for the effects of sertraline and fluoxetine on spontaneous and amphetamine-induced locomotion. It is probable that sertraline and fluoxetine augment the locomotor stimulatory effect of amphetamine by decreasing the metabolism of amphetamine, perhaps via actions on cytochrome P450 isozymes.

  13. Stress-Induced Locomotor Sensitization to Amphetamine in Adult, but not in Adolescent Rats, Is Associated with Increased Expression of ΔFosB in the Nucleus Accumbens

    PubMed Central

    Carneiro de Oliveira, Paulo E.; Leão, Rodrigo M.; Bianchi, Paula C.; Marin, Marcelo T.; Planeta, Cleopatra da Silva; Cruz, Fábio C.

    2016-01-01

    While clinical and pre-clinical evidence suggests that adolescence is a risk period for the development of addiction, the underlying neural mechanisms are largely unknown. Stress during adolescence has a huge influence on drug addiction. However, little is known about the mechanisms related to the interaction among stress, adolescence and addiction. Studies point to ΔFosB as a possible target for this phenomenon. In the present study, adolescent and adult rats (postnatal day 28 and 60, respectively) were restrained for 2 h once a day for 7 days. Three days after their last exposure to stress, the animals were challenged with saline or amphetamine (1.0 mg/kg i.p.) and amphetamine-induced locomotion was recorded. Immediately after the behavioral tests, rats were decapitated and the nucleus accumbens was dissected to measure ΔFosB protein levels. We found that repeated restraint stress increased amphetamine-induced locomotion in both the adult and adolescent rats. Furthermore, in adult rats, stress-induced locomotor sensitization was associated with increased expression of ΔFosB in the nucleus accumbens. Our data suggest that ΔFosB may be involved in some of the neuronal plasticity changes associated with stress induced-cross sensitization with amphetamine in adult rats. PMID:27672362

  14. 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

  15. Subchronic MK-801 treatment and post-weaning social isolation in rats: differential effects on locomotor activity and hippocampal long-term potentiation.

    PubMed

    Ashby, Donovan M; Habib, Diala; Dringenberg, Hans C; Reynolds, James N; Beninger, Richard J

    2010-09-01

    Subchronic NMDA receptor antagonist treatment and post-weaning social isolation are two animal models of schizophrenia symptoms. However, behavioral and physiological changes following a combination of these two procedures have not been investigated. Thus, we examined effects of a novel, "double hit" model combining these two treatments, comparing them to standard models involving only NMDA antagonist treatment or social isolation. Male, Sprague-Dawley rats were either group-housed or maintained in social isolation (starting at postnatal day [PD] 21 and continuing throughout the study). Each housing condition was further subdivided into two groups, receiving either subchronic treatment with either saline or MK-801 (0.5mg/kg, i.p., 2xday for seven days starting at PD 56). Post-weaning social isolation increased locomotor activity (assessed at PD 70) in response to a novel environment and an acute amphetamine injection, while subchronic MK-801 increased only amphetamine induced locomotor activity. Subsequent electrophysiological experiments (under urethane anesthesia) assessing changes in plasticity of hippocampal synapses showed that subchronic MK-801 treatment resulted in an increase in long-term potentiation in area CA1 in response to high frequency stimulation of the contralateral CA3 area, while housing condition had no effect. No other changes in hippocampal electrophysiology (input-output curves, paired-pulse facilitation) were observed. These data are the first to demonstrate an enhancement in hippocampal long-term plasticity in vivo following subchronic MK-801 administration, an effect that may be related to the well-characterized changes in glutamatergic and GABAergic systems seen after subchronic NMDA receptor blockade. That lack of additive or synergistic effects in the "double hit model" suggests that combining isolation and subchronic MK-801 treatment does not necessarily produce greater behavioral or physiological dysfunction than that seen with either

  16. Supplementation of Spirulina (Arthrospira platensis) Improves Lifespan and Locomotor Activity in Paraquat-Sensitive DJ-1β(Δ93) Flies, a Parkinson's Disease Model in Drosophila melanogaster.

    PubMed

    Kumar, Ajay; Christian, Pearl K; Panchal, Komal; Guruprasad, B R; Tiwari, Anand K

    2017-09-03

    Spirulina (Arthrospira platensis) is a cyanobacterium (blue-green alga) consumed by humans and other animals because of its nutritional values and pharmacological properties. Apart from high protein contents, it also contains high levels of antioxidant and anti-inflammatory compounds, such as carotenoids, β-carotene, phycocyanin, and phycocyanobilin, indicating its possible pharmaco-therapeutic utility. In the present study using DJ-1β(Δ93) flies, a Parkinson's disease model in Drosophila, we have demonstrated the therapeutic effect of spirulina and its active component C-phycocyanin (C-PC) in the improvement of lifespan and locomotor behavior. Our findings indicate that dietary supplementation of spirulina significantly improves the lifespan and locomotor activity of paraquat-fed DJ-1β(Δ93) flies. Furthermore, supplementation of spirulina and C-PC individually and independently reduced the cellular stress marked by deregulating the expression of heat shock protein 70 and Jun-N-terminal kinase signaling in DJ-1β(Δ93) flies. A significant decrease in superoxide dismutase and catalase activities in spirulina-fed DJ-1β(Δ93) flies tends to indicate the involvement of antioxidant properties associated with spirulina in the modulation of stress-induced signaling and improvement in lifespan and locomotor activity in Drosophila DJ-1β(Δ93) flies. Our results suggest that antioxidant boosting properties of spirulina can be used as a nutritional supplement for improving the lifespan and locomotor behavior in Parkinson's disease.

  17. 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

  18. 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.

  19. 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

  20. Phenolsulfonphthalein transport by potential-sensitive urate transport system.

    PubMed

    Itagaki, Shirou; Shimamoto, Soji; Sugawara, Mitsuru; Kobayashi, Michiya; Miyazaki, Katsumi; Hirano, Takeshi; Iseki, Ken

    2005-08-22

    The purpose of this study was to elucidate the transporter-mediated secretion systems for phenolsulfonphthalein in brush-border membranes. In human and rat renal brush-border membranes, a potential-sensitive transport system has been shown to be involved in the efflux of organic anions. The uptake of phenolsulfonphthalein into rat renal brush-border membrane vesicles was stimulated by an inside-positive membrane potential. This potential-sensitive uptake of phenolsulfonphthalein was inhibited by probenecid, pyrazinoate and urate. p-Aminohippurate had no effect on the potential-sensitive uptake of phenolsulfonphthalein. Moreover, urate competitively inhibited the uptake of phenolsulfonphthalein. On the other hand, the uptake of phenolsulfonphthalein was slightly increased in the presence of an outward Cl- gradient. These results suggest that phenolsulfonphthalein has high affinity for the potential-sensitive urate transport system but has low affinity for an anion exchanger.

  1. Long-lasting changes in morphine-induced locomotor sensitization and tolerance in Long-Evans mother rats as a result of periodic postpartum separation from the litter: a novel model of increased vulnerability to drug abuse?

    PubMed

    Kalinichev, Mikhail; Easterling, Keith W; Holtzman, Stephen G

    2003-02-01

    Daily postpartum separations from the litter produce enduring changes in anxiety and sensitivity to the antinociceptive effects of morphine in Long-Evans dams. We tested whether postpartum experience alters sensitivity to the effects of morphine on locomotor activity. Dams were tested 4-6 weeks after their pups were weaned, and had one of the following backgrounds: daily separation from the litter on postpartum days 2-14 for either 3 h (prolonged separation-LS) or 15 min (brief separation-BS), or no separation (nonhandled control-NH). After 2 consecutive days (B1-2) of baseline activity measurements, subjects were tested daily after s.c. injections of either morphine (10 mg/kg) or saline for 7 days and again on day 10. Beginning 5 days later, saline and 1.0-10 mg/kg of morphine were tested in all dams. On B1, LS and BS dams habituated slower than NH controls, yielding higher horizontal counts. LS dams failed to habituate across baseline days and were more active than other dams on B2. Sensitization, a progressive increase in horizontal activity, was more rapid and robust in LS and BS dams compared to NH animals. LS was the only group that developed tolerance to morphine-induced decreases in vertical activity. In LS dams with the history of morphine treatment, injection of saline resulted in higher horizontal activity and center time compared to saline-treated counterparts, indicative of conditioning. Among animals with a history of saline treatment, LS dams were more sensitive to morphine challenges than BS and NH dams. As a result of the robust and long-lasting increases in the ability of morphine to induce behavioral sensitization in litter-separated dams, periodic postpartum separation may represent a new animal model of increased vulnerability to substance abuse.

  2. Inhibiting AP-1 activity alters cocaine induced gene expression and potentiates sensitization

    PubMed Central

    Paletzki, Ronald F.; Myakishev, Max V.; Polesskaya, Oksana; Orosz, Andras; Hyman, Steven E.; Vinson, Charles

    2008-01-01

    We have expressed A-FOS, an inhibitor of AP-1 DNA binding, in adult mouse striatal neurons. We observe 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 responses to cocaine. We analyzed mRNA from the striatum before and 4 and 24 hours 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 hours following cocaine treatment relative to controls. However, 24 hours after an acute cocaine treatment, 84 genes were identified that were differentially expressed between the A-FOS and control mice. 56 gene are down regulated while 28 genes are up regulated including previously identified candidates for addiction including BDNF and Per1. 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 to human genome scans of addiction to identify potential genes in humans that are involved in addiction. PMID:18355967

  3. *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...

  4. Locomotor adaptations of some gelatinous zooplankton.

    PubMed

    Bone, Q

    1985-01-01

    Swimming behaviour and locomotor adaptations are described in chaetognaths, larvacean tunicates, some cnidaria, and thaliacean tunicates. The first two groups swim by oscillating a flattened tail, the others by jet propulsion. In chaetognaths, the locomotor muscle fibres are extensively coupled and relatively sparsely innervated, they exhibit compound spike-like potentials. The motoneurons controlling the rhythmic activity of the locomotor muscle lie in a ventral ganglion whose organization is briefly described. Rhythmic swimming bursts in larvaceans are similarly driven by a caudal ganglion near the base of the tail, but each caudal muscle cell is separately innervated by two sets of motor nerves, as well as being coupled to its neighbours. The external epithelium is excitable, and linked to the caudal ganglion by the axons of central cells. Mechanical stimulation of the epithelium evokes receptor potentials followed by action potentials and by bursts of rapid swimming. The trachyline medusa Aglantha and the small siphonophore Chelophyes also show rapid escape responses; in Aglantha these are driven by a specialized giant axon system lacking in other hydromedusae, and in Chelophyes. Slow swimming in Aglantha apparently involves a second nerve supply to the same muscle sheets used in rapid swimming, whereas in Chelophyes slow swimming results from the activity of the smaller posterior nectophore. Slow swimming in siphonophores is more economical than the rapid responses. In the hydrozoan medusa Polyorchis (as in Chelophyes) action potentials in the locomotor muscle sheet change in shape during swimming bursts, and their duration is related to the size of the medusa; they are not simply triggers of muscular contraction. The two groups of thaliacean tunicates are specialized differently. Doliolum is adapted for single rapid jet pulses (during which it achieves instantaneous velocities of 50 body lengths s-l), whilst salps are adapted for slow continuous swimming. The

  5. 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.

  6. 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

  7. Auditory evoked potential could reflect emotional sensitivity and impulsivity

    PubMed Central

    Kim, Ji Sun; Kim, Sungkean; Jung, Wookyoung; Im, Chang-Hwan; Lee, Seung-Hwan

    2016-01-01

    Emotional sensitivity and impulsivity could cause interpersonal conflicts and neuropsychiatric problems. Serotonin is correlated with behavioral inhibition and impulsivity. This study evaluated whether the loudness dependence of auditory evoked potential (LDAEP), a potential biological marker of central serotonergic activity, could reflect emotional sensitivity and impulsivity. A total of 157 healthy individuals were recruited, who performed LDAEP and Go/Nogo paradigms during electroencephalogram measurement. Barratt impulsivity scale (BIS), Conners’ Adult ADHD rating scale (CAARS), and affective lability scale (ALS) were evaluated. Comparison between low and high LDAEP groups was conducted for behavioural, psychological, and event-related potential (ERP) measures. The high LDAEP group showed significantly increased BIS, a subscale of the CAARS, ALS, and false alarm rate of Nogo stimuli compared to the low LDAEP group. LDAEP showed significant positive correlations with the depression scale, ALS scores, subscale of the CAARS and Nogo-P3 amplitude. In the source activity of Nogo-P3, the cuneus, lingual gyrus, and precentral gyrus activities were significantly increased in the high LDAEP group. Our study revealed that LDAEP could reflect emotional sensitivity and impulsivity. LDAEP, an auditory evoked potential could be a useful tool to evaluate emotional regulation. PMID:27910865

  8. Sensitivity of Global Warming Potentials to the assumed background atmosphere

    SciTech Connect

    Wuebbles, D.J.; Patten, K.O.

    1992-03-05

    This is the first in a series of papers in which we will examine various aspects of the Global Warming Potential (GWP) concept and the sensitivity and uncertainties associated with the GWP values derived for the 1992 updated scientific assessment report of the Intergovernmental Panel on Climate Change (IPCC). One of the authors of this report (DJW) helped formulate the GWP concept for the first IPCC report in 1990. The Global Warming Potential concept was developed for that report as an attempt to fulfill the request from policymakers for a way of relating the potential effects on climate from various greenhouse gases, in much the same way as the Ozone Depletion Potential (ODP) concept (Wuebbles, 1981) is used in policy analyses related to concerns about the relative effects of CFCs and other compounds on stratospheric ozone destruction. We are also coauthors of the section on radiative forcing and Global Warming Potentials for the 1992 IPCC update; however, there was too little time to prepare much in the way of new research material for that report. Nonetheless, we have recognized for some time that there are a number of uncertainties and limitations associated with the definition of GWPs used in both the original and new IPCC reports. In this paper, we examine one of those uncertainties, namely, the effect of the assumed background atmospheric concentrations on the derived GWPs. Later papers will examine the sensitivity of GWPs to other uncertainties and limitations in the current concept.

  9. Evaluation of the skin sensitizing potential of biodegradable magnesium alloys.

    PubMed

    Witte, Frank; Abeln, Inken; Switzer, Elinor; Kaese, Volker; Meyer-Lindenberg, Andrea; Windhagen, Henning

    2008-09-15

    Corroding metals made of magnesium alloys represent a new class of degradable implants for musculoskeletal surgery. These implants may be associated with skin sensitizing reactions because of the release of metal ions. This study was conducted to compare the sensitizing potential of four different magnesium alloys (AZ31, AZ91, WE43, and LAE442) to current implant materials such as titanium (TiAl6V4) and a degradable polymer (SR-PLA96). Solutions and solid chips of these materials were prepared and tested in 156 guinea pigs according to the Magnusson-Kligman test. A standard allergen (hydroxy-cinnamon-aldehyde) causing allergic erythema was used as positive control and a standard irritant (sodium-lauryl-sulfate) causing local skin irritation for less than 24 h was used as negative control. All erythema were graded immediately and 24 h after patch removal by three independent observers. Histomorphological analyses were performed on skin biopsies taken 24 h after patch removal. We found that initial erythema in animals treated with solid chips diminished within 24 h and were caused by local skin irritation. Local skin irritation was also determined in erythema remaining for 24 h after patch removal in animals treated with dissolved test materials. No allergenic reactions according to the histomorphological criteria were observed in skin biopsies. We conclude that no skin sensitizing potential were detected for standard materials as well as for all tested magnesium alloys by the used methods.

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

    PubMed Central

    Cui, Guiying

    2015-01-01

    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

  11. 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.

  12. 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

  13. Movement Exploration and Locomotor Skills.

    ERIC Educational Resources Information Center

    National Center on Educational Media and Materials for the Handicapped, Columbus, OH.

    Selected from the National Instructional Materials Information System (NIMIS)--a computer based on-line interactive retrieval system on special education materials--the bibliography covers 23 materials for teaching movement exploration and locomotor skills to handicapped students at all educational levels. Entries are presented in order of NIMIS…

  14. White - cGMP Interaction Promotes Fast Locomotor Recovery from Anoxia in Adult Drosophila

    PubMed Central

    2017-01-01

    Increasing evidence indicates that the white (w) gene in Drosophila possesses extra-retinal functions in addition to its classical role in eye pigmentation. We have previously shown that w+ promotes fast and consistent locomotor recovery from anoxia, but how w+ modulates locomotor recovery is largely unknown. Here we show that in the absence of w+, several PDE mutants, especially cyclic guanosine monophosphate (cGMP)-specific PDE mutants, display wildtype-like fast locomotor recovery from anoxia, and that during the night time, locomotor recovery was light-sensitive in white-eyed mutant w1118, and light-insensitive in PDE mutants under w1118 background. Data indicate the involvement of cGMP in the modulation of recovery timing and presumably, light-evoked cGMP fluctuation is associated with light sensitivity of locomotor recovery. This was further supported by the observations that w-RNAi-induced delay of locomotor recovery was completely eliminated by upregulation of cGMP through multiple approaches, including PDE mutation, simultaneous overexpression of an atypical soluble guanylyl cyclase Gyc88E, or sildenafil feeding. Lastly, prolonged sildenafil feeding promoted fast locomotor recovery from anoxia in w1118. Taken together, these data suggest that a White-cGMP interaction modulates the timing of locomotor recovery from anoxia. PMID:28060942

  15. 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

  16. Exendin-4 Decreases Amphetamine-induced Locomotor Activity

    PubMed Central

    Erreger, Kevin; Davis, Adeola R.; Poe, Amanda M.; Greig, Nigel H.; Stanwood, Gregg D.; Galli, Aurelio

    2012-01-01

    Glucagon-like peptide-1 (GLP-1) is released in response to nutrient ingestion and is a regulator of energy metabolism and consummatory behaviors through both peripheral and central mechanisms. The GLP-1 receptor (GLP-1R) is widely distributed in the central nervous system, however little is known about how GLP-1Rs regulate ambulatory behavior. The abused psychostimulant amphetamine (AMPH) promotes behavioral locomotor activity primarily by inducing the release of the neurotransmitter dopamine. Here, we identify the GLP-1R agonist exendin-4 (Ex-4) as a modulator of behavioral activation by AMPH. We report that in rats a single acute administration of Ex-4 decreases both basal locomotor activity as well as AMPH-induced locomotor activity. Ex-4 did not induce behavioral responses reflecting anxiety or aversion. Our findings implicate GLP-1R signaling as a novel modulator of psychostimulant-induced behavior and therefore a potential therapeutic target for psychostimulant abuse. PMID:22465309

  17. Strategies of locomotor collision avoidance.

    PubMed

    Basili, Patrizia; Sağlam, Murat; Kruse, Thibault; Huber, Markus; Kirsch, Alexandra; Glasauer, Stefan

    2013-03-01

    Collision avoidance during locomotion can be achieved by a variety of strategies. While in some situations only a single trajectory will successfully avoid impact, in many cases several different strategies are possible. Locomotor experiments in the presence of static boundary conditions have suggested that the choice of an appropriate trajectory is based on a maximum-smoothness strategy. Here we analyzed locomotor trajectories of subjects avoiding collision with another human crossing their path orthogonally. In such a case, changing walking direction while keeping speed or keeping walking direction while changing speed would be two extremes of solving the problem. Our participants clearly favored changing their walking speed while keeping the path on a straight line between start and goal. To interpret this result, we calculated the costs of the chosen trajectories in terms of a smoothness-maximization criterion and simulated the trajectories with a computational model. Data analysis together with model simulation showed that the experimentally chosen trajectory to avoid collision with a moving human is not the optimally smooth solution. However, even though the trajectory is not globally smooth, it was still locally smooth. Modeling further confirmed that, in presence of the moving human, there is always a trajectory that would be smoother but would deviate from the straight line. We therefore conclude that the maximum smoothness strategy previously suggested for static environments no longer holds for locomotor path planning and execution in dynamically changing environments such as the one tested here.

  18. 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…

  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. Sensitivity of direct global warming potentials to key uncertainties

    SciTech Connect

    Wuebbles, D.J.; Patten, K.O.; Grant, K.E. ); Jain, A.K. )

    1992-07-01

    A series of sensitivity studies examines the effect of several uncertainties in Global Wanning Potentials (GWPs). For example, the original evaluation of GWPs for the Intergovernmental Panel on Climate Change (EPCC, 1990) did not attempt to account for the possible sinks of carbon dioxide (CO{sub 2}) that could balance the carbon cycle and produce atmospheric concentrations of C0{sub 2} that match observations. In this study, a balanced carbon cycle model is applied in calculation of the radiative forcing from C0{sub 2}. Use of the balanced model produces up to 20 percent enhancement of the GWPs for most trace gases compared with the EPCC (1990) values for time horizons up to 100 years, but a decreasing enhancement with longer time horizons. Uncertainty limits of the fertilization feedback parameter contribute a 10 percent range in GWP values. Another systematic uncertainty in GWPs is the assumption of an equilibrium atmosphere (one in which the concentration of trace gases remains constant) versus a disequilibrium atmosphere. The latter gives GWPs that are 15 to 30 percent greater than the former, dependening upon the carbon dioxide emission scenario chosen. Seven scenarios are employed: constant emission past 1990 and the six EPCC (1992) emission scenarios. For the analysis of uncertainties in atmospheric lifetime ({tau}), the GWP changes in direct proportion to {tau} for short-lived gases, but to a lesser extent for gases with {tau} greater than the time horizon for the GWP calculation.

  1. Greater Ethanol-Induced Locomotor Activation in DBA/2J versus C57BL/6J Mice Is Not Predicted by Presynaptic Striatal Dopamine Dynamics

    PubMed Central

    Rose, Jamie H.; Calipari, Erin S.; Mathews, Tiffany A.; Jones, Sara R.

    2013-01-01

    A large body of research has aimed to determine the neurochemical factors driving differential sensitivity to ethanol between individuals in an attempt to find predictors of ethanol abuse vulnerability. Here we find that the locomotor activating effects of ethanol are markedly greater in DBA/2J compared to C57BL/6J mice, although it is unclear as to what neurochemical differences between strains mediate this behavior. Dopamine elevations in the nucleus accumbens and caudate-putamen regulate locomotor behavior for most drugs, including ethanol; thus, we aimed to determine if differences in these regions predict strain differences in ethanol-induced locomotor activity. Previous studies suggest that ethanol interacts with the dopamine transporter, potentially mediating its locomotor activating effects; however, we found that ethanol had no effects on dopamine uptake in either strain. Ex vivo voltammetry allows for the determination of ethanol effects on presynaptic dopamine terminals, independent of drug-induced changes in firing rates of afferent inputs from either dopamine neurons or other neurotransmitter systems. However, differences in striatal dopamine dynamics did not predict the locomotor-activating effects of ethanol, since the inhibitory effects of ethanol on dopamine release were similar between strains. There were differences in presynaptic dopamine function between strains, with faster dopamine clearance in the caudate-putamen of DBA/2J mice; however, it is unclear how this difference relates to locomotor behavior. Because of the role of the dopamine system in reinforcement and reward learning, differences in dopamine signaling between the strains could have implications for addiction-related behaviors that extend beyond ethanol effects in the striatum. PMID:24349553

  2. Limits to human locomotor performance: phylogenetic origins and comparative perspectives.

    PubMed

    Dudley, R

    2001-09-01

    Studies of human exercise physiology have been conducted from a largely ahistorical perspective. This approach usefully elucidates proximate limits to locomotor performance, but ignores potential sources of biomechanical and physiological variation that derive from adaptation to ancestral environments. Phylogenetic reconstruction suggests that multiple hominoid lineages, including that leading to Homo sapiens, evolved in African highlands at altitudes of 1000-2000 m. The evolution of human locomotor physiology therefore occurred under conditions of hypobaric hypoxia. In contrast to present-day humans running on treadmills or exercising in otherwise rectilinear trajectories, ancestral patterns of hominid locomotion probably involved intermittent knuckle-walking over variable terrain, occasional bouts of arboreality and an evolving capacity for bipedalism. All such factors represent potential axes of locomotor variation at present unstudied in extant hominoid taxa. As with humans, hummingbirds evolved in mid-montane contexts but pose an extreme contrast with respect to body size, locomotor mode and metabolic capacity. Substantial biomechanical and physiological challenges are associated with flight in hypobaria. Nonetheless, hummingbird lineages demonstrate a progressive invasion of higher elevations and a remarkable tolerance to hypoxia during hovering. Upregulation of aerobic capacity and parallel resistance to hypoxia may represent coupled evolutionary adaptations to flight under high-altitude conditions.

  3. Development of action potentials and apamin-sensitive after-potentials in mouse vestibular nucleus neurones.

    PubMed

    Dutia, M B; Johnston, A R

    1998-01-01

    The postnatal maturation of medial vestibular nucleus (MVN) neurones was examined in slices of the dorsal brainstem prepared from balb/c mice at specific stages during the first postnatal month. Using spike-shape averaging to analyse the intracellularly recorded action potentials and after-hyperpolarizations (AHPs) in each cell, all the MVN neurones recorded in the young adult (postnatal day 30; P30) mouse were shown to have either a single deep AHP (type A cells), or an early fast and a delayed slow AHP (type B cells). The relative proportions of the two subtypes were similar to those in the young adult rat. At P5, all the MVN cells recorded showed immature forms of either the type A or the type B action potential shape. Immature type A cells had broad spontaneous spikes, and the characteristic single AHP was small in amplitude. Immature type B cells had somewhat narrower spontaneous spikes that were followed by a delayed, apamin-sensitive AHP. The delayed AHP was separated from the repolarisation phase of the spike by a period of isopotentiality. Over the period P10-P15, the mean resting potentials of the MVN cells became more negative, their action potential fall-times became shorter, the single AHP in type A cells became deeper, and the early fast AHP appeared in type B cells. Until P15 cells of varying degrees of electrophysiological maturity were found in the MVN but by P30 all MVN cells recorded were typical adult type A or type B cells. Exposure to the selective blocker of SK-type Ca-activated K channels, apamin (0.3 microM), induced depolarising plateaux and burst firing in immature type B cells at rest. The duration of the apamin-induced bursts and the spike frequency during the bursts were reduced but not abolished after blockade of Ca channels in Ca-free artificial cerebrospinal fluid containing Cd2+. By contrast, in mature type B cells at rest apamin selectively abolished the delayed slow AHP but did not induce bursting activity. Apamin had no effect

  4. 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...

  5. Dermal Sensitization Potential of Guanidine Hydrochloride in Guinea Pigs

    DTIC Science & Technology

    1986-01-09

    Landsteiner K, Jacobs J. Studies on sensitization of animals with . simple chemical compounds. J Exp Med 1935; 61:643-656. 4. Buehler EV. Delayed...An.flytical data/pnirity: Water content 0.1% by Karl Fischer analysts.* The material is at least 98% pure and chromatographs 6 as one spot by thin

  6. 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…

  7. Emerging contaminants: a potential human health concern for sensitive populations.

    PubMed

    Mangalgiri, Kiranmayi P; He, Ke; Blaney, Lee

    2015-01-01

    Pharmaceuticals and other xenobiotic molecules are being increasingly detected in drinking water, food crops, and breast milk. This issue represents a novel toxicological concern, especially for sensitive populations like pregnant women and breastfeeding infants. This commentary calls for more interdisciplinary research efforts focused on elucidating the transfer of contaminants of emerging concern from mother to child, as well as the relevant toxicological impacts on the child. The need for more tangible efforts to reduce pharmaceutical loads in environmental systems is also highlighted.

  8. 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

  9. Capturing the Potential of Dye-Sensitized Solar Cells

    NASA Astrophysics Data System (ADS)

    Benson, James

    2010-10-01

    Dye-sensitized solar cells are a continually developing type of low-cost solar cells that have commercial efficiency around 6-10%. The proposed research here will be focusing on the photo-bleaching and improving techniques for electron transport. Nature has given us a goal to reach towards with proven techniques for converting light into energy with around 30-40% efficiency, however, chlorophyll, the light absorber in plants, is expensive and it is not practical to make solar cells with only chlorophyll as the absorber. One such alternative to chlorophyll is phthalocyanines which is a common industrial dye used in many applications. This dye has a common similar ring without the long phytol chain that chlorophyll has. Previous research has shown that encapsulating organic dyes can magnify the properties of dye from the increased concentration with a possible benefit of stabilizing the dye allowing it to slow down the photo bleaching significantly. Likewise, such encapsulation may help with thermal stability since many dye-sensitized solar cells require a liquid or gel solution that is sensitive to thermal expansion. Many researchers are also finding new ways to encapsulate the dyes or dope the p-n layers with nano and meso tubes to help with electron transport or build the p-n layers right in the tubes. This allows for countless layers and an overall more efficient design.

  10. The role of age, genotype, sex, and route of acute and chronic administration of methylphenidate: a review of its locomotor effects.

    PubMed

    Dafny, Nachum; Yang, Pamela B

    2006-02-15

    Children with attention deficit hyperactivity disorder (ADHD) are treated for extended periods of time with the psychostimulant methylphenidate (MPD). The psychostimulants cocaine, amphetamine, and MPD exhibit similar structural configuration and pharmacological profile. The consequence of the long-term use of psychostimulants such as MPD as treatment for ADHD in the developing brain of children is unknown. Repeated treatment with psychostimulants has been shown to elicit adverse effects in behavior, such as dependence, paranoia, schizophrenia, and behavioral sensitization. Behavioral sensitization and cross-sensitization between two drugs are used as experimental markers to determine the potential of a drug to develop dependence/addiction. Although there are many reviews written about behavioral sensitization involving psychostimulants, scarcely any have focused specifically on MPD-elicited behavioral sensitization and cross-sensitization with other psychostimulants. Moreover, the response to MPD and the expression of ADHD vary among females and males and among different populations due to genetic variability. Since the interpretation and synthesis of the data reported are controversial, this review focuses on the adverse effects of MPD and the role of age, sex, and genetic composition on the acute and chronic effects of MPD, such as MPD-elicited behavioral sensitization and cross-sensitization with amphetamine in animal models. Animal models of drug-induced locomotor stimulation, particularly locomotor sensitization, can be used to understand the mechanisms underlying human drug-induced dependence.

  11. Action potentials of isolated single muscle fibers recorded by potential-sensitive dyes

    PubMed Central

    Nakajima, S.; Gilai, A.

    1980-01-01

    Light transmission changes upon massive stimulation of single muscle fibers of Xenopus were studied with the potential-sensitive nonpermeant dyes, merocyanine rhodanine (WW375) and merocyanine oxazolone (NK2367). Upon stimulation an absorption change (wave a) occurred, which probably represents the sum of action potentials in the transverse tubules and surface membrane. In WW375-stained fibers wave a is a decrease in transmission over the range of 630 to 730 nm (with NK2367, over the range of 590 to 700 nm) but becomes an increase outside this range, thus showing a triphasic spectral pattern. This spectrum differs from that of the squid axon, in which depolarization produces only an increase in transmission over the whole range of wavelengths (Ross et al. 1977. J. Membr. Biol. 33:141-183). When wave a was measured at the edge of the fiber to obtain more signal from the surface membrane, the spectrum did not seem to differ markedly from that obtained from the entire width of the fiber. Thus, the difference in the spectrum between the squid axon and the vertebrate muscle cannot be attributed to the presence of the tubular system. PMID:10822501

  12. Dermal Sensitization Potential of Niclosamide in Guinea Pigs

    DTIC Science & Technology

    1988-09-01

    compound were observed in any of the animals that remained in the study. Pathologic changes consistent with subclinical salmonellosis were observed in...potential. The presence of subclinical salmonellosis in the study animals did not appear to compromise the study results. Ten study animals assigned...the negative control group showed evidence of salmonellosis . None of these animals responded to the challenge dose of the test compound, which indicates

  13. Skin sensitizers induce antioxidant response element dependent genes: application to the in vitro testing of the sensitization potential of chemicals.

    PubMed

    Natsch, Andreas; Emter, Roger

    2008-03-01

    Tests for skin sensitization are required prior to the market launch of new cosmetic ingredients and in vitro tests are needed to replace the current animal tests. Protein reactivity is the common feature of skin sensitizers and it is a crucial question whether a cellular in vitro assay can detect protein reactivity of diverse test chemicals. The signaling pathway involving the repressor protein Keap1 and the transcription factor nuclear factor-erythroid 2-related factor 2, which binds to the antioxidant response element (ARE) in the promoter of many phase II detoxification genes, is a potential cellular marker because Keap1 had been shown to be covalently modified by electrophiles which leads to activation of ARE-dependent genes. To evaluate whether this regulatory pathway can be used to develop a predictive cellular in vitro test for sensitization, 96 different chemicals of known skin sensitization potential were added to Hepa1C1C7 cells and the induction of the ARE-regulated quinone reductase (QR) activity was determined. In parallel, 102 chemicals were tested on the reporter cell line AREc32, which contains an eightfold repeat of the ARE sequence upstream of a luciferase gene. Among the strong/extreme skin sensitizers 14 out of 15 and 30 out of 34 moderate sensitizers induced the ARE-dependent luciferase activity and in many cases this response was paralleled by an induction of QR activity in Hepa1C1C7 cells. Sixty percent of the weak sensitizers also induced luciferase activity, and the overall accuracy of the assay was 83 percent. Only four of 30 tested nonsensitizers induced low levels of luciferase activity, indicating a high specificity of the assay. Thus, measurement of the induction of this signaling pathway provides an interesting in vitro test to screen for the skin sensitization potential of novel chemicals.

  14. 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

  15. [Semax potentiates effects of D-amphetamine on the level of extracellular dopamine in the Sprague-Dawley rat striatum and on the locomotor activity of C57BL/6 mice].

    PubMed

    Eremin, K O; Saransaari, P; Oja, S; Raevskiĭ, K S

    2004-01-01

    The synthetic peptide semax (a fragment of ACTH 4-7 Pro-Gly-Pro) enhances the release of extracell dopamine (DA) induced by D-amphetamine (5 mg/kg) in the striatum of Spraig-Dowley (SD) rats and increases the locomotor activity stimulated by D-amphetamine (2 mg/kg) in C57/BL6 mice. The basal content of DA, 3,4-dihydroxyphenylacetic acid (DHPAA), and homovanillic acid (HVA) in dialysate of SD rats was 0.5-1.0, 996 +/- 25, and 761 +/- 37 pmole/ml, respectively (n = 7). D-amphetamine (5 mg/kg) induced a sharp increases in the DA level (up to 20 pmole/ml) 20-40 min after treatment and reduced the extracell DHPAA content to 30% of the basal level for a prolonged time (over the entire experimental period). Preliminary (20 min before D-amphetamine) administration of semax resulted in a greater peak of DA concentration (p < 0.05) and a more pronounced drop in DHPAA level (p < 0.01) as compared to the effects produced by the psychostimulant alone. In behavioral tests on C57/BL6 mice, D-amphetamine (2 mg/kg) increased the locomotor activity to a level of 182% (p < 0.01). Simultaneous introduction of semax (0.6 mg/kg) and D-amphetamine (2 mg/kg) led to a more pronounced increase in the locomotor activity of mice (261%, p < 0.01). It is suggested that the peptide modulates dopaminergic systems involved in the formation of the psychostimulant effect.

  16. 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.

  17. Dynamics and plasticity of spinal locomotor circuits.

    PubMed

    El Manira, Abdeljabbar

    2014-12-01

    Spinal circuits generate coordinated locomotor movements. These hardwired circuits are supplemented with neuromodulation that provide the necessary flexibility for animals to move smoothly through their environment. This review will highlight some recent insights gained in understanding the functional dynamics and plasticity of the locomotor circuits. First the mechanisms governing the modulation of the speed of locomotion will be discussed. Second, advantages of the modular organization of the locomotor networks with multiple circuits engaged in a task-dependent manner will be examined. Finally, the neuromodulation and the resulting plasticity of the locomotor circuits will be summarized with an emphasis on endocannabinoids and nitric oxide. The intention is to extract general principles of organization and discuss some onto-genetic and phylogenetic divergences.

  18. 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.

  19. Repeatability of locomotor performance and morphology-locomotor performance relationships.

    PubMed

    Conradsen, Cara; Walker, Jeffrey A; Perna, Catherine; McGuigan, Katrina

    2016-09-15

    There is good evidence that natural selection drives the evolution of locomotor performance, but the processes that generate the among-individual variation for selection to act on are relatively poorly understood. We measured prolonged swimming performance, Ucrit, and morphology in a large cohort (n=461) of wild-type zebrafish (Danio rerio) at ∼6 months and again at ∼9 months. Using mixed-model analyses to estimate repeatability as the intraclass correlation coefficient, we determined that Ucrit was significantly repeatable (r=0.55; 95% CI: 0.45-0.64). Performance differences between the sexes (males 12% faster than females) and changes with age (decreasing 0.07% per day) both contributed to variation in Ucrit and, therefore, the repeatability estimate. Accounting for mean differences between sexes within the model decreased the estimate of Ucrit repeatability to 21% below the naïve estimate, while fitting age in the models increased the estimate to 14% above the naïve estimate. Greater consideration of factors such as age and sex is therefore necessary for the interpretation of performance repeatability in wild populations. Body shape significantly predicted Ucrit in both sexes in both assays, with the morphology-performance relationship significantly repeatable at the population level. However, morphology was more strongly predicative of performance in older fish, suggesting a change in the contribution of morphology relative to other factors such as physiology and behaviour. The morphology-performance relationship changed with age to a greater extent in males than females.

  20. Sex-related effects of agmatine on caffeine-induced locomotor activity in Swiss Webster mice.

    PubMed

    Uzbay, Tayfun; Kose, Akin; Kayir, Hakan; Ulusoy, Gokhan; Celik, Turgay

    2010-03-25

    In mammalian brain, agmatine is an endogenous amine that is synthesized through the decarboxylation of l-arginine by arginine decarboxylase. It has been proposed as a new neurotransmitter and/or neuromodulator. It was shown that agmatine had some beneficial effects in animal models of opioid and alcohol addiction. Locomotor stimulant properties of drugs such as ethanol, caffeine, nicotine and amphetamine have been linked to their addictive properties. The present study investigates the effects of agmatine on caffeine-induced locomotor activity both in male and female mice. Adult Swiss Webster mice were used in the study. Locomotor activity was measured for 30min immediately following caffeine (2.5, 5, 10 and 20mg/kg, i.p.) or saline treatments. Agmatine (5, 10 and 20mg/kg, i.p.) were injected 20min before caffeine (2.5 and 5mg/kg, i.p.) administration. In both sexes, agmatine (5-20mg/kg) were also tested for ability to depress or stimulate locomotor activity in the absence of caffeine. Caffeine (5mg/kg) induced a significant increase in locomotor activity of both male and female mice. There was no significant difference in the locomotor-activating effects of caffeine between male and female mice. Agmatine blocked the caffeine (5mg/kg)-induced locomotor stimulation dose dependently in male but not female mice. Agmatine had not any effect on the lower dose (2.5mg/kg) of caffeine in both sexes. These results suggest that agmatine has sex-related inhibitory effects on caffeine-induced locomotor activity in Swiss Webster mice, and male mice are more sensitive than the females to the effect of agmatine.

  1. 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

  2. Locomotor conditioning by amphetamine requires cyclin-dependent kinase 5 signaling in the nucleus accumbens.

    PubMed

    Singer, Bryan F; Neugebauer, Nichole M; Forneris, Justin; Rodvelt, Kelli R; Li, Dongdong; Bubula, Nancy; Vezina, Paul

    2014-10-01

    Intermittent systemic exposure to psychostimulants leads to several forms of long-lasting behavioral plasticity including nonassociative sensitization and associative conditioning. In the nucleus accumbens (NAcc), the protein serine/threonine kinase cyclin-dependent kinase 5 (Cdk5) and its phosphorylation target, the guanine-nucleotide exchange factor kalirin-7 (Kal7), may contribute to the neuroadaptations underlying the formation of conditioned associations. Pharmacological inhibition of Cdk5 in the NAcc prevents the increases in dendritic spine density normally observed in this site following repeated cocaine. Mice lacking the Kal7 gene display similar effects. As increases in spine density may relate to the formation of associative memories and both Cdk5 and Kal7 regulate the generation of spines following repeated drug exposure, we hypothesized that either inhibiting Cdk5 or preventing its phosphorylation of Kal7 in the NAcc may prevent the induction of drug conditioning. In the present experiments, blockade in rats of NAcc Cdk5 activity with roscovitine (40 nmol/0.5 μl/side) prior to each of 4 injections of amphetamine (1.5 mg/kg; i.p.) prevented the accrual of contextual locomotor conditioning but spared the induction of locomotor sensitization as revealed on tests conducted one week later. Similarly, transient viral expression in the NAcc exclusively during amphetamine exposure of a threonine-alanine mutant form of Kal7 [mKal7(T1590A)] that is not phosphorylated by Cdk5 also prevented the accrual of contextual conditioning and spared the induction of sensitization. These results indicate that signaling via Cdk5 and Kal7 in the NAcc is necessary for the formation of context-drug associations, potentially through the modulation of dendritic spine dynamics in this site.

  3. Identification of multisegmental nociceptive afferents that modulate locomotor circuits in the neonatal mouse spinal cord.

    PubMed

    Mandadi, Sravan; Hong, Peter; Tran, Michelle A; Bráz, Joao M; Colarusso, Pina; Basbaum, Allan I; Whelan, Patrick J

    2013-08-15

    Compared to proprioceptive afferent collateral projections, less is known about the anatomical, neurochemical, and functional basis of nociceptive collateral projections modulating lumbar central pattern generators (CPG). Quick response times are critical to ensure rapid escape from aversive stimuli. Furthermore, sensitization of nociceptive afferent pathways can contribute to a pathological activation of motor circuits. We investigated the extent and role of collaterals of capsaicin-sensitive nociceptive sacrocaudal afferent (nSCA) nerves that directly ascend several spinal segments in Lissauer's tract and the dorsal column and regulate motor activity. Anterograde tracing demonstrated direct multisegmental projections of the sacral dorsal root 4 (S4) afferent collaterals in Lissauer's tract and in the dorsal column. Subsets of the traced S4 afferent collaterals expressed transient receptor potential vanilloid 1 (TRPV1), which transduces a nociceptive response to capsaicin. Electrophysiological data revealed that S4 dorsal root stimulation could evoke regular rhythmic bursting activity, and our data suggested that capsaicin-sensitive collaterals contribute to CPG activation across multiple segments. Capsaicin's effect on S4-evoked locomotor activity was potent until the lumbar 5 (L5) segments, and diminished in rostral segments. Using calcium imaging we found elevated calcium transients within Lissauer's tract and dorsal column at L5 segments when compared to the calcium transients only within the dorsal column at the lumbar 2 (L2) segments, which were desensitized by capsaicin. We conclude that lumbar locomotor networks in the neonatal mouse spinal cord are targets for modulation by direct multisegmental nSCA, subsets of which express TRPV1 in Lissauer's tract and the dorsal column. J. Comp. Neurol. 521:2870-2887, 2013. © 2013 Wiley Periodicals, Inc.

  4. Potential biomarkers for paclitaxel sensitivity in hypopharynx cancer cell

    PubMed Central

    Xu, Cheng-Zhi; Shi, Run-Jie; Chen, Dong; Sun, Yi-Yuan; Wu, Qing-Wei; Wang, Tao; Wang, Pei-Hua

    2013-01-01

    Paclitaxel has been proved to be active in treatment and larynx preservation of HNSCC, however, the fact that about 20-40% patients do not respond to paclitaxel makes it urgent to figure out the biomarkers for paclitaxel-based treatment in Hypopharynx cancer (HPC) patients to improve the therapy effect. In this work, Fadu cells, treated or untreated with low dose of paclitaxel for 24 h, were applied to DNA microarray chips. The differential expression in mRNAs and miRs was analyzed and the network between expression-altered mRNAs and miRs was constructed. Differentially expressed genes were mainly enriched in superpathway of cholesterol biosynthesis (ACAT2, MSMO1, LSS, FDFT1 and FDPS etc.), complement system (C3, C1R, C1S, CFR and CFB etc.), interferon signaling (IFIT1, IFIT3, IFITM1 and MX1 etc.), mTOR signaling (MRAS, PRKAA2, PLD1, RND3 and EIF4A1 etc.) and IGF1 signaling (MRAS, IGFBP7, JUN and FOS etc.), most of these pathways are implicated in tumorigenesis or chemotherapy resistance. The first three pathways were predicted to be suppressed, while the last two pathways were predicted to be induced by paclitaxel, suggesting the combination therapy with mTOR inhibition and paclitaxel might be better than single one. The dramatically expression-altered miRs were miR-112, miR-7, miR-1304, miR-222*, miR-29b-1* (these five miRs were upregulated) and miR-210 (downregulated). The 26 putative target genes mediated by the 6 miRs were figured out and the miR-gene network was constructed. Furthermore, immunoblotting assay showed that ERK signaling in Fadu cells was active by low dose of paclitaxel but repressed by high dose of paclitaxel. Collectively, our data would provide potential biomarkers and therapeutic targets for paclitaxel-based therapy in HPC patients. PMID:24294361

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

    PubMed Central

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

    2015-01-01

    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 sloping walkway as their mothers encouraged and discouraged descent. A psychophysical procedure was used to estimate infants’ ability to crawl/walk down slopes, followed by test trials in which mothers encouraged and discouraged infants to crawl/walk down. Both locomotor experience and social incentives affected perceptual judgments. In the encourage condition, crawlers only attempted safe slopes within their abilities, but walkers repeatedly attempted impossibly risky slopes, replicating previous work. The discourage condition showed where judgments are most malleable. When mothers provided negative social incentives, crawlers occasionally avoided safe slopes, and walkers occasionally avoided the most extreme 50° increment, although they attempted to walk on more than half the trials. Findings indicate that both locomotor experience and social incentives play key roles in adaptive responding, but the benefits are specific to the posture that infants use for balance and locomotion. PMID:18999332

  6. Locomotor experience and use of social information are posture specific.

    PubMed

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

    2008-11-01

    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 sloping walkway as their mothers encouraged and discouraged descent. A psychophysical procedure was used to estimate infants' ability to crawl/walk down slopes, followed by test trials in which mothers encouraged and discouraged infants to crawl/walk down. Both locomotor experience and social incentives affected perceptual judgments. In the encourage condition, crawlers only attempted safe slopes within their abilities, but walkers repeatedly attempted impossibly risky slopes, replicating previous work. The discourage condition showed where judgments are most malleable. When mothers provided negative social incentives, crawlers occasionally avoided safe slopes, and walkers occasionally avoided the most extreme 50 degrees increment, although they attempted to walk on more than half the trials. Findings indicate that both locomotor experience and social incentives play key roles in adaptive responding, but the benefits are specific to the posture that infants use for balance and locomotion.

  7. 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.

  8. Locomotor activity and zonation of upper shore arthropods in a sandy beach of north central Chile

    NASA Astrophysics Data System (ADS)

    Jaramillo, E.; Contreras, H.; Duarte, C.; Avellanal, M. H.

    2003-10-01

    The tenebrionid beetle Phalerisida maculata Kulzer, the talitrid amphipod Orchestoidea tuberculata Nicolet and the oniscid isopod Tylos spinulosus Dana are semi-terrestrial burrowing species, which coexist on sandy beaches of north central Chile (28-30°S). During the night, these scavengers emerge to make downshore migrations. Given the similarity in niches of these three species (all are known to include macroalgal detritus in their diet) and their relatively high abundance on that beaches, there is the potential for some degree of interaction, both inter- and intraspecific. Field studies were carried out to examine zonation of these burrowing organisms and eventual time and/or space partitioning of locomotor activity during night hours. Locomotor activity on the beach surface was analyzed over 12 h periods during spring and neap tides of September and December 2000, and March 2001. Scavengers moving over the beach surface were captured using pitfall traps buried with their rims flush with the beach surface along a transect extended from the foot of the dunes to the highest levels reached by the swashes. Every 1 h the captured animals in the traps were collected. Locomotor activity was also studied in the laboratory with chambers equipped with infrared recording systems (actographs). Data downloaded from the actographs were graphed to obtain a display of locomotor activity per 15 min interval during the course of the 7 day experiments. Results show space partitioning of burrowed organisms and time partitioning in the locomotor activity of O. tuberculata, T. spinulosus and P. maculata over the beach surface. Circular statistics showed that usually the activity peaks of O. tuberculata were more different from those of P. maculata and T. spinulosus than those of the last two species when compared with each other. Intraspecific differences were also found in the surface locomotor activity, primarily between juveniles and adults of O. tuberculata. Interseasonal

  9. Locomotor expertise predicts infants' perseverative errors.

    PubMed

    Berger, Sarah E

    2010-03-01

    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 13-month-old infants crawled through a tunnel to reach a goal at the other end and received the same control condition as in Experiment 1. In both experiments, perseverative errors occurred more often in the high-demand condition than in the low-demand condition. Moreover, in Experiment 2, walkers perseverated more than crawlers, and extent of perseveration was related to infants' locomotor experience. In Experiment 3, the authors addressed a possible confound in Experiment 2 between locomotor expertise and locomotor posture. Novice crawlers perseverated in the difficult tunnels condition, behaving more like novice walkers than expert crawlers. As predicted by a cognitive capacity account of infant perseveration, overtaxed attentional resources resulted in a cognition-action trade-off. Experts who found the task less motorically effortful than novices had more cognitive resources available for problem solving.

  10. 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.

  11. HIGH ETHANOL DOSE DURING EARLY ADOLESCENCE INDUCES LOCOMOTOR ACTIVATION AND INCREASES SUBSEQUENT ETHANOL INTAKE DURING LATE ADOLESCENCE

    PubMed Central

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

    2011-01-01

    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, adolescents 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

  12. 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.

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

    PubMed

    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, Authorization and Restriction of chemical substances" (REACH, 2006) to replace animal models.

  14. 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.

  15. 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

  16. 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…

  17. Targeting drug sensitivity predictors: New potential strategies to improve pharmacotherapy of human brain disorders.

    PubMed

    Kalueff, Allan V; Stewart, Adam Michael; Nguyen, Michael; Song, Cai; Gottesman, Irving I

    2015-12-03

    One of the main challenges in medicine is the lack of efficient drug therapies for common human disorders. For example, although depressed patients receive powerful antidepressants, many often remain resistant to psychopharmacotherapy. The growing recognition of complex interplay between the drug targets and the predictors of drug sensitivity requires an improved understanding of these two key aspects of drug action and their potentially shared molecular networks. Here, we apply the concept of endophenotypes and their interplay to drug action and sensitivity. Based on these analyses, we postulate that novel drugs may be developed by targeting specific molecular pathways that integrate drug targets with drug sensitivity predictors.

  18. Effect of chronic caffeine consumption on changes in locomotor activity of WAG/G and Fischer-344 rats induced by nicotine, ethanol, and morphine.

    PubMed

    Sudakov, S K; Rusakova, I V; Medvedeva, O F

    2003-12-01

    We studied the effect of single treatment with nicotine, ethanol, and morphine on locomotor activity of WAG/G and Fischer-344 rats chronically drinking caffeine solution. In Fischer-344 rats receiving caffeine locomotor activity in the open-field test was much lower than in animals drinking water, while in WAG/G rats no differences in locomotor activity were found. Chronic caffeine intake increased rat sensitivity to the stimulating effect of nicotine and ethanol, but decreased their sensitivity to the depressant effect of morphine. Chronic caffeine treatment most significantly modulated the effects of nicotine, ethanol, and morphine in Fischer-344 rats.

  19. Perspectives on Non-Animal Alternatives for Assessing Sensitization Potential in Allergic Contact Dermatitis.

    PubMed

    Sharma, Nripen S; Jindal, Rohit; Mitra, Bhaskar; Lee, Serom; Li, Lulu; Maguire, Tim J; Schloss, Rene; Yarmush, Martin L

    2012-03-01

    Skin sensitization remains a major environmental and occupational health hazard. Animal models have been used as the gold standard method of choice for estimating chemical sensitization potential. However, a growing international drive and consensus for minimizing animal usage have prompted the development of in vitro methods to assess chemical sensitivity. In this paper, we examine existing approaches including in silico models, cell and tissue based assays for distinguishing between sensitizers and irritants. The in silico approaches that have been discussed include Quantitative Structure Activity Relationships (QSAR) and QSAR based expert models that correlate chemical molecular structure with biological activity and mechanism based read-across models that incorporate compound electrophilicity. The cell and tissue based assays rely on an assortment of mono and co-culture cell systems in conjunction with 3D skin models. Given the complexity of allergen induced immune responses, and the limited ability of existing systems to capture the entire gamut of cellular and molecular events associated with these responses, we also introduce a microfabricated platform that can capture all the key steps involved in allergic contact sensitivity. Finally, we describe the development of an integrated testing strategy comprised of two or three tier systems for evaluating sensitization potential of chemicals.

  20. Locomotor function in the early stage of Parkinson's disease.

    PubMed

    Carpinella, Ilaria; Crenna, Paolo; Calabrese, Elena; Rabuffetti, Marco; Mazzoleni, Paolo; Nemni, Raffaello; Ferrarin, Maurizio

    2007-12-01

    The cardinal motor symptoms of Parkinson's disease (PD) have been widely investigated with particular reference to abnormalities of steady-state walking. The great majority of studies, however are related to severe forms of PD patients (phases > = 3 of Hoehn and Yahr scale), where locomotor abnormalities are clearly manifested. Goal of the present study was to quantitatively describe locomotor symptoms in subjects with mild PD. Accordingly, a multitask protocol involving instrumental analysis of steady-state linear walking, initiation of gait, and turning while walking was applied to a group of patients with idiopathic PD in their early clinical stage (phases 1 and 2 of Hoehn and Yahr scale), as well as in age-matched elderly controls. Kinematic, kinetic, and myoelectric measures were obtained by optoelectronic motion analysis, force platform, and telemetric electromyography. Results in PD patients showed a tendency to bradykinetic gait, with reduction of walking speed and cadence. Impairments of gait initiation consisted in reduction of the backward shift of the center of pressure (CoP) and prolongation of the stepping phase. Alterations of the turning task were more consistent and included delayed reorientation of the head toward the new direction, altered head-upper trunk rotational strategy, and adoption of a greater number of steps to complete the turning. It is concluded that patients in the early stage of PD reveal mild alterations of steady-state linear walking and more significant anomalies in the transitional conditions, especially during changes in the travel direction. Quantitative analysis of nonstationary locomotor tasks might be a potentially useful starting point for further studies on the pathophysiology of PD.

  1. Effects of sensitization and crevices on critical cracking potential for SCC of Alloy 600

    SciTech Connect

    Anzai, H.; Kuniya, J.; Shoji, T.; Yoshida, K.

    1992-12-31

    Effects of sensitization and crevices on critical cracking potential for stress corrosion cracking (SCC) of Alloy 600 were evaluated by slow strain rate tests (SSRTs). Tests were conducted under both potentiostatic controlled, and under free corrosion potential, conditions. For the former, boric acid and lithium hydroxide were added to pure water to maintain sufficient conductivity. Crevices were formed by inter-granular corrosion and wrapping stainless steel foil around the specimen. All tests were performed in 288{degrees}C water and applied strain rate was 7x10{sup {minus}7} (1/s). For the potentiostatic controlled condition, it was found that above a certain threshold potential SCC susceptibility increased with increasing applied potential. Sensitization lowered the critical cracking potential by around 200mV and inter-granular crevices shifted it even lower, by about 250mV. The critical cracking potentials obtained were not less than 200mV vs SHE, which is higher than those of sensitized stainless steel (0 to -230mV) and low alloy steel (-100 to -250mV).

  2. 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...

  3. 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…

  4. Role of melanin-concentrating hormone in the nucleus accumbens shell in rats behaviourally sensitized to methamphetamine.

    PubMed

    Sun, Li-Li; Zhang, Yan; Liu, Jian-feng; Wang, Jun; Zhu, Wei-li; Zhao, Li-yan; Xue, Yan-xue; Lu, Lin; Shi, Jie

    2013-09-01

    Melanin-concentrating hormone (MCH) is a neuropeptide and its receptor is extensively expressed throughout the brain. MCH has been suggested to regulate the rewarding and reinforcing effects of psychostimulants by potentiating the dopaminergic system within the midbrain. Moreover, MCH and its receptor can regulate ERK activity. The present study investigated the role of MCH in the nucleus accumbens (NAc) in rats behaviourally sensitized to methamphetamine (Meth). We found that the development of Meth-induced locomotor sensitization was attenuated by MCH infused into the NAc shell but not core. Moreover, the elevation of ERK phosphorylation in the NAc shell induced by Meth was inhibited by locally infused MCH. Infusion of the MCH receptor 1 (MCHR1) antagonist SNAP 94847 into the NAc shell but not core augmented the initiation of locomotor sensitization and amplitude of elevated phosphorylated ERK levels induced by Meth. The expression of Meth-induced locomotor sensitization and ERK alterations after 1 wk withdrawal were not affected by either MCH or SNAP 94847 infused into the NAc shell or core. These results indicate that MCH in the NAc shell plays a critical role in the development but not expression of Meth-induced locomotor sensitization in rats, which might be mediated by the ERK signalling pathway. Our study suggests that MCH might be a potential target for the treatment of Meth addiction.

  5. 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

  6. An improvement of LLNA:DA to assess the skin sensitization potential of chemicals.

    PubMed

    Zhang, Hongwei; Shi, Ying; Wang, Chao; Zhao, Kangfeng; Zhang, Shaoping; Wei, Lan; Dong, Li; Gu, Wen; Xu, Yongjun; Ruan, Hongjie; Zhi, Hong; Yang, Xiaoyan

    2017-01-01

    We developed a modified local lymph node assay based on ATP (LLNA:DA), termed the Two-Stage LLNA:DA, to further reduce the animal numbers in the identification of sensitizers. In the Two-Stage LLNA:DA procedure, 13 chemicals ranging from non-sensitizers to extreme sensitizers were selected. The first stage used reduced LLNA:DA (rLLNA:DA) to screen out sensitive chemicals. The second stage used LLNA:DA based on OECD 442 (A) to classify those potential sensitizers screened out in the first stage. In the first stage, the SIs of the methyl methacrylate, salicylic acid, methyl salicylate, ethyl salicylate, isopropanol and propanediol were below 1.8 and need not to be tested in the second step. Others continued to be tested by LLNA:DA. In the second stage, sodium lauryl sulphate and xylene were classified as weak sensitizers. a-hexyl cinnamic aldehyde and eugenol were moderate sensitizers. Benzalkonium chloride and glyoxal were strong sensitizers, and phthalic anhydride was an extreme sensitizer. The 9/9, 11/12, 10/11, and 8/13 (positive or negative only) categories of the Two-Stage LLNA:DA were consistent with those from the other methods (LLNA, LLNA:DA, GPMT/BT and HMT/HPTA), suggesting that Two-Stage LLNA:DA have a high coincidence rate with reported data. In conclusion, The Two-Stage LLNA:DA is in line with the "3R" rules, and can be a modification of LLNA:DA but needs more study.

  7. Food deprivation increases the low-dose locomotor stimulant response to ethanol in Drosophila melanogaster.

    PubMed

    Kliethermes, Christopher L

    2013-10-01

    Acute and chronic states of food deprivation result in increased sensitivity to a variety of natural reinforcers as well as to drugs of abuse. Food deprived animals show increased locomotor activity during periods of food deprivation, as well as increased locomotor stimulant responses to drugs of abuse, including cocaine, amphetamine, morphine, and ethanol, implying that drugs of abuse act in part on neural systems that underlie responses towards food. To determine whether this effect extends to an invertebrate, highly genetically tractable animal, the locomotor stimulant effects of low dose ethanol were assessed under a variety of feeding conditions in the fruit fly, Drosophila melanogaster. Food deprivation resulted in strain specific increases in ethanol-stimulated locomotor activity in most strains tested, although elevated baseline activity confounded interpretation in some strains. Experiments conducted with Canton S flies found that the effects of food deprivation on the locomotor stimulant response to ethanol increased with the duration of deprivation, and could be blocked by refeeding the flies with standard food or sucrose, but not yeast, immediately prior to the ethanol exposure. Life-span extending dietary depletion procedures or previous periods of food deprivation did not affect the response to ethanol, indicating that only animals in an acutely food deprived state are more sensitive to the stimulant effects of ethanol. These results suggest that increased sensitivity to the stimulant effects of some drugs of abuse might reflect an evolutionarily conserved neural mechanism that underlies behavioral responses to natural reinforcers and drugs of abuse. The identification of this mechanism, and the genes that underlie its development and function, will constitute a novel approach towards the study of alcohol abuse and dependence.

  8. Withdrawal from THC during adolescence: sex differences in locomotor activity and anxiety.

    PubMed

    Harte-Hargrove, Lauren C; Dow-Edwards, Diana L

    2012-05-16

    Research suggests that the use and abuse of marijuana can be especially harmful if it occurs during adolescence, a period of vast developmental changes throughout the brain. Due to the localization of cannabinoid receptors within the limbic system and the established effects of cannabinoids on emotional states and anxiety levels of rats and humans, we studied the sex- and dose-related effects of Δ⁹-tetrahydrocannabinol (THC, the main psychoactive component in marijuana) on behavior and anxiety during spontaneous withdrawal. Male and female Sprague Dawley rats were administered 2, 7.5 or 15 mg/kg THC or vehicle from postnatal day 35-41 (approximating mid-adolescence in humans). Locomotor activity and anxiety-related behaviors were measured during drug administration and abstinence. THC caused significant dose-dependent locomotor depression during drug administration. Locomotor depression initially abated upon drug cessation, but re-emerged by the end of the abstinence period and was greater in female than male rats. We found sensitization to the locomotor-depressing effects of THC in middle- and high-dose rats and the subsequent development of tolerance in high-dose rats. The high dose of THC increased anxiety-like behaviors while the low dose decreased anxiety-like behaviors during drug administration, with females more sensitive to the anxiogenic effects of THC than males. During abstinence, females were again especially sensitive to the anxiogenic effects of THC. This study demonstrates sexually-dimorphic effects of THC on anxiety-related behaviors and locomotor activity during and after THC administration during adolescence. This information may be useful in the development of therapeutic approaches for the treatment of marijuana withdrawal in adolescents.

  9. Potential Inhibitory Influence of miRNA 210 on Regulatory T Cells during Epicutaneous Chemical Sensitization

    PubMed Central

    Long, Carrie Mae; Lukomska, Ewa; Marshall, Nikki B.; Nayak, Ajay; Anderson, Stacey E.

    2016-01-01

    Toluene diisocyanate (TDI) is a potent low molecular weight chemical sensitizer and a leading cause of chemical-induced occupational asthma. The regulatory potential of microRNAs (miRNAs) has been recognized in a variety of disease states, including allergic disease; however, the roles of miRNAs in chemical sensitization are largely unknown. In a previous work, increased expression of multiple miRNAs during TDI sensitization was observed and several putative mRNA targets identified for these miRNAs were directly related to regulatory T-cell (Treg) differentiation and function including Foxp3 and Runx3. In this work, we show that miR-210 expression is increased in the mouse draining lymph node (dLN) and Treg subsets following dermal TDI sensitization. Alterations in dLN mRNA and protein expression of Treg related genes/putative miR-210 targets (foxp3, runx3, ctla4, and cd25) were observed at multiple time points following TDI exposure and in ex vivo systems. A Treg suppression assay, including a miR-210 mimic, was utilized to investigate the suppressive ability of Tregs. Cells derived from TDI sensitized mice treated with miR-210 mimic had less expression of miR-210 compared to the acetone control suggesting other factors, such as additional miRNAs, might be involved in the regulation of the functional capabilities of these cells. These novel findings indicate that miR-210 may have an inhibitory role in Treg function during TDI sensitization. Because the functional roles of miRNAs have not been previously elucidated in a model of chemical sensitization, these data contribute to the understanding of the potential immunologic mechanisms of chemical induced allergic disease. PMID:28035981

  10. 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

  11. 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.

  12. Locomotor activity and tissue levels following acute ...

    EPA Pesticide Factsheets

    Pyrethroids produce neurotoxicity that depends, in part, on the chemical structure. Common behavioral effects include locomotor activity changes and specific toxic syndromes (types I and II). In general these neurobehavioral effects correlate well with peak internal dose metrics. Products of cyhalothrin, a type II pyrethroid, include mixtures of isomers (e.g., λ-cyhalothrin) as well as enriched active isomers (e.g., γ-cyhalothrin). We measured acute changes in locomotor activity in adult male rats and directly correlated these changes to peak brain and plasma concentrations of λ- and γ-cyhalothrin using a within-subject design. One-hour locomotor activity studies were conducted 1.5 h after oral gavage dosing, and immediately thereafter plasma and brains were collected for analyzing tissue levels using LC/MS/MS methods. Both isomers produced dose-related decreases in activity counts, and the effective dose range for γ-cyhalothrin was lower than for λ-cyhalothrin. Doses calculated to decrease activity by 50% were 2-fold lower for the γ-isomer (1.29 mg/kg) compared to λ-cyhalothrin (2.65 mg/kg). Salivation, typical of type II pyrethroids, was also observed at lower doses of γ-cyhalothrin. Administered dose correlated well with brain and plasma concentrations, which furthermore showed good correlations with activity changes. Brain and plasma levels were tightly correlated across doses. While γ-cyhalothrin was 2-fold more potent based on administ

  13. A draining lymph node assay (DLNA) for assessing the sensitizing potential of proteins.

    PubMed

    Boverhof, Darrell R; Gollapudi, B Bhaskar; Hotchkiss, Jon A; Osterloh-Quiroz, Mandy; Woolhiser, Michael R

    2010-03-15

    There is a need for a simple and predictive model to identify the respiratory sensitization potential of (novel) proteins. The present study examined the use of a mouse draining lymph node assay (DLNA) approach, employing several routes of exposure, as a possible starting point for assessing protein sensitization potential. Consistent with the experimental procedure for the standard local lymph node assay (LLNA), female BALB/c mice were dosed dermally (topical), intranasally (IN) or by oropharyngeal aspiration (OP) on days 1, 2 and 3, and proliferation in the relevant draining lymph nodes was measured on day 6. For each route, the auricular, superficial cervical and tracheobronchial lymph nodes (TBLN) were evaluated following treatment with Subtilisin Carlsberg (SUB; a potent sensitizer/allergen), ovalbumin (OVA; a potent food allergen), beta-lactoglobulin (BLG; a moderate food allergen), and keyhole limpet hemocyanin (KLH; a strong immunogen with no reports of respiratory sensitization). Initial studies with OVA indicated that dermal administration did not stimulate lymph node proliferation. Responses in the tracheobronchial lymph node were most dramatic (stimulation indices up to 100) and reproducible for both the IN and OP routes. In a comparative experiment, all proteins induced lymph node proliferation with a rank order potency of SUB>KLH>OVA>BLG. The influence of the endotoxin content on lymph node proliferation was determined to be minimal, and did not impact the rank order potency. Molecular characterization of the TBLN at an equipotent proliferative dose was conducted for select gene transcripts based on research examining chemical sensitizers. Expression profiles differed among the four proteins, but the relevance of these responses was not clear and they did not further discriminate their allergic potential. These data illustrate both the opportunities and challenges associated with the examination of the draining lymph node proliferative response to

  14. Development and characterization of an equine behaviour chamber and the effects of amitraz and detomidine on spontaneous locomotor activity.

    PubMed

    Harkins, J D; Queiroz-Neto, A; Mundy, G D; West, D; Tobin, T

    1997-10-01

    This report describes the development of a behaviour chamber and the validation of the chamber of measure locomotor activity of a horse. Locomotor activity was detected by four Mini-beam sensors and recorded on a data logger every 5 min for 22 h. Horses were more active during daytime than in the evening, which was at least partially related to human activity in their surroundings. To validate the ability of the chambers to detect changes in activity, fentanyl citrate and xylazine HCl, agents well-characterized as a stimulant and a depressant, respectively, were administered to five horses. Fentanyl citrate (0.016 mg/kg) significantly increased locomotor activity which persisted for 30 min. Xylazine HCl (1 mg/kg) significantly reduced locomotor activity for 90 min. Amitraz produced a dose-dependent decrease in locomotor activity, lasting 75 min for the 0.05 mg/kg dose, 120 min for the 0.10 mg/kg dose, and 180 min for the 0.15 mg/kg dose. In a separate experiment, yohimbine administration immediately reversed the sedative effect of amitraz. This suggests there is a similarity in the mode of action of amitraz, xylazine and detomidine, as yohimbine acts primarily by blocking central alpha 2 -adrenoceptors that are stimulated by agents like xylazine. There was also a significant decrease in locomotor activity following injection of detomidine (0.02, 0.04 and 0.08 mg/kg) for 1.5, 3.5 and 5.0 h, respectively. The locomotor chamber is a useful, sensitive and highly reproducible tool for measuring spontaneous locomotor activity in the horse, which allows investigators to determine an agent's average time of onset, duration and intensity of effect on movement.

  15. Differential roles of GABAB1 subunit isoforms on locomotor responses to acute and repeated administration of cocaine.

    PubMed

    Jacobson, Laura H; Sweeney, Fabian F; Kaupmann, Klemens; O'Leary, Olivia F; Gassmann, Martin; Bettler, Bernhard; Cryan, John F

    2016-02-01

    GABAB receptors are crucial modulators of the behavioural effects of drug abuse, and agonists and positive allosteric modulators show promise as pharmacological strategies for anti-addiction therapeutics. GABAB receptors are functional heterodimers of GABAB1 and GABAB2 subunits. The predominant neuronal GABAB1 subunit isoforms are GABAB1a and GABAB1b. Selective ablation of these isoforms in mice revealed differential behavioural responses in fear, cognition and stress sensitivity. However, the influence of the two GABAB1 isoforms on responses to drugs of abuse is unclear. Therefore we examined the responses of GABAB1 subunit isoform null mice to cocaine in acute locomotor activity and conditioned place preference (CPP) paradigms. During habituation for the acute locomotor activity assay, GABAB1b(-/-) mice showed higher levels of locomotor activity relative to wild-type (WT) and GABAB1a(-/-) mice, in accordance with previous studies. Acute cocaine (10 mg/kg) increased locomotor activity in habituated mice of all three genotypes, with GABAB1a(-/-) mice showing sustained hyperlocomotor responses 30 min after cocaine relative to WT and GABAB1b(-/-) mice. No genotypes demonstrated a cocaine-induced place preference, however, GABAB1a(-/-) mice demonstrated enhanced locomotor sensitisation to chronic cocaine in the CPP paradigm in comparison to WT mice, whereas GABAB1b(-/-) mice failed to develop locomotor sensitisation, despite higher levels of basal locomotor activity. These findings indicate that GABAB1a and GABAB1b isoforms differentially regulate behavioural responses to cocaine, with deletion of GABAB1a enhancing cocaine-induced locomotor activity and deletion of GABAB1b protecting from cocaine-induced sensitisation.

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

    NASA Astrophysics Data System (ADS)

    Bartholomeus, R. P.; Stagge, J. H.; Tallaksen, L. M.; Witte, J. P. M.

    2015-02-01

    Hydrological modeling frameworks require an accurate representation of evaporation fluxes for appropriate quantification of, e.g., the water balance, soil moisture budget, recharge and groundwater processes. Many frameworks have used the concept of potential evaporation, often estimated for different vegetation classes by multiplying the evaporation from a reference surface ("reference evaporation") by 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. In this paper, rather than simply warning about the dangers of extrapolation, we quantify 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. Quantification of errors provides a possibility to correct potential evaporation calculations and to rate them for their suitability to model climate conditions that differ significantly from the historical record, so-called no-analog climate conditions.

  17. Ozone sensitivity of currant tomato (Lycopersicon pimpinellifolium), a potential bioindicator species.

    PubMed

    Iriti, Marcello; Belli, Lucia; Nali, Cristina; Lorenzini, Giacomo; Gerosa, Giacomo; Faoro, Franco

    2006-05-01

    The wild tomato species Lycopersicon pimpinellifolium (currant tomato) was exposed to different O3 concentration, both in controlled environment fumigation facilities and in open-top chambers, to assess its sensitivity and to verify its potential as a bioindicator plant. Plants appeared particularly sensitive to O3 at an early stage of growth, responding with typical chlorotic spots within 24 h after exposure to a single pulse of 50 ppb for 3 h, and differentiating peculiar symptoms, such as reddish necrotic stipples, bronzing and extensive necrosis, depending on O3 concentration. Histo-cytochemical investigations with 3,3'-diaminobenzidine, to localize H2O2, and Evans blue, to detect dead cells, suggested that currant tomato sensitivity to O3 could be due to a deficiency in the anti-oxidant pools. The combination of these stainings proved to be useful, either to predict visible symptoms, early before their appearance, and to validate leaf ozone injury.

  18. 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.

  19. Evaluation of in silico tools to predict the skin sensitization potential of chemicals.

    PubMed

    Verheyen, G R; Braeken, E; Van Deun, K; Van Miert, S

    2017-01-01

    Public domain and commercial in silico tools were compared for their performance in predicting the skin sensitization potential of chemicals. The packages were either statistical based (Vega, CASE Ultra) or rule based (OECD Toolbox, Toxtree, Derek Nexus). In practice, several of these in silico tools are used in gap filling and read-across, but here their use was limited to make predictions based on presence/absence of structural features associated to sensitization. The top 400 ranking substances of the ATSDR 2011 Priority List of Hazardous Substances were selected as a starting point. Experimental information was identified for 160 chemically diverse substances (82 positive and 78 negative). The prediction for skin sensitization potential was compared with the experimental data. Rule-based tools perform slightly better, with accuracies ranging from 0.6 (OECD Toolbox) to 0.78 (Derek Nexus), compared with statistical tools that had accuracies ranging from 0.48 (Vega) to 0.73 (CASE Ultra - LLNA weak model). Combining models increased the performance, with positive and negative predictive values up to 80% and 84%, respectively. However, the number of substances that were predicted positive or negative for skin sensitization in both models was low. Adding more substances to the dataset will increase the confidence in the conclusions reached. The insights obtained in this evaluation are incorporated in a web database www.asopus.weebly.com that provides a potential end user context for the scope and performance of different in silico tools with respect to a common dataset of curated skin sensitization data.

  20. Sensitivity Analysis of CLIMEX Parameters in Modelling Potential Distribution of Lantana camara L.

    PubMed Central

    Taylor, Subhashni; Kumar, Lalit

    2012-01-01

    A process-based niche model of L. camara L. (lantana), a highly invasive shrub species, was developed to estimate its potential distribution using CLIMEX. Model development was carried out using its native and invasive distribution and validation was carried out with the extensive Australian distribution. A good fit was observed, with 86.7% of herbarium specimens collected in Australia occurring within the suitable and highly suitable categories. A sensitivity analysis was conducted to identify the model parameters that had the most influence on lantana distribution. The changes in suitability were assessed by mapping the regions where the distribution changed with each parameter alteration. This allowed an assessment of where, within Australia, the modification of each parameter was having the most impact, particularly in terms of the suitable and highly suitable locations. The sensitivity of various parameters was also evaluated by calculating the changes in area within the suitable and highly suitable categories. The limiting low temperature (DV0), limiting high temperature (DV3) and limiting low soil moisture (SM0) showed highest sensitivity to change. The other model parameters were relatively insensitive to change. Highly sensitive parameters require extensive research and data collection to be fitted accurately in species distribution models. The results from this study can inform more cost effective development of species distribution models for lantana. Such models form an integral part of the management of invasive species and the results can be used to streamline data collection requirements for potential distribution modelling. PMID:22815881

  1. Sensitivity analysis of CLIMEX parameters in modelling potential distribution of Lantana camara L.

    PubMed

    Taylor, Subhashni; Kumar, Lalit

    2012-01-01

    A process-based niche model of L. camara L. (lantana), a highly invasive shrub species, was developed to estimate its potential distribution using CLIMEX. Model development was carried out using its native and invasive distribution and validation was carried out with the extensive Australian distribution. A good fit was observed, with 86.7% of herbarium specimens collected in Australia occurring within the suitable and highly suitable categories. A sensitivity analysis was conducted to identify the model parameters that had the most influence on lantana distribution. The changes in suitability were assessed by mapping the regions where the distribution changed with each parameter alteration. This allowed an assessment of where, within Australia, the modification of each parameter was having the most impact, particularly in terms of the suitable and highly suitable locations. The sensitivity of various parameters was also evaluated by calculating the changes in area within the suitable and highly suitable categories. The limiting low temperature (DV0), limiting high temperature (DV3) and limiting low soil moisture (SM0) showed highest sensitivity to change. The other model parameters were relatively insensitive to change. Highly sensitive parameters require extensive research and data collection to be fitted accurately in species distribution models. The results from this study can inform more cost effective development of species distribution models for lantana. Such models form an integral part of the management of invasive species and the results can be used to streamline data collection requirements for potential distribution modelling.

  2. 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.

  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. 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.

  5. Temperature sensitivity of microbial respiration, nitrogen mineralization, and potential soil enzyme activities in organic alpine soils

    NASA Astrophysics Data System (ADS)

    Koch, Oliver; Tscherko, Dagmar; Kandeler, Ellen

    2007-12-01

    Investigations focusing on the temperature sensitivity of microbial activity and nutrient turnover in soils improve our understanding of potential effects of global warming. This study investigates the temperature sensitivity of C mineralization, N mineralization, and potential enzyme activities involved in the C and N cycle (tyrosine amino-peptidase, leucine amino-peptidase, ß-glucosidase, ß-xylosidase, N-acetyl-ß-glucosaminidase). Four different study sites in the Austrian alpine zone were selected, and soils were sampled in three seasons (summer, autumn, and winter). A simple first-order exponential equation was used to calculate constant Q10 values for the C and N mineralization over the investigated temperature range (0-30°C). The Q10 values of the C mineralization (average 2.0) for all study sites were significantly higher than for the N mineralization (average 1.7). The Q10 values of both activities were significantly negatively related to a soil organic matter quality index calculated by the ratios of respiration to the organic soil carbon and mineralized N to the total soil nitrogen. The chemical soil properties or microbial biomass did not affect the Q10 values of C and N mineralization. Moreover, the Q10 values showed no distinct pattern according to sampling date, indicating that the substrate quality and other factors are more important. Using a flexible model function, the analysis of relative temperature sensitivity (RTS) showed that the temperature sensitivity of activities increased with decreasing temperature. The C and N mineralization and potential amino-peptidase activities (tyrosine and leucine) showed an almost constant temperature dependence over 0-30°C. In contrast, ß-glucosidase, ß-xylosidase, and N-acetyl-ß-glucosaminidase showed a distinctive increase in temperature sensitivity with decreasing temperature. Low temperature at the winter sampling date caused a greater increase in the RTS of all microbial activities than for the

  6. 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.

  7. 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.

  8. Chemical reactivity and skin sensitization potential for benzaldehydes: can Schiff base formation explain everything?

    PubMed

    Natsch, Andreas; Gfeller, Hans; Haupt, Tina; Brunner, Gerhard

    2012-10-15

    Skin sensitizers chemically modify skin proteins rendering them immunogenic. Sensitizing chemicals have been divided into applicability domains according to their suspected reaction mechanism. The widely accepted Schiff base applicability domain covers aldehydes and ketones, and detailed structure-activity-modeling for this chemical group was presented. While Schiff base formation is the obvious reaction pathway for these chemicals, the in silico work was followed up by limited experimental work. It remains unclear whether hydrolytically labile Schiff bases can form sufficiently stable epitopes to trigger an immune response in the living organism with an excess of water being present. Here, we performed experimental studies on benzaldehydes of highly differing skin sensitization potential. Schiff base formation toward butylamine was evaluated in acetonitrile, and a detailed SAR study is presented. o-Hydroxybenzaldehydes such as salicylaldehyde and the oakmoss allergens atranol and chloratranol have a high propensity to form Schiff bases. The reactivity is highly reduced in p-hydroxy benzaldehydes such as the nonsensitizing vanillin with an intermediate reactivity for p-alkyl and p-methoxy-benzaldehydes. The work was followed up under more physiological conditions in the peptide reactivity assay with a lysine-containing heptapeptide. Under these conditions, Schiff base formation was only observable for the strong sensitizers atranol and chloratranol and for salicylaldehyde. Trapping experiments with NaBH₃CN showed that Schiff base formation occurred under these conditions also for some less sensitizing aldehydes, but the reaction is not favored in the absence of in situ reduction. Surprisingly, the Schiff bases of some weaker sensitizers apparently may react further to form stable peptide adducts. These were identified as the amides between the lysine residues and the corresponding acids. Adduct formation was paralleled by oxidative deamination of the parent

  9. [High sensitivity cardiac troponin assays 2009: clinical potential, current practice and benefits, the future].

    PubMed

    Englis, M; Sochman, J; Pudil, R; Franeková, J; Jabor, A

    2009-11-01

    At present, determination of cardiac troponins (cTn) is the biomarker method of choice for diagnostics and risk stratification in patients with a myocardial injury. Past clinical practice had provided sound evidence that low cTn concentrations, measured with unacceptable imprecision by the currently used methods, hold important clinical, diagnostic and stratification potential. The new generation cTn assays, so called high-sensitivity assays, enable determination of very low cTn concentrations with satisfactory analytical precision and open the way to early identification of small but often prognostically important myocardial damage. Introduction of high-sensitivity cTn assays in practice is, however, associated with some difficulties: their superior diagnostic sensitivity to identify small injuries to myocardium is often linked to lower specificity, higher incidence of elevated cTn concentrations is frequently associated with less obvious clinical symptomatology (overdiagnosis), resulting in greater demand for further patient assessment (overcrowding), repeated analyses and trend monitoring of cTn fluctuation. These initial difficulties cannot lessen the by now indisputable, established benefit of high-sensitivity cTn assays that we briefly describe in the present paper.

  10. Effects of pinealectomy on the neuroendocrine reproductive system and locomotor activity in male European sea bass, Dicentrarchus labrax.

    PubMed

    Cowan, Mairi; Paullada-Salmerón, José A; López-Olmeda, José Fernando; Sánchez-Vázquez, Francisco Javier; Muñoz-Cueto, José A

    2017-02-08

    The seasonally changing photoperiod controls the timing of reproduction in most fish species, however, the transduction of this photoperiodic information to the reproductive axis is still unclear. This study explored the potential role of two candidate neuropeptide systems, gonadotropin-inhibitory hormone (Gnih) and kisspeptin, as mediators between the pineal organ (a principle transducer of photoperiodic information) and reproductive axis in male European sea bass, Dicentrarchus labrax. Two seven-day experiments of pinealectomy (Px) were performed, in March (end of reproductive season) and August (resting season). Effects of Px and season on the brain expression of gnih (sbgnih) and its receptor (sbgnihr), kisspeptins (kiss1, kiss2) and their receptors (kissr2, kissr3) and gonadotropin-releasing hormone (gnrh1, gnrh2, gnrh3) and the main brain receptor (gnrhr-II-2b) genes, plasma melatonin levels and locomotor activity rhythms were examined. Results showed that Px reduced night-time plasma melatonin levels. Gene expression analyses demonstrated a sensitivity of the Gnih system to Px in March, with a reduction in sbgnih in the mid-hindbrain, a region with bilateral connections to the pineal organ. In August, kiss2 levels increased in Px animals but not in controls. Significant differences in expression were observed for diencephalic sbgnih, sbgnihr, kissr3 and tegmental gnrh2 between seasons. Recordings of locomotor activity following surgery revealed a change from light-synchronised to free-running rhythmic behavior. Altogether, the Gnih and Kiss2 sensitivity to Px and seasonal differences observed for Gnih and its receptor, Gnrh2, and the receptor for Kiss2 (Kissr3), suggested they could be mediators involved in the relay between environment and seasonal reproduction.

  11. 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.

  12. 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

  13. 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

  14. 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

  15. 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

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

    PubMed

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

    2011-12-01

    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 CO(2) 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.

  17. The GABAB agonist baclofen blocks the expression of sensitisation to the locomotor stimulant effect of amphetamine.

    PubMed

    Bartoletti, M; Gubellini, C; Ricci, F; Gaiardi, M

    2004-09-01

    The purpose of the present study was to test the possible influence of baclofen, a GABAB agonist, on the long-term sensitisation to amphetamine in rats. As expected, chronic amphetamine treatment (1.5 mg/kg i.p. daily for 10 days) led to an increased locomotor response to amphetamine (0.75 mg/kg i.p.), when the animals were challenged 20 days after the end of repeated treatment. Baclofen (2 mg/kg i.p.), administered before the test session, did not significantly modify the spontaneous locomotor activity of rats, but decreased the normal and, to a greater extent, the sensitised locomotor response to amphetamine; thus baclofen prevented the expression of sensitisation to amphetamine. Moreover a previous chronic treatment with baclofen (2 mg/kg i.p. daily for 10 days) attenuated the amphetamine-induced locomotor activity in sensitised, but not in control animals. This effect was observed 20 days after the last baclofen administration. In conclusion, the present results demonstrate that GABAB receptors play an important role in the expression of the sensitised behavioural response to amphetamine and further support a potential role of GABAB agonists in the treatment of psychostimulant addiction.

  18. Influences of acute ethanol exposure on locomotor activities of zebrafish larvae under different illumination.

    PubMed

    Guo, Ning; Lin, Jia; Peng, Xiaolan; Chen, Haojun; Zhang, Yinglan; Liu, Xiuyun; Li, Qiang

    2015-11-01

    Larval zebrafish present unique opportunities to study the behavioral responses of a model organism to environmental challenges during early developmental stages. The purpose of the current study was to investigate the locomotor activities of AB strain zebrafish larvae at 5 and 7 days post-fertilization (dpf) in response to light changes under the influence of ethanol, and to explore potential neurological mechanisms that are involved in ethanol intoxication. AB strain zebrafish larvae at both 5 and 7 dpf were treated with ethanol at 0% (control), 0.1%, 0.25%, 0.5%, 1%, and 2% (v/v%). The locomotor activities of the larvae during alternating light-dark challenges, as well as the locomotor responses immediately following the light transitions, were investigated. The levels of various neurotransmitters were also measured in selected ethanol-treated groups. The larvae at 5 and 7 dpf demonstrated similar patterns of locomotor responses to ethanol treatment. Ethanol treatment at 1% increased the swimming distances of the zebrafish larvae in the dark periods, but had no effect on the swimming distances in the light periods. In contrast, ethanol treatment at 2% increased the swimming distances in the light periods, but did not potentiate the swimming activity in the dark periods, compared to controls. Differences in the levels of neurotransmitters that are involved in norepinephrine, dopamine, and serotonin pathways were also observed in groups with different ethanol treatments. These results indicated the behavioral studies concerning the ethanol effects on locomotor activities of zebrafish larvae could be carried out as early as 5 dpf. The 1% and 2% ethanol-treated zebrafish larvae modeled ethanol effects at different intoxication states, and the differences in neurotransmitter levels suggested the involvement of various neurotransmitter pathways in different ethanol intoxication states.

  19. 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

  20. 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.

  1. 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.

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

    PubMed

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

    2012-12-01

    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 0.03mg/kg) in a 90-min session. Experiment 2 was conducted to test higher meth doses (0.3-10mg/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.

  3. Pelvic Breadth and Locomotor Kinematics in Human Evolution.

    PubMed

    Gruss, Laura Tobias; Gruss, Richard; Schmitt, Daniel

    2017-04-01

    A broad pelvis is characteristic of most, if not all, pre-modern hominins. In at least some early australopithecines, most notably the female Australopithecus afarensis specimen known as "Lucy," it is very broad and coupled with very short lower limbs. In 1991, Rak suggested that Lucy's pelvic anatomy improved locomotor efficiency by increasing stride length through rotation of the wide pelvis in the axial plane. Compared to lengthening strides by increasing flexion and extension at the hips, this mechanism could avoid potentially costly excessive vertical oscillations of the body's center of mass (COM). Here, we test this hypothesis. We examined 3D kinematics of walking at various speeds in 26 adult subjects to address the following questions: Do individuals with wider pelves take longer strides, and do they use a smaller degree of hip flexion and extension? Is pelvic rotation greater in individuals with shorter legs, and those with narrower pelves? Our results support Rak's hypothesis. Subjects with wider pelves do take longer strides for a given velocity, and for a given stride length they flex and extend their hips less, suggesting a smoother pathway of the COM. Individuals with shorter legs do use more pelvic rotation when walking, but pelvic breadth was not related to pelvic rotation. These results suggest that a broad pelvis could benefit any bipedal hominin, but especially a short-legged australopithecine such as Lucy, by improving locomotor efficiency, particularly when carrying an infant or traveling in a foraging group with individuals of varying sizes. Anat Rec, 300:739-751, 2017. © 2017 Wiley Periodicals, Inc.

  4. Evaluation of furfuryl alcohol sensitization potential following dermal and pulmonary exposure: enhancement of airway responsiveness.

    PubMed

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

    2012-01-01

    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.

  5. Transition from ethanol-induced sensitization to tolerance across early and late infancy in the rat.

    PubMed

    Castello, Stefania; D'Aloisio, Genesis; Arias, Carlos; Molina, Juan Carlos

    Drugs of abuse, as cocaine or amphetamine, induce locomotor sensitization during infancy and adulthood of the rat. This effect during the preweanling period is observed only after a short interval of time between training and testing. We recently reported short-term locomotor sensitization induced by ethanol in pups chronically exposed to the drug during the second postnatal week of life. The present series of experiments was designed to explore the persistence of the sensitization effect across the preweanling period. Pups were chronically exposed to ethanol in five consecutive days during the second or the third postnatal weeks, and their locomotor activity was evaluated in an open field 3, 8 or 15days later. Our results showed that, contrarily to what has been observed with other drugs during infancy, sensitization to ethanol persisted at least 8days in rats exposed to the drug during the second postnatal week. Surprisingly, in older pups, the same procedure induced tolerance instead sensitization. This ontogenetic model offers a potentially interesting tool for studying within the same species, how tolerance and sensitization are interrelated, and how these effects affect ethanol-mediated reinforcement and ethanol intake during ontogeny.

  6. Loss of cocaine locomotor response in Pitx3-deficient mice lacking a nigrostriatal pathway.

    PubMed

    Beeler, Jeff A; Cao, Zhen Fang Huang; Kheirbek, Mazen A; Zhuang, Xiaoxi

    2009-04-01

    Both the dorsal and ventral striatum have been demonstrated to have a critical role in reinforcement learning and addiction. Dissecting the specific function of these striatal compartments and their associated nigrostriatal and mesoaccumbens dopamine pathways, however, has proved difficult. Previous studies using lesions to isolate the contribution of nigrostriatal and mesoaccumbens dopamine in mediating the locomotor and reinforcing effects of psychostimulant drugs have yielded inconsistent and inconclusive results. Using a naturally occurring mutant mouse line, aphakia, that lacks a nigrostriatal dopamine pathway but retains an intact mesoaccumbens pathway, we show that the locomotor activating effects of cocaine, including locomotor sensitization, are dependent on an intact nigrostriatal dopamine projection. In contrast, cocaine reinforcement, as measured by conditioned place preference and cocaine sensitization of sucrose preference, is intact in these mice. In light of the well-established role of the nucleus accumbens in mediating the effects of psychostimulants, these data suggest that the nigrostriatal pathway can act as a critical effector mechanism for the nucleus accumbens highlighting the importance of intrastriatal connectivity and providing insight into the functional architecture of the striatum.

  7. 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

  8. Locomotor training: experiencing the changing body.

    PubMed

    Hannold, Elizabeth M; Young, Mary Ellen; Rittman, Maude R; Bowden, Mark G; Behrman, Andrea L

    2006-01-01

    This study examined the experiences of persons with incomplete spinal cord injury who participated in loco-motor training (LT). LT is an emerging rehabilitation intervention for enhancing the recovery of walking in persons with central nervous system disorders. Multiple interviews and field observations provided data from eight participants, including four veterans. Findings indicate that experiences of bodily changes were prevalent among participants. Themes included (1) experiencing impaired or absent proprioception, (2) struggling for bodily control, and (3) experiencing emergent bodily sensations. Themes 1 and 2 reflected bodily disruption as a result of spinal cord injury and were challenging to participants as they attempted to reconnect the body and self through LT. Theme 3 reflected bodily sensations (burning, soreness) that were seen as positive signs of recovery and resulted in hope and motivation. Understanding how LT participants experience bodily changes may enable therapists to develop improved participant-centered intervention approaches.

  9. The influence of locomotor rehabilitation on module quality and post-stroke hemiparetic walking performance.

    PubMed

    Routson, Rebecca L; Clark, David J; Bowden, Mark G; Kautz, Steven A; Neptune, Richard R

    2013-07-01

    Recent studies have suggested the biomechanical subtasks of walking can be produced by a reduced set of co-excited muscles or modules. Individuals post-stroke often exhibit poor inter-muscular coordination characterized by poor timing and merging of modules that are normally independent in healthy individuals. However, whether locomotor therapy can influence module composition and timing and whether these improvements lead to improved walking performance is unclear. The goal of this study was to examine the influence of a locomotor rehabilitation therapy on module composition and timing and post-stroke hemiparetic walking performance. Twenty-seven post-stroke hemiparetic subjects participated in a 12-week locomotor intervention incorporating treadmill training with body weight support and manual trainers accompanied by training overground walking. Electromyography (EMG), kinematic and ground reaction force data were collected from subjects both pre- and post-therapy and from 19 age-matched healthy controls walking on an instrumented treadmill at their self-selected speed. Non-negative matrix factorization was used to identify the module composition and timing from the EMG data. Module timing and composition, and various measures of walking performance were compared pre- and post-therapy. In subjects with four modules pre- and post-therapy, locomotor training resulted in improved timing of the ankle plantarflexor module and a more extended paretic leg angle that allowed the subjects to walk faster and with more symmetrical propulsion. In addition, subjects with three modules pre-therapy increased their number of modules and improved walking performance post-therapy. Thus, locomotor training has the potential to influence module composition and timing, which can lead to improvements walking performance.

  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. Semicarbazide-sensitive amine oxidase substrates potentiate hydralazine hypotension: possible role of hydrogen peroxide.

    PubMed

    Vidrio, Horacio; Medina, Martha; González-Romo, Pilar; Lorenzana-Jiménez, Marte; Díaz-Arista, Patricia; Baeza, Alejandro

    2003-11-01

    The relation between inhibition of semicarbazide-sensitive amine oxidase (SSAO) and vasodilation by hydralazine (HYD) was evaluated in chloralose/urethane-anesthetized rats pretreated with various substrates of the enzyme and subsequently administered a threshold hypotensive dose of the vasodilator. The SSAO substrates benzylamine, phenethylamine, and methylamine potentiate the hypotensive response to HYD. Methylamine, which was studied in greater detail because of its status as a possible endogenous SSAO substrate, does not influence the response to the reference vasodilator pinacidil; it does enhance HYD relaxation in aortic rings obtained from pretreated rats. Experiments designed to identify the product of SSAO activity responsible for potentiation by methylamine suggest involvement of hydrogen peroxide (H2O2), as evidenced by the findings that such potentiation is abolished by additional pretreatment with the H2O2-metabolizing enzyme catalase, and that the plasma concentration of H2O2 is increased by methylamine and decreased by HYD. These results are interpreted as a substantiation of the relation between the known SSAO inhibitory effect of HYD and its vasodilator activity. Pretreatment with the SSAO substrates would increase production of H2O2 in vascular smooth muscle and thus magnify the influence of this vasoconstrictor agent on vascular tone. In these conditions, the decrease in H2O2 production and hence in vascular tone caused by SSAO inhibition by HYD would also be magnified. It is speculated that inhibition of vascular SSAO could represent a novel mechanism of vasodilation.

  12. Locomotor activation by theacrine, a purine alkaloid structurally similar to caffeine: involvement of adenosine and dopamine receptors.

    PubMed

    Feduccia, Allison A; Wang, Yuanyuan; Simms, Jeffrey A; Yi, Henry Y; Li, Rui; Bjeldanes, Leonard; Ye, Chuangxing; Bartlett, Selena E

    2012-08-01

    Purine compounds, such as caffeine, have many health-promoting properties and have proven to be beneficial in treating a number of different conditions. Theacrine, a purine alkaloid structurally similar to caffeine and abundantly present in Camellia kucha, has recently become of interest as a potential therapeutic compound. In the present study, theacrine was tested using a rodent behavioral model to investigate the effects of the drug on locomotor activity. Long Evans rats were injected with theacrine (24 or 48 mg/kg, i.p.) and activity levels were measured. Results showed that the highest dose of theacrine (48 mg/kg, i.p.) significantly increased locomotor activity compared to control animals and activity remained elevated throughout the duration of the session. To test for the involvement of adenosine receptors underlying theacrine's motor-activating properties, rats were administered a cocktail of the adenosine A₁ agonist, N⁶-cyclopentyladenosine (CPA; 0.1 mg/kg, i.p.) and A(2A) receptor agonist 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine (CGS-21680; 0.2 mg/kg, i.p.). Pre-treatment with theacrine significantly attenuated the motor depression induced by the adenosine receptor agonists, indicating that theacrine is likely acting as an adenosine receptor antagonist. Next, we examined the role of DA D₁ and D₂ receptor antagonism on theacrine-induced hyperlocomotion. Both antagonists, D₁R SCH23390 (0.1 or 0.05 mg/kg, i.p.) and D₂R eticlopride (0.1 mg/kg, i.p.), significantly reduced theacrine-stimulated activity indicating that this behavioral response, at least in part, is mediated by DA receptors. In order to investigate the brain region where theacrine may be acting, the drug (10 or 20 μg) was infused bilaterally into nucleus accumbens (NAc). Theacrine enhanced activity levels in a dose-dependent manner, implicating a role of the NAc in modulating theacrine's effects on locomotion. In addition, theacrine did not induce locomotor

  13. 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.

  14. Effect of MOG Sensitization on Somatosensory Evoked Potential in Lewis Rats

    PubMed Central

    All, Angelo H.; Walczak, Piotr; Agrawal, Gracee; Gorelik, Michael; Lee, Christopher; Thakor, Nitish V.; Bulte, Jeff W.M.; Kerr, Douglas A.

    2009-01-01

    Myelin oligodendrocyte glycoprotein (MOG) is commonly used as an immunogen to induce an immune response against endogenous myelin, thereby modeling multiple sclerosis in rodents. When MOG is combined with complete Freund’s adjuvant (CFA), multifocal, multiphasic disease ensues; whereas when MOG is combined with incomplete Freund’s adjuvant (IFA), clinical disease is usually absent. MOG-IFA immunized animals can be induced to have neurological disease after intraspinal injections of cytokines and ethidium bromide (EtBr). In this study, we investigated whether MOG-IFA immunized rats exhibited subclinical injury as defined by Somatosensory Evoked Potential (SEP) recordings. The titration of Anti-MOG-125 antibodies showed robust peripheral mounting of immune response against myelin in MOG-immunized rats. However the SEP measures showed no significant change over time. Upon injecting cytokine-EtBr in the spinal cord after MOG sensitization, the SEP recordings showed reduced amplitude and prolonged latency, suggestive of axonal injury and demyelination in the dorsal column, respectively. These findings were later confirmed using T2-weighted MRI and histological hematoxilin-eosin stain of the spinal cord. This report establishes that MOG-IFA immunization alone does not alter neuronal conduction in SEP-related neural-pathways and that longitudinal in-vivo SSEP recordings provide a sensitive read-out for focal myelitis (MOG-IFA & intraspinal cytokine-EtBr) in rats. PMID:19423134

  15. Effect of MOG sensitization on somatosensory evoked potential in Lewis rats

    PubMed Central

    All, Angelo H.; Walczak, Piotr; Agrawal, Gracee; Gorelik, Michael; Lee, Christopher; Thakor, Nitish V.; Bulte, Jeff W.M.; Kerr, Douglas A.

    2011-01-01

    Myelin oligodendrocyte glycoprotein (MOG) is commonly used as an immunogen to induce an immune response against endogenous myelin, thereby modeling multiple sclerosis in rodents. When MOG is combined with complete Freund's adjuvant (CFA), multifocal, multiphasic disease ensues; whereas when MOG is combined with incomplete Freund's adjuvant (IFA), clinical disease is usually absent. MOG–IFA immunized animals can be induced to have neurological disease after intraspinal injections of cytokines and ethidium bromide (EtBr). In this study, we investigated whether MOG–IFA immunized rats exhibited subclinical injury as defined by somatosensory evoked potential (SEP) recordings. The titration of anti-MOG-125 antibodies showed robust peripheral mounting of immune response against myelin in MOG-immunized rats. However the SEP measures showed no significant change over time. Upon injecting cytokine–EtBr in the spinal cord after MOG sensitization, the SEP recordings showed reduced amplitude and prolonged latency, suggestive of axonal injury and demyelination in the dorsal column, respectively. These findings were later confirmed using T2-weighted MRI and histological hematoxylin–eosin stain of the spinal cord. This report establishes that MOG–IFA immunization alone does not alter neuronal conduction in SEP-related neural-pathways and that longitudinal in-vivo SEP recordings provide a sensitive read-out for focal myelitis (MOG–IFA and intraspinal cytokine–EtBr) in rats. PMID:20508959

  16. Identification of a compound isolated from German chamomile (Matricaria chamomilla) with dermal sensitization potential.

    PubMed

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

    2017-03-01

    German chamomile is one of the most popular herbal ingredients used in cosmetics and personal care products. Allergic skin reactions following topical application of German chamomile have been occasionally reported, although it is not fully understood which of the chemical constituents is responsible for this adverse effect. In the present work, three candidate sensitizers were isolated from German chamomile based on activity-guided fractionation of chamomile extracts tested using the in vitro KeratinoSens™ assay. The compounds were identified as the polyacetylene tonghaosu (1), and both trans- and cis-glucomethoxycinnamic acids (2 and 3). These three compounds were classified as non- to weakly reactive using in chemico methods; however, aged tonghaosu was found to be more reactive when compared to freshly isolated tonghaosu. The polyacetylene (1) constituent was determined to be chemically unstable, generating a small electrophilic spirolactone, 1,6-dioxaspiro[4.4]non-3-en-2-one (4), upon aging. This small lactone (4) was strongly reactive in both in chemico HTS- and NMR-DCYA methods and further confirmed as a potential skin sensitizer by Local Lymph Node Assay (LLNA).

  17. The potential role of postsynaptic phospholipase C activity in synaptic facilitation and behavioral sensitization in Aplysia.

    PubMed

    Fulton, Daniel; Condro, Michael C; Pearce, Kaycey; Glanzman, David L

    2008-07-01

    Previous findings indicate that synaptic facilitation, a cellular mechanism underlying sensitization of the siphon withdrawal response (SWR) in Aplysia, depends on a cascade of postsynaptic events, including activation of inositol triphosphate (IP3) receptors and release of Ca2+ from postsynaptic intracellular stores. These findings suggest that phospholipase C (PLC), the enzyme that catalyzes IP3 formation, may play an important role in postsynaptic signaling during facilitation and learning in Aplysia. Using the PLC inhibitor U73122, we found that PLC activity is required for synaptic facilitation following a 10-min treatment with 5-HT, as measured at 20 min after 5-HT washout. Prior work has indicated that facilitation at this time is supported primarily by postsynaptic processes. To determine whether postsynaptic PLC activity is involved in 5-HT-mediated facilitatory actions, we examined the effect of U73122 on enhancement of the response of motor neurons isolated in cell culture to glutamate, the sensory neuron transmitter. A 10-min application of 5-HT induced persistent (>40 min) enhancement of glutamate-evoked potentials (Glu-EPs) recorded from isolated motor neurons, and this enhancement was blocked by U73122. Finally, we showed that injecting U73122 into intact animals before behavioral training impaired intermediate-term sensitization, indicating that PLC activity contributes to this form of nonassociative learning.

  18. 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

  19. Sensitivity of the projected hydroclimatic environment of the Delaware River basin to formulation of potential evapotranspiration

    USGS Publications Warehouse

    Williamson, Tanja N.; Nystrom, Elizabeth A.; Milly, Paul C.D.

    2016-01-01

    The Delaware River Basin (DRB) encompasses approximately 0.4 % of the area of the United States (U.S.), but supplies water to 5 % of the population. We studied three forested tributaries to quantify the potential climate-driven change in hydrologic budget for two 25-year time periods centered on 2030 and 2060, focusing on sensitivity to the method of estimating potential evapotranspiration (PET) change. Hydrology was simulated using the Water Availability Tool for Environmental Resources (Williamson et al. 2015). Climate-change scenarios for four Coupled Model Intercomparison Project Phase 5 (CMIP5) global climate models (GCMs) and two Representative Concentration Pathways (RCPs) were used to derive monthly change factors for temperature (T), precipitation (PPT), and PET according to the energy-based method of Priestley and Taylor (1972). Hydrologic simulations indicate a general increase in annual (especially winter) streamflow (Q) as early as 2030 across the DRB, with a larger increase by 2060. This increase in Q is the result of (1) higher winter PPT, which outweighs an annual actual evapotranspiration (AET) increase and (2) (for winter) a major shift away from storage of PPT as snow pack. However, when PET change is evaluated instead using the simpler T-based method of Hamon (1963), the increases in Q are small or even negative. In fact, the change of Q depends as much on PET method as on time period or RCP. This large sensitivity and associated uncertainty underscore the importance of exercising caution in the selection of a PET method for use in climate-change analyses.

  20. Mechanisms of transient receptor potential vanilloid 1 activation and sensitization by allyl isothiocyanate.

    PubMed

    Gees, Maarten; Alpizar, Yeranddy A; Boonen, Brett; Sanchez, Alicia; Everaerts, Wouter; Segal, Andrei; Xue, Fenqin; Janssens, Annelies; Owsianik, Grzegorz; Nilius, Bernd; Voets, Thomas; Talavera, Karel

    2013-09-01

    Allyl isothiocyanate (AITC; aka, mustard oil) is a powerful irritant produced by Brassica plants as a defensive trait against herbivores and confers pungency to mustard and wasabi. AITC is widely used experimentally as an inducer of acute pain and neurogenic inflammation, which are largely mediated by the activation of nociceptive cation channels transient receptor potential ankyrin 1 and transient receptor potential vanilloid 1 (TRPV1). Although it is generally accepted that electrophilic agents activate these channels through covalent modification of cytosolic cysteine residues, the mechanism underlying TRPV1 activation by AITC remains unknown. Here we show that, surprisingly, AITC-induced activation of TRPV1 does not require interaction with cysteine residues, but is largely dependent on S513, a residue that is involved in capsaicin binding. Furthermore, AITC acts in a membrane-delimited manner and induces a shift of the voltage dependence of activation toward negative voltages, which is reminiscent of capsaicin effects. These data indicate that AITC acts through reversible interactions with the capsaicin binding site. In addition, we show that TRPV1 is a locus for cross-sensitization between AITC and acidosis in nociceptive neurons. Furthermore, we show that residue F660, which is known to determine the stimulation by low pH in human TRPV1, is also essential for the cross-sensitization of the effects of AITC and low pH. Taken together, these findings demonstrate that not all reactive electrophiles stimulate TRPV1 via cysteine modification and help understanding the molecular bases underlying the surprisingly large role of this channel as mediator of the algesic properties of AITC.

  1. Assessment of sensitization potential of monoterpenes using the rat popliteal lymph node assay.

    PubMed

    Friedrich, Karen; Delgado, Isabella F; Santos, Laísa M F; Paumgartten, Francisco J R

    2007-08-01

    The popliteal lymph node assay (PLNA) has been proposed as a screening test for detecting chemicals with potential of inducing allergic and auto-immune-like reactions in humans. In the present study, we used the rat PLNA to evaluate the immuno-sensitizing potential of 10 monoterpenes found in the essential oils of a variety of aromatic, edible and medicinal plants. The primary or direct PLNA was performed with the monoterpenes, and chlorpromazine (CPZ) and barbital were used as positive and negative controls, respectively. Female, 7-8 week-old Wistar rats were injected subcutaneously (50 microL) with the test substance (0.5, 2.5 or 5mg) into the right hind footpad while the contralateral footpad was injected with the vehicle (DMSO) alone. Weight (WI) and cellularity (CI) indices for draining PLNs were determined 7 days after treatment. PLNA was positive (WI >or= 2 and CI >or= 5) for CPZ, citral, alpha-terpinene, beta-myrcene and (-)-alpha-pinene, and negative for barbital, DMSO, (-)-menthol, 1,8-cineole, (+/-) citronellal, (+)-limonene, (+/-) camphor and terpineol. A secondary PLNA, a T-cell priming test, was carried out with the four substances that had been positive in the primary assay. Six weeks after being locally primed with 5 mg/paw, rats were sc injected into the same footpad with a dose (0.5 mg/paw) of the substance that had been previously found to be insufficient to cause a positive response. WI and CI were then calculated 4 and 7 days after the second injection. CPZ was also positive in the secondary assay thereby confirming that it is a sensitizing agent. Citral, alpha-terpinene, beta-myrcene and (-)-alpha-pinene, however, were negative in the secondary assay. In summary, citral, alpha-terpinene, beta-myrcene and (-)-alpha-pinene induced a clear immuno-stimulatory response due to their irritant properties but no monoterpene proved to be a sensitizing agent in the PLNA.

  2. Experience with a mouse intranasal test for the predictive identification of respiratory sensitization potential of proteins.

    PubMed

    Blaikie, L; Basketter, D A

    1999-08-01

    The predictive identification of respiratory allergenic potential is an important primary step in the safety evaluation of (novel) proteins, such as the enzymes used in a range of consumer laundry products. In the past this has been achieved by assessing the relative ability of proteins to give rise to the formation of anaphylactic antibody in the guinea pig. Recently, an alternative model has been proposed which assesses the formation of specific IgG1 antibody in a mouse intranasal test (MINT), the assumption being that specific IgG1 antibody is a surrogate for anaphylactic antibody in the mouse. This procedure has undergone successful initial intralaboratory and interlaboratory assessment. In the present work, the MINT has been evaluated in a more thorough intralaboratory study using eight enzymes plus ovalbumin. While the data generated with a reference enzyme protein, Alcalase, showed good reproducibility, results with the remaining eight proteins led to estimates of their relative antigenic or sensitization potential several of which were at variance from those derived from the guinea pig/ human experience. In consequence, it is concluded that the MINT requires substantial further investigation before it can be adopted as a model for the assessment of the relative ability of proteins to behave as respiratory allergens.

  3. 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.

  4. 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.

  5. [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.

  6. Locomotor Activity and Body Temperature Patterns over a Temperature Gradient in the Highveld Mole-Rat (Cryptomys hottentotus pretoriae).

    PubMed

    Haupt, Meghan; Bennett, Nigel C; Oosthuizen, Maria K

    2017-01-01

    African mole-rats are strictly subterranean mammals that live in extensive burrow systems. High humidity levels in the burrows prevent mole-rats from thermoregulating using evaporative cooling. However, the relatively stable environment of the burrows promotes moderate temperatures and small daily temperature fluctuations. Mole-rats therefore display a relatively wide range of thermoregulation abilities. Some species cannot maintain their body temperatures at a constant level, whereas others employ behavioural thermoregulation. Here we test the effect of ambient temperature on locomotor activity and body temperature, and the relationship between the two parameters, in the highveld mole-rat. We exposed mole-rats to a 12L:12D and a DD light cycle at ambient temperatures of 30°C, 25°C and 20°C while locomotor activity and body temperature were measured simultaneously. In addition, we investigated the endogenous rhythms of locomotor activity and body temperature at different ambient temperatures. Mole-rats displayed nocturnal activity at all three ambient temperatures and were most active at 20°C, but least active at 30°C. Body temperature was highest at 30°C and lowest at 20°C, and the daily cycle was highly correlated with locomotor activity. We show that the mole-rats have endogenous rhythms for both locomotor activity and body temperature. However, the endogenous body temperature rhythm appears to be less robust compared to the locomotor activity rhythm. Female mole-rats appear to be more sensitive to temperature changes than males, increased heterothermy is evident at lower ambient temperatures, whilst males show smaller variation in their body temperatures with changing ambient temperatures. Mole-rats may rely more heavily on behavioural thermoregulation as it is more energy efficient in an already challenging environment.

  7. Locomotor Activity and Body Temperature Patterns over a Temperature Gradient in the Highveld Mole-Rat (Cryptomys hottentotus pretoriae)

    PubMed Central

    Haupt, Meghan; Bennett, Nigel C.

    2017-01-01

    African mole-rats are strictly subterranean mammals that live in extensive burrow systems. High humidity levels in the burrows prevent mole-rats from thermoregulating using evaporative cooling. However, the relatively stable environment of the burrows promotes moderate temperatures and small daily temperature fluctuations. Mole-rats therefore display a relatively wide range of thermoregulation abilities. Some species cannot maintain their body temperatures at a constant level, whereas others employ behavioural thermoregulation. Here we test the effect of ambient temperature on locomotor activity and body temperature, and the relationship between the two parameters, in the highveld mole-rat. We exposed mole-rats to a 12L:12D and a DD light cycle at ambient temperatures of 30°C, 25°C and 20°C while locomotor activity and body temperature were measured simultaneously. In addition, we investigated the endogenous rhythms of locomotor activity and body temperature at different ambient temperatures. Mole-rats displayed nocturnal activity at all three ambient temperatures and were most active at 20°C, but least active at 30°C. Body temperature was highest at 30°C and lowest at 20°C, and the daily cycle was highly correlated with locomotor activity. We show that the mole-rats have endogenous rhythms for both locomotor activity and body temperature. However, the endogenous body temperature rhythm appears to be less robust compared to the locomotor activity rhythm. Female mole-rats appear to be more sensitive to temperature changes than males, increased heterothermy is evident at lower ambient temperatures, whilst males show smaller variation in their body temperatures with changing ambient temperatures. Mole-rats may rely more heavily on behavioural thermoregulation as it is more energy efficient in an already challenging environment. PMID:28072840

  8. 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

  9. 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.

  10. 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

  11. Locomotor sequence learning in visually guided walking.

    PubMed

    Choi, Julia T; Jensen, Peter; Nielsen, Jens Bo

    2016-04-01

    Voluntary limb modifications must be integrated with basic walking patterns during visually guided walking. In this study we tested whether voluntary gait modifications can become more automatic with practice. We challenged walking control by presenting visual stepping targets that instructed subjects to modify step length from one trial to the next. Our sequence learning paradigm is derived from the serial reaction-time (SRT) task that has been used in upper limb studies. Both random and ordered sequences of step lengths were used to measure sequence-specific and sequence-nonspecific learning during walking. In addition, we determined how age (i.e., healthy young adults vs. children) and biomechanical factors (i.e., walking speed) affected the rate and magnitude of locomotor sequence learning. The results showed that healthy young adults (age 24 ± 5 yr,n= 20) could learn a specific sequence of step lengths over 300 training steps. Younger children (age 6-10 yr,n= 8) had lower baseline performance, but their magnitude and rate of sequence learning were the same compared with those of older children (11-16 yr,n= 10) and healthy adults. In addition, learning capacity may be more limited at faster walking speeds. To our knowledge, this is the first study to demonstrate that spatial sequence learning can be integrated with a highly automatic task such as walking. These findings suggest that adults and children use implicit knowledge about the sequence to plan and execute leg movement during visually guided walking.

  12. The locomotor anatomy of Australopithecus afarensis.

    PubMed

    Stern, J T; Susman, R L

    1983-03-01

    The postcranial skeleton of Australopithecus afarensis from the Hadar Formation, Ethiopia, and the footprints from the Laetoli Beds of northern Tanzania, are analyzed with the goal of determining (1) the extent to which this ancient hominid practiced forms of locomotion other than terrestrial bipedality, and (2) whether or not the terrestrial bipedalism of A. afarensis was notably different from that of modern humans. It is demonstrated that A. afarensis possessed anatomic characteristics that indicate a significant adaptation for movement in the trees. Other structural features point to a mode of terrestrial bipedality that involved less extension at the hip and knee than occurs in modern humans, and only limited transfer of weight onto the medial part of the ball of the foot, but such conclusions remain more tentative than that asserting substantive arboreality. A comparison of the specimens representing smaller individuals, presumably female, to those of larger individuals, presumably male, suggests sexual differences in locomotor behavior linked to marked size dimorphism. The males were probably less arboreal and engaged more frequently in terrestrial bipedalism. In our opinion, A. afarensis from Hadar is very close to what can be called a "missing link." We speculate that earlier representatives of the A. afarensis lineage will present not a combination of arboreal and bipedal traits, but rather the anatomy of a generalized ape.

  13. The anatomy and physiology of the locomotor system.

    PubMed

    Farley, Alistair; McLafferty, Ella; Hendry, Charles

    Mobilisation is one of the activities of living. The term locomotor system refers to those body tissues and organs responsible for movement. Nurses and healthcare workers should be familiar with the body structures that enable mobilisation to assist those in their care with this activity. This article outlines the structure and function of the locomotor system, including the skeleton, joints, muscles and muscle attachments. Two common bone disorders, osteoporosis and osteoarthritis, are also considered.

  14. 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.

  15. 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

    2015-03-05

    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.

  16. Transient receptor potential (TRP) A1 activated currents in TRPV1 and cholecystokinin-sensitive cranial visceral afferent neurons.

    PubMed

    Choi, Myung-Jin; Jin, Zhenhua; Park, Yong Seek; Rhee, Young Kyoung; Jin, Young-Ho

    2011-04-06

    Culinary use of the pungent spices has potential health benefits including a reduction in food intake. Pungent spices often contain ingredients that activate members of the transient receptor potential (TRP) family A1 and evoke pain from capsaicin-sensitive somatosensory neurons. TRPA1 channel have also been identified on cranial visceral afferent neurons but their distribution and functional contributions are poorly understood. Visceral vagal neurons transduce mechanical and chemical signals from peripheral organs to the nucleus tractus solitarii. Many capsaicin-sensitive vagal afferents participate in peripheral satiety signaling that includes cholecystokinin (CCK) sensitive neurons. To assess signaling, the TRPA1 selective agonist allyl isothiocyanate (AITC) was tested together with CCK and capsaicin (200nM), a TRPV1 specific agonist. In isolated nodose neurons, AITC (0.05-0.2mM) evoked concentration-dependent inward currents in 38% of the tested neurons. The TRPA1 specific antagonist HC-030031 (10μM) blocked AITC responses. TRPA1 responses were mixed across neurons that were capsaicin-sensitive and -insensitive. However CCK evoked inward currents only on capsaicin-sensitive neurons and 28% of the CCK-sensitive neurons expressed TRPA1. Our results indicate that TRPA1 is co-expressed with TRPV1 in CCK-sensitive nodose neurons. The findings indicate a potential mechanism by which spices can act within cranial visceral afferent pathways mediating satiety and contribute to the reduction of the food intake associated with spiced diets.

  17. C57BL/6J MICE EXHIBIT REDUCED DOPAMINE D3 RECEPTOR-MEDIATED LOCOMOTOR-INHIBITORY FUNCTION RELATIVE TO DBA/2J MICE

    PubMed Central

    McNAMARA, R. K.; LEVANT, B.; TAYLOR, B.; AHLBRAND, R.; LIU, Y.; SULLIVAN, J. R.; STANFORD, K.; RICHTAND, N. M.

    2007-01-01

    Previous reports have identified greater sensitivity to the locomotor-stimulating, sensitizing, and reinforcing effects of amphetamine in inbred C57BL/6J mice relative to inbred DBA/2J mice. The dopamine D3 receptor (D3R) plays an inhibitory role in the regulation of rodent locomotor activity, and exerts inhibitory opposition to D1 receptor (D1R)-mediated signaling. Based on these observations, we investigated D3R expression and D3R-mediated locomotor-inhibitory function, as well as D1R binding and D1R-mediated locomotor-stimulating function, in C57BL/6J and DBA/2J mice. C57BL/6J mice exhibited lower D3R binding density (−32%) in the ventral striatum (nucleus accumbens/islands of Calleja), lower D3R mRNA expression (−26%) in the substantia nigra/ventral tegmentum, and greater D3R mRNA expression (+40%) in the hippocampus, relative to DBA/2J mice. There were no strain differences in DR3 mRNA expression in the ventral striatum or prefrontal cortex, nor were there differences in D1R binding in the ventral striatum. Behaviorally, C57BL/6J mice were less sensitive to the locomotor-inhibitory effect of the D3R agonist PD128907 (10 μg/kg), and more sensitive to the locomotor-stimulating effects of novelty, amphetamine (1 mg/kg), and the D1R-like agonist ±-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8,-diol hydrochloride (SKF38393) (5–20 mg/kg) than DBA/2J mice. While the selective D3R antagonist N-(4-[4-{2,3-dichlorphenyl}-1 piperazinyl]butyl)-2-fluorenylcarboxamide (NGB 2904) (0.01–1.0 mg/kg) augmented novelty-, amphetamine-, and SKF38393-induced locomotor activity in DBA/2J mice, it reduced novelty-induced locomotor activity in C57BL/6J mice. Collectively, these results demonstrate that C57BL/6J mice exhibit less D3R-mediated inhibitory function relative to DBA/2J mice, and suggest that reduced D3R-mediated inhibitory function may contribute to heightened sensitivity to the locomotor-stimulating effects of amphetamine in the C57BL/6J mouse strain

  18. 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.

  19. 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.

  20. Aversive startle potentiation and fear pathology: Mediating role of threat sensitivity and moderating impact of depression.

    PubMed

    Yancey, James R; Vaidyanathan, Uma; Patrick, Christopher J

    2015-11-01

    Enhanced startle reactivity during exposure to unpleasant cues (aversive startle potentiation; ASP) appears in the RDoC matrix as a physiological index of acute threat response. Increased ASP has been linked to focal fear disorders and to scale measures of dispositional fearfulness (i.e., threat sensitivity; THT+). However, some studies have reported reduced ASP for fear pathology accompanied by major depressive disorder (MDD) or pervasive distress. The current study evaluated whether (a) THT+ as indexed by reported dispositional fearfulness mediates the relationship between fear disorders (when unaccompanied by depression) and ASP, and (b) depression moderates relations of THT+ and fear disorders with ASP. Fear disorder participants without MDD showed enhanced ASP whereas those with MDD (or other distress conditions) showed evidence of reduced ASP. Continuous THT+ scores also predicted ASP, and this association: (a) was likewise moderated by depression/distress, and (b) accounted for the relationship between ASP and fear pathology without MDD. These findings point to a role for the RDoC construct of acute threat, operationalized dispositionally, in enhanced ASP shown by individuals with fear pathology unaccompanied by distress pathology.

  1. Spatial representation in the social interaction potential metric: an analysis of scale and parameter sensitivity

    NASA Astrophysics Data System (ADS)

    Li, Xiao; Farber, Steven

    2016-10-01

    The social interaction potential (SIP) metric measures urban structural constraints on social interaction opportunities of a metropolitan region based on the time geographic concept of joint accessibility. Previous implementations of the metric used an interaction surface based on census tracts and the locations of their centroids. This has been shown to be a shortcoming, as the metric strongly depends on the scale of the zoning system in the region, making it difficult to compare the SIP metric between metropolitan regions. This research explores the role of spatial representation in the SIP metric and identifies a suitable grid-based representation that allows for comparison between regions while retaining cost-effectiveness with respect to computational burden. We also report on findings from an extensive sensitivity analysis investigating the SIP metric's input parameters such as a travel flow congestion factor and the length of the allowable time budget for social activities. The results provide new insights on the role of the modifiable areal unit problem in the computation of time geographic measures of accessibility.

  2. 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

  3. Chemical reactivity trends of ergotamine and butenolide from electrostatic potentials and charge sensitivities

    SciTech Connect

    Mrozek, J.; Michalak, A.

    1995-12-05

    A set of reactivity indices, including maps of the electrostatic potential and local and condensed Fukui function (FF) indices in the atomic resolution, are reported for two vasoconstricting mycotoxins: butenolide and ergotamine; both the finite difference approach of Parr and Yan as well as charge sensitivity analysis, determining the charge responses via the inversion of the hardness tensor, have been used to generate the FF data. These two routes of arriving at the atomic FF indices provide an opportunity to evaluate the available parametrizations of the semiempirical NDDO-type of methods which have been used to determine the input charge distribution; namely, the best parametrization should generate consistent FF predictions resulting from both approaches. For butenolide, the MNDO parametrization was found to fulfill this consistency requirement. The chemical reactivity information has been used to trace possible similarities in reactivity trends of the butenolide molecule and the related fragment of ergotamine, toward hypothetical nucleophilic, electrophilic, and radical attacks. These predictions have been compared to experimental data available for other unsaturated lactones. 13 refs., 18 figs., 1 tab.

  4. 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.

  5. Damage caused during hypoxia and reoxygenation in the locomotor muscle of the crab Neohelice granulata (Decapoda: Varunidae).

    PubMed

    Geihs, Márcio Alberto; Vargas, Marcelo Alves; Nery, Luiz Eduardo Maia

    2014-06-01

    The aim of this work was to determine whether different durations of severe hypoxia (0.5 mg O2 L(-1)) followed by reoxygenation cause damage to the locomotor muscle of the crab Neohelice granulata. We evaluated reactive oxygen species (ROS), lipid peroxidation (LPO), mitochondrial membrane potential, and aerobic fiber area of the locomotor muscle after different periods of hypoxia (1, 4, or 10h) followed by 30 or 120 min of reoxygenation. Additionally, changes in cell volume, mitochondrial dysfunction, and infiltration of hemocytes were evaluated after hypoxia and a subsequent 2, 24, or 48 h of reoxygenation. After hypoxia, neither ROS nor LPO increased. However, mitochondrial membrane potential and aerobic fiber area decreased in a time-dependent manner. After reoxygenation, the ROS and LPO levels increased and mitochondrial membrane potential decreased, but these quickly recovered in crabs exposed to 4h of hypoxia. On the other hand, alterations of mitochondria resulted in morphological changes in aerobic fibers, which required more time to recover during reoxygenation after 10h of hypoxia. The locomotor muscles of the crab N. granulata suffer damage after hypoxia and reoxygenation. The intensity of this damage is dependent on the duration of hypoxia. In all experimental situations analyzed, the locomotor muscle of this crab was capable of recovery.

  6. Naloxone blocks ethanol-mediated appetitive conditioning and locomotor activation in adolescent rats.

    PubMed

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

    2011-01-01

    Age-related differences in ethanol sensitivity could put adolescents at risk for developing alcohol-related problems. Little information exists, however, about adolescent sensitivity to ethanol's appetitive effects and the neurobiological mechanisms underlying ethanol reinforcement during this developmental stage. The present study assessed the role of the opioid system in adolescent rats in an appetitive second-order schedule of ethanol reinforcement and ethanol-induced locomotor stimulation. On postnatal day 32 (PD32), animals were pretreated with the general opioid antagonist naloxone (0.0, 0.75, 1.50, or 2.5 mg/kg) and then given pairings of ethanol (0.0 or 2.0 g/kg, intragastrically) with intraoral pulses of water (conditioned stimulus 1 [CS₁], first-order conditioning phase). CS₁ delivery occurred 30-45 min after ethanol administration when the effect of ethanol was assumed to be appetitive. On PD33, adolescents were exposed to CS₁ (second-order conditioning phase) while in a chamber featuring distinctive exteroceptive cues (CS₂). Preference for CS₂ was then tested. Adolescents given CS₁-ethanol pairings exhibited greater preference for CS₂ than controls, indicating ethanol-mediated reinforcement, but only when not pretreated with naloxone. Blood alcohol levels during conditioning were not altered by naloxone. Experiment 2 revealed that ethanol-induced locomotor activation soon after administration, and naloxone dose-dependently suppressed this stimulating effect. The present study indicates that adolescent rats are sensitive to ethanol's reinforcing and locomotor-stimulating effects. Both effects of ethanol appear to be mediated by endogenous opioid system activation.

  7. NALOXONE BLOCKS ETHANOL-MEDIATED APPETITIVE CONDITIONING AND LOCOMOTOR ACTIVATION IN ADOLESCENT RATS

    PubMed Central

    Pautassi, Ricardo Marcos; Nizhnikov, Michael E.; Acevedo, María Belén; Spear, Norman E.

    2010-01-01

    Age-related differences in ethanol sensitivity could put adolescents at risk for developing alcohol-related problems. Little information exists, however, about adolescent sensitivity to ethanol's appetitive effects and the neurobiological mechanisms underlying ethanol reinforcement during this developmental stage. The present study assessed the role of the opioid system in adolescent rats in an appetitive second-order schedule of ethanol reinforcement and ethanol-induced locomotor stimulation. On postnatal day 32 (PD32), animals were pretreated with the general opioid antagonist naloxone (0.0, 0.75, 1.50, or 2.5 mg/kg) and then given pairings of ethanol (0.0 or 2.0 g/kg, intragastrically) with intraoral pulses of water (conditioned stimulus 1 [CS1], first-order conditioning phase). CS1 delivery occurred 30–45 min after ethanol administration when the effect of ethanol was assumed to be appetitive. On PD33, adolescents were exposed to CS1 (second-order conditioning phase) while in a chamber featuring distinctive exteroceptive cues (CS2). Preference for CS2 was then tested. Adolescents given CS1-ethanol pairings exhibited greater preference for CS2 than controls, indicating ethanol-mediated reinforcement, but only when not pretreated with naloxone. Blood alcohol levels during conditioning were not altered by naloxone. Experiment 2 revealed that ethanol induced locomotor activation soon after administration, and naloxone dose-dependently suppressed this stimulating effect. The present study indicates that adolescent rats are sensitive to ethanol's reinforcing and locomotor-stimulating effects. Both effects of ethanol appear to be mediated by endogenous opioid system activation. PMID:20708642

  8. Adaptive locomotor behavior in larval zebrafish.

    PubMed

    Portugues, Ruben; Engert, Florian

    2011-01-01

    In this study we report that larval zebrafish display adaptive locomotor output that can be driven by unexpected visual feedback. We develop a new assay that addresses visuomotor integration in restrained larval zebrafish. The assay involves a closed-loop environment in which the visual feedback a larva receives depends on its own motor output in a way that resembles freely swimming conditions. The experimenter can control the gain of this closed feedback loop, so that following a given motor output the larva experiences more or less visual feedback depending on whether the gain is high or low. We show that increases and decreases in this gain setting result in adaptive changes in behavior that lead to a generalized decrease or increase of motor output, respectively. Our behavioral analysis shows that both the duration and tail beat frequency of individual swim bouts can be modified, as well as the frequency with which bouts are elicited. These changes can be implemented rapidly, following an exposure to a new gain of just 175 ms. In addition, modifications in some behavioral parameters accumulate over tens of seconds and effects last for at least 30 s from trial to trial. These results suggest that larvae establish an internal representation of the visual feedback expected from a given motor output and that the behavioral modifications are driven by an error signal that arises from the discrepancy between this expectation and the actual visual feedback. The assay we develop presents a unique possibility for studying visuomotor integration using imaging techniques available in the larval zebrafish.

  9. Adaptive Locomotor Behavior in Larval Zebrafish

    PubMed Central

    Portugues, Ruben; Engert, Florian

    2011-01-01

    In this study we report that larval zebrafish display adaptive locomotor output that can be driven by unexpected visual feedback. We develop a new assay that addresses visuomotor integration in restrained larval zebrafish. The assay involves a closed-loop environment in which the visual feedback a larva receives depends on its own motor output in a way that resembles freely swimming conditions. The experimenter can control the gain of this closed feedback loop, so that following a given motor output the larva experiences more or less visual feedback depending on whether the gain is high or low. We show that increases and decreases in this gain setting result in adaptive changes in behavior that lead to a generalized decrease or increase of motor output, respectively. Our behavioral analysis shows that both the duration and tail beat frequency of individual swim bouts can be modified, as well as the frequency with which bouts are elicited. These changes can be implemented rapidly, following an exposure to a new gain of just 175 ms. In addition, modifications in some behavioral parameters accumulate over tens of seconds and effects last for at least 30 s from trial to trial. These results suggest that larvae establish an internal representation of the visual feedback expected from a given motor output and that the behavioral modifications are driven by an error signal that arises from the discrepancy between this expectation and the actual visual feedback. The assay we develop presents a unique possibility for studying visuomotor integration using imaging techniques available in the larval zebrafish. PMID:21909325

  10. Limitations imposed by wearing armour on Medieval soldiers' locomotor performance.

    PubMed

    Askew, Graham N; Formenti, Federico; Minetti, Alberto E

    2012-02-22

    In Medieval Europe, soldiers wore steel plate armour for protection during warfare. Armour design reflected a trade-off between protection and mobility it offered the wearer. By the fifteenth century, a typical suit of field armour weighed between 30 and 50 kg and was distributed over the entire body. How much wearing armour affected Medieval soldiers' locomotor energetics and biomechanics is unknown. We investigated the mechanics and the energetic cost of locomotion in armour, and determined the effects on physical performance. We found that the net cost of locomotion (C(met)) during armoured walking and running is much more energetically expensive than unloaded locomotion. C(met) for locomotion in armour was 2.1-2.3 times higher for walking, and 1.9 times higher for running when compared with C(met) for unloaded locomotion at the same speed. An important component of the increased energy use results from the extra force that must be generated to support the additional mass. However, the energetic cost of locomotion in armour was also much higher than equivalent trunk loading. This additional cost is mostly explained by the increased energy required to swing the limbs and impaired breathing. Our findings can predict age-associated decline in Medieval soldiers' physical performance, and have potential implications in understanding the outcomes of past European military battles.

  11. Spinocerebellar ataxia type 13 mutant potassium channel alters neuronal excitability and causes locomotor deficits in zebrafish.

    PubMed

    Issa, Fadi A; Mazzochi, Christopher; Mock, Allan F; Papazian, Diane M

    2011-05-04

    Whether changes in neuronal excitability can cause neurodegenerative disease in the absence of other factors such as protein aggregation is unknown. Mutations in the Kv3.3 voltage-gated K(+) channel cause spinocerebellar ataxia type 13 (SCA13), a human autosomal-dominant disease characterized by locomotor impairment and the death of cerebellar neurons. Kv3.3 channels facilitate repetitive, high-frequency firing of action potentials, suggesting that pathogenesis in SCA13 is triggered by changes in electrical activity in neurons. To investigate whether SCA13 mutations alter excitability in vivo, we expressed the human dominant-negative R420H mutant subunit in zebrafish. The disease-causing mutation specifically suppressed the excitability of Kv3.3-expressing, fast-spiking motor neurons during evoked firing and fictive swimming and, in parallel, decreased the precision and amplitude of the startle response. The dominant-negative effect of the mutant subunit on K(+) current amplitude was directly responsible for the reduced excitability and locomotor phenotype. Our data provide strong evidence that changes in excitability initiate pathogenesis in SCA13 and establish zebrafish as an excellent model system for investigating how changes in neuronal activity impair locomotor control and cause cell death.

  12. Morphology and locomotor adaptations of the bovid femur in relation to habitat.

    PubMed

    Kappelman, J

    1988-10-01

    Extant bovids inhabit a wide diversity of environments that range from forest to savanna and display locomotor patterns that are habitat specific. I report here on an investigation of the linkage between these locomotor patterns and habitat based on a study of the morphology of the bovid femur. Femoral head shape, shaft dimensions, and knee structure are examined and support a statistically significant separation of the different morphological complexes present in bovids from forest, broken cover, and savanna habitats. Morphological differences are primarily related to locomotor patterns as reflected in the degree of cursoriality displayed by bovids in different habitats. Cursorial bovids from savanna environments have laterally expanded femoral heads that act to limit the degree of abduction and axial rotation at the hip, and elliptically shaped distal femora that increase the moment arm of the extensor muscles that cross the knee. Forest bovids have spherically shaped femoral heads. This morphology permits a much higher degree of abduction and axial rotation at the hip and appears to provide greater maneuverability in a vegetationally complex habitat. Bovids living in broken cover environments that fall between the extremes of closed canopy forest and savanna display an intermediate set of femoral characters. This approach to the relationship between habitat and locomotion offers a potentially powerful means with which to examine the interplay between structural form and function in bovid evolution.

  13. Impact of Tail Loss on the Behaviour and Locomotor Performance of Two Sympatric Lampropholis Skink Species

    PubMed Central

    Cromie, Gillian L.; Chapple, David G.

    2012-01-01

    Caudal autotomy is an anti-predator behaviour that is used by many lizard species. Although there is an immediate survival benefit, the subsequent absence of the tail may inhibit locomotor performance, alter activity and habitat use, and increase the individuals' susceptibility to future predation attempts. We used laboratory experiments to examine the impact of tail autotomy on locomotor performance, activity and basking site selection in two lizard species, the delicate skink (Lampropholis delicata) and garden skink (L. guichenoti), that occur sympatrically throughout southeastern Australia and are exposed to an identical suite of potential predators. Post-autotomy tail movement did not differ between the two Lampropholis species, although a positive relationship between the shed tail length and distance moved, but not the duration of movement, was observed. Tail autotomy resulted in a substantial decrease in sprint speed in both species (28–39%), although this impact was limited to the optimal performance temperature (30°C). Although L. delicata was more active than L. guichenoti, tail autotomy resulted in decreased activity in both species. Sheltered basking sites were preferred over open sites by both Lampropholis species, although this preference was stronger in L. delicata. Caudal autotomy did not alter the basking site preferences of either species. Thus, both Lampropholis species had similar behavioural responses to autotomy. Our study also indicates that the impact of tail loss on locomotor performance may be temperature-dependent and highlights that future studies should be conducted over a broad thermal range. PMID:22523555

  14. Perturbation schedule does not alter retention of a locomotor adaptation across days

    PubMed Central

    Hussain, Sara J.

    2014-01-01

    Motor adaptation in response to gradual vs. abrupt perturbation schedules may involve different neural mechanisms, potentially leading to different levels of motor memory. However, no study has investigated whether perturbation schedules alter memory of a locomotor adaptation across days. We measured adaptation and retention (memory) of altered interlimb symmetry during walking in two groups of participants over 2 days. On day 1, participants adapted to either a single, large perturbation (abrupt schedule) or a series of small perturbations that increased in size over time (gradual schedule). Retention was examined on day 2. On day 1, initial swing time and foot placement symmetry error sizes differed between groups but overall adaptation magnitudes were similar. On day 2, participants in both groups showed similar retention, readaptation, and aftereffect sizes, although there were some trends for improved memory in the abrupt group. These results conflict with previous data but are consistent with newer studies reporting no behavioral differences following adaptation using abrupt vs. gradual schedules. Although memory levels were very similar between groups, we cannot rule out the possibility that the neural mechanisms underlying this memory storage differ. Overall, it appears that adaptation of locomotor patterns via abrupt and gradual perturbation schedules produces similar expression of locomotor memories across days. PMID:24647433

  15. 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.

  16. Interactions between morphine and the morphine-glucuronides measured by conditioned place preference and locomotor activity.

    PubMed

    Vindenes, Vigdis; Ripel, Ase; Handal, Marte; Boix, Fernando; Mørland, Jørg

    2009-07-01

    After intake of heroin or morphine, active metabolites are formed in the body. The two most important morphine metabolites are morphine-6-glucuronide (M6G) and morphine-3-glucuronide (M3G). M6G and M3G are present for longer time periods and in higher concentrations than the parent drug, but their potential contribution to reward and to development of dependence and addiction is not clear. We tested the effects of morphine and M6G separately (doses of 10, 20, 30 and 50 micromol/kg), administered together, and also in combination with with 200 microm l/kg M3G in male C57BL/6J-Bom mice. M3G in doses of 50, 100, 200, 300 and 400 micromol/kg were also tested alone. We evaluated the rewarding effects in a conditioning place preference (CPP) model and the psychomotor stimulating effects by recording locomotor activity. Mice were subjected to three consecutive conditioning days with drugs or saline before testing. Changes in locomotor activity from conditioning day one to day three were also compared to the expression of CPP on the test day. This study revealed that coadministration of morphine and M6G induced CPP of similar magnitude to the sum of equimolar doses of these compounds alone, and different ratios of the two drugs did not affect the results. M3G did not cause CPP and reduced the CPP induced by both morphine and M6G when coadministered with these drugs. Morphine induced locomotor activity was reduced by coadministration of M3G, but this was not seen when M3G was co-injected with M6G. The changes in locomotor activity during the conditioning periods did not correlated with the expression of CPP. This study revealed that the morphine-glucuronides in different and complex ways can influence the pharmacological effects of psychomotor activation and reward observed after intake of morphine.

  17. Characterization of sacral interneurons that mediate activation of locomotor pattern generators by sacrocaudal afferent input.

    PubMed

    Etlin, Alex; Finkel, Eran; Mor, Yoav; O'Donovan, Michael J; Anglister, Lili; Lev-Tov, Aharon

    2013-01-09

    Identification of the neural pathways involved in retraining the spinal central pattern generators (CPGs) by afferent input in the absence of descending supraspinal control is feasible in isolated rodent spinal cords where the locomotor CPGs are potently activated by sacrocaudal afferent (SCA) input. Here we study the involvement of sacral neurons projecting rostrally through the ventral funiculi (VF) in activation of the CPGs by sensory stimulation. Fluorescent labeling and immunostaining showed that VF neurons are innervated by primary afferents immunoreactive for vesicular glutamate transporters 1 and 2 and by intraspinal neurons. Calcium imaging revealed that 55% of the VF neurons were activated by SCA stimulation. The activity of VF neurons and the sacral and lumbar CPGs was abolished when non-NMDA receptors in the sacral segments were blocked by the antagonist CNQX. When sacral NMDA receptors were blocked by APV, the sacral CPGs were suppressed, VF neurons with nonrhythmic activity were recruited and a moderate-drive locomotor rhythm developed during SCA stimulation. In contrast, when the sacral CPGs were activated by SCA stimulation, rhythmic and nonrhythmic VF neurons were recruited and the locomotor rhythm was most powerful. The activity of 73 and 27% of the rhythmic VF neurons was in-phase with the ipsilateral and contralateral motor output, respectively. Collectively, our studies indicate that sacral VF neurons serve as a major link between SCA and the hindlimb CPGs and that the ability of SCA to induce stepping can be enhanced by the sacral CPGs. The nature of the ascending drive to lumbar CPGs, the identity of subpopulations of VF neurons, and their potential role in activating the locomotor rhythm are discussed.

  18. 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.

  19. 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

  20. 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.

  1. 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.

  2. 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.

  3. 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...

  4. Modafinil Induces Rapid-Onset Behavioral Sensitization and Cross-Sensitization with Cocaine in Mice: Implications for the Addictive Potential of Modafinil

    PubMed Central

    Wuo-Silva, Raphael; Fukushiro, Daniela F.; Hollais, André W.; Santos-Baldaia, Renan; Mári-Kawamoto, Elisa; Berro, Laís F.; Yokoyama, Thaís S.; Lopes-Silva, Leonardo B.; Bizerra, Carolina S.; Procópio-Souza, Roberta; Hashiguchi, Debora; Figueiredo, Lilian A.; Costa, Jose L.; Frussa-Filho, Roberto; Longo, Beatriz M.

    2016-01-01

    There is substantial controversy about the addictive potential of modafinil, a wake-promoting drug used to treat narcolepsy, proposed as pharmacotherapy for cocaine abuse, and used indiscriminately by healthy individuals due to its positive effects on arousal and cognition. The rapid-onset type of behavioral sensitization (i.e., a type of sensitization that develops within a few hours from the drug priming administration) has been emerged as a valuable tool to study binge-like patterns of drug abuse and the neuroplastic changes that occur quickly after drug administration that ultimately lead to drug abuse. Our aim was to investigate the possible development of rapid-onset behavioral sensitization to modafinil and bidirectional rapid-onset cross-sensitization with cocaine in male Swiss mice. A priming injection of a high dose of modafinil (64 mg/kg) induced rapid-onset behavioral sensitization to challenge injections of modafinil at the doses of 16, 32, and 64 mg/kg, administered 4 h later. Furthermore, rapid-onset cross-sensitization was developed between modafinil and cocaine (64 mg/kg modafinil and 20 mg/kg cocaine), in a bidirectional way. These results were not due to residual levels of modafinil as the behavioral effects of the priming injection of modafinil were no longer present and modafinil plasma concentration was reduced at 4 h post-administration. Taken together, the present findings provide preclinical evidence that modafinil can be reinforcing per se and can enhance the reinforcing effects of stimulants like cocaine within hours after administration. PMID:27872594

  5. Modafinil Induces Rapid-Onset Behavioral Sensitization and Cross-Sensitization with Cocaine in Mice: Implications for the Addictive Potential of Modafinil.

    PubMed

    Wuo-Silva, Raphael; Fukushiro, Daniela F; Hollais, André W; Santos-Baldaia, Renan; Mári-Kawamoto, Elisa; Berro, Laís F; Yokoyama, Thaís S; Lopes-Silva, Leonardo B; Bizerra, Carolina S; Procópio-Souza, Roberta; Hashiguchi, Debora; Figueiredo, Lilian A; Costa, Jose L; Frussa-Filho, Roberto; Longo, Beatriz M

    2016-01-01

    There is substantial controversy about the addictive potential of modafinil, a wake-promoting drug used to treat narcolepsy, proposed as pharmacotherapy for cocaine abuse, and used indiscriminately by healthy individuals due to its positive effects on arousal and cognition. The rapid-onset type of behavioral sensitization (i.e., a type of sensitization that develops within a few hours from the drug priming administration) has been emerged as a valuable tool to study binge-like patterns of drug abuse and the neuroplastic changes that occur quickly after drug administration that ultimately lead to drug abuse. Our aim was to investigate the possible development of rapid-onset behavioral sensitization to modafinil and bidirectional rapid-onset cross-sensitization with cocaine in male Swiss mice. A priming injection of a high dose of modafinil (64 mg/kg) induced rapid-onset behavioral sensitization to challenge injections of modafinil at the doses of 16, 32, and 64 mg/kg, administered 4 h later. Furthermore, rapid-onset cross-sensitization was developed between modafinil and cocaine (64 mg/kg modafinil and 20 mg/kg cocaine), in a bidirectional way. These results were not due to residual levels of modafinil as the behavioral effects of the priming injection of modafinil were no longer present and modafinil plasma concentration was reduced at 4 h post-administration. Taken together, the present findings provide preclinical evidence that modafinil can be reinforcing per se and can enhance the reinforcing effects of stimulants like cocaine within hours after administration.

  6. 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

    2015-10-23

    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.

  7. 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

  8. Two Components of Nocturnal Locomotor Suppression by Light

    PubMed Central

    Morin, Lawrence P.; Lituma, Pablo J.; Studholme, Keith M.

    2010-01-01

    In nocturnal rodents, millisecond light (“flash”) stimuli can induce both a large circadian rhythm phase shift and an associated state change from highly active to quiescence followed by behavioral sleep. Suppression of locomotion (“negative masking”) is an easily measured correlate of the state change. The present mouse studies used both flashes and longer light stimuli (“pulses”) to distinguish initiation from maintenance effects of light on locomotor suppression and to determine whether the locomotor suppression exhibits temporal integration as is thought to be characteristic of phase shift responses to pulse, but not flash, stimuli. In Expt. 1, locomotor suppression increased with irradiance (0.01–100 μW/cm2), in accordance with previous reports. It also increased with stimulus duration (3–3000 sec), but interpretation of this result is complicated by the ability of light to both initiate and maintain locomotor suppression. In Expt. 2, an irradiance response curve was determined using a stimulus series of 10 flashes, 2 msec each, with total flash energy varying from 0.0025 – 110.0 J/m2. This included a test for temporal integration in which the effects of two equal energy series of flashes were compared, but which differed in the number of flashes per series (10 vs 100). The 10 flash series more effectively elicited locomotor suppression than the 100 flash series, a result consistent with prior observations involving flash-induced phase shifts. In Expt. 3, exposure of mice to an 11 hr light stimulus yielded irradiance-dependent locomotor suppression that can be maintained for the entire stimulus duration by a 100 μW/cm2 stimulus. Light has the ability to initiate a time-limited (30–40 min) interval of locomotor suppression (initiation effect) that can be extended by additional light (maintenance effect). Temporal integration resembling that seen in phase shifting responses to light does not exist for either phase shift or locomotor

  9. Validation of a microwave radar system for the monitoring of locomotor activity in mice

    PubMed Central

    Pasquali, Vittorio; Scannapieco, Eugenio; Renzi, Paolo

    2006-01-01

    Background The general or spontaneous motor activity of animals is a useful parameter in chronobiology. Modified motion detectors can be used to monitor locomotor activity rhythms. We modified a commercial microwave-based detection device and validated the device by recording circadian and ultradian rhythms. Methods Movements were detected by microwave radar based on the Doppler effect. The equipment was designed to detect and record simultaneously 12 animals in separate cages. Radars were positioned at the bottom of aluminium bulkheads. Animal cages were positioned above the bulkheads. The radars were connected to a computer through a digital I/O board. Results The apparatus was evaluated by several tests. The first test showed the ability of the apparatus to detect the exact frequency of the standard moving object. The second test demonstrated the stability over time of the sensitivity of the radars. The third was performed by simultaneous observations of video-recording of a mouse and radar signals. We found that the radars are particularly sensitive to activities that involve a displacement of the whole body, as compared to movement of only a part of the body. In the fourth test, we recorded the locomotor activity of Balb/c mice. The results were in agreement with published studies. Conclusion Radar detectors can provide automatic monitoring of an animal's locomotor activity in its home cage without perturbing the pattern of its normal behaviour or initiating the spurt of exploration occasioned by transfer to a novel environment. Recording inside breeding cages enables long-term studies with uninterrupted monitoring. The use of electromagnetic waves allows contactless detection and freedom from interference of external stimuli. PMID:16674816

  10. Differentiating event-related potential components sensitive to emotion in middle childhood: evidence from temporal-spatial PCA.

    PubMed

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

    2013-07-01

    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 9-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.

  11. 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.

  12. ERK potentiates p38 in central sensitization induced by traumatic occlusion.

    PubMed

    Jing, Lei; Liu, Xiao-Dong; Yang, Hong-Xu; Zhang, Mian; Wang, Ying; Duan, Li; Zhang, Jing; Lu, Lei; Yang, Ting; Wang, Dong-Mei; Chen, Liang-Wei; Wang, Mei-Qing

    2017-01-06

    This study was to investigate the role of p38 activation via ERK1/2 phosphorylation in neurons and microglia of the spinal trigeminal subnucleus caudalis (Vc) in the promotion of orofacial hyperalgesia induced by unilateral anterior crossbite (UAC) traumatic occlusion in adult rats. U0126, a p-ERK1/2 inhibitor, was injected intracisternally before UAC implant. The effects of the U0126 injection were compared to those following the injection of SB203580, a p-p38 inhibitor. Mechanical hyperalgesia was evaluated via pressure pain threshold measurements. Brain stem tissues were processed for a Western blot analysis to evaluate the activation of ERK1/2 and p38. Double immunofluorescence was also performed to observe the expression of p-ERK1/2 and p-p38 in neurons (labeled by NeuN) and microglia (labeled by OX42). The data showed that UAC caused orofacial hyperalgia ipsilaterally on d1 to d7, peaking on d3 (P<0.05). An upregulation of p-ERK1/2 was observed in the ipsilateral Vc on d1 to d3, peaking on d1. An upregulation of p-p38 was also observed on d1 to d7, peaking on d3 (P<0.05). p-ERK1/2 primarily co-localized with NeuN and, to a lesser extent, with OX42, while p-p38 co-localized with both NeuN and OX42. Pretreatment with U0126 prevented the upregulation of both p-ERK1/2 and p-p38. Similarly to an intracisternal injection of SB203580, U0126 pretreatment attenuated the UAC-induced orofacial hyperalgesia. These data indicate that UAC caused orofacial hyperalgesia by inducing central sensitization via the activation of ERK1/2 and p38 in both neurons and microglia in the Vc, potentially impacting the effects of p-ERK1/2 during p38 activation.

  13. 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

  14. 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…

  15. 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

    2016-07-04

    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.

  16. 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.

  17. Perception--action coupling model for human locomotor pointing.

    PubMed

    de Rugy, A; Taga, G; Montagne, G; Buekers, M J; Laurent, M

    2002-08-01

    How do humans achieve the precise positioning of the feet during walking, for example, to reach the first step of a stairway? We addressed this question at the visuomotor integration level. Based on the optical specification of the required adaptation, a dynamical system model of the visuomotor control of human locomotor pointing was devised for the positioning of a foot on a visible target on the floor during walking. Visuomotor integration consists of directly linking optical information to a motor command that specifically modulates step length in accordance with the ongoing dynamics of locomotor pattern generation. The adaptation of locomotion emerges from a perception-action coupling type of control based on temporal information rather than on feedforward planning of movements. The proposed model reproduces experimental results obtained for human locomotor pointing.

  18. 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.

  19. Chronic Treatment With Aripiprazole Prevents Development of Dopamine Supersensitivity and Potentially Supersensitivity Psychosis

    PubMed Central

    Tadokoro, Shigenori; Okamura, Naoe; Sekine, Yoshimoto; Kanahara, Nobuhisa; Hashimoto, Kenji; Iyo, Masaomi

    2012-01-01

    Background: Long-term treatment of schizophrenia with antipsychotics is crucial for relapse prevention, but a prolonged blockade of D2 dopamine receptors may lead to the development of supersensitivity psychosis. We investigated the chronic effects of aripiprazole (ARI) on dopamine sensitivity. Methods: We administered ARI (1.5 mg/kg/d), haloperidol (HAL; 0.75 mg/kg/d), or vehicle (VEH) via minipump for 14 days to drug-naive rats or to rats pretreated with HAL (0.75 mg/kg/d) or VEH via minipump for 14 days. On the seventh day following treatment cessation, we examined the effects of the treatment conditions on the locomotor response to methamphetamine and on striatal D2 receptor density (N = 4-10/condition/experiment). Results: Chronic treatment with HAL led to significant increases in locomotor response and D2 receptor density, compared with the effects of chronic treatment with either VEH or ARI; there were no significant differences in either locomotor response or D2 density between the VEH- and ARI-treated groups. We also investigated the effects of chronic treatment with HAL, ARI, or VEH preceded by HAL or VEH treatment on locomotor response and D2 density. ANOVA analysis indicated that the rank ordering of groups for both locomotor response and D2 density was HAL-HAL > HAL-VEH > HAL-ARI > VEH-VEH. Conclusions: Chronic treatment with ARI prevents development of dopamine supersensitivity and potentially supersensitivity psychosis, suggesting that by reducing excessive sensitivity to dopamine and by stabilizing sensitivity for an extended period of time, ARI may be helpful for some patients with treatment-resistant schizophrenia. PMID:21402722

  20. Heteromeric heat-sensitive transient receptor potential channels exhibit distinct temperature and chemical response.

    PubMed

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

    2012-03-02

    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.

  1. Nitric oxide-mediated modulation of the murine locomotor network.

    PubMed

    Foster, Joshua D; Dunford, Catherine; Sillar, Keith T; Miles, Gareth B

    2014-02-01

    Spinal motor control networks are regulated by neuromodulatory systems to allow adaptability of movements. The present study aimed to elucidate the role of nitric oxide (NO) in the modulation of mammalian spinal locomotor networks. This was investigated with isolated spinal cord preparations from neonatal mice in which rhythmic locomotor-related activity was induced pharmacologically. Bath application of the NO donor diethylamine NONOate (DEA/NO) decreased the frequency and modulated the amplitude of locomotor-related activity recorded from ventral roots. Removal of endogenous NO with coapplication of a NO scavenger (PTIO) and a nitric oxide synthase (NOS) blocker [nitro-l-arginine methyl ester (l-NAME)] increased the frequency and decreased the amplitude of locomotor-related activity. This demonstrates that endogenously derived NO can modulate both the timing and intensity of locomotor-related activity. The effects of DEA/NO were mimicked by the cGMP analog 8-bromo-cGMP. In addition, the soluble guanylyl cyclase (sGC) inhibitor ODQ blocked the effects of DEA/NO on burst amplitude and frequency, although the frequency effect was only blocked at low concentrations of DEA/NO. This suggests that NO-mediated modulation involves cGMP-dependent pathways. Sources of NO were studied within the lumbar spinal cord during postnatal development (postnatal days 1-12) with NADPH-diaphorase staining. NOS-positive cells in the ventral horn exhibited a rostrocaudal gradient, with more cells in rostral segments. The number of NOS-positive cells was also found to increase during postnatal development. In summary, we have shown that NO, derived from sources within the mammalian spinal cord, modulates the output of spinal motor networks and is therefore likely to contribute to the fine-tuning of locomotor behavior.

  2. 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

  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. Plasticity of connections underlying locomotor recovery after central and/or peripheral lesions in the adult mammals

    PubMed Central

    Rossignol, Serge

    2006-01-01

    This review discusses some aspects of plasticity of connections after spinal injury in adult animal models as a basis for functional recovery of locomotion. After reviewing some pitfalls that must be avoided when claiming functional recovery and the importance of a conceptual framework for the control of locomotion, locomotor recovery after spinal lesions, mainly in cats, is summarized. It is concluded that recovery is partly due to plastic changes within the existing spinal locomotor networks. Locomotor training appears to change the excitability of simple reflex pathways as well as more complex circuitry. The spinal cord possesses an intrinsic capacity to adapt to lesions of central tracts or peripheral nerves but, as a rule, adaptation to lesions entails changes at both spinal and supraspinal levels. A brief summary of the spinal capacity of the rat, mouse and human to express spinal locomotor patterns is given, indicating that the concepts derived mainly from work in the cat extend to other adult mammals. It is hoped that some of the issues presented will help to evaluate how plasticity of existing connections may combine with and potentiate treatments designed to promote regeneration to optimize remaining motor functions. PMID:16939980

  5. Modulation of spontaneous locomotor and respiratory drives to hindlimb motoneurons temporally related to sympathetic drives as revealed by Mayer waves

    PubMed Central

    Wienecke, Jacob; Enríquez Denton, Manuel; Stecina, Katinka; Kirkwood, Peter A.; Hultborn, Hans

    2015-01-01

    In this study we investigated how the networks mediating respiratory and locomotor drives to lumbar motoneurons interact and how this interaction is modulated in relation to periodic variations in blood pressure (Mayer waves). Seven decerebrate cats, under neuromuscular blockade, were used to study central respiratory drive potentials (CRDPs, usually enhanced by added CO2) and spontaneously occurring locomotor drive potentials (LDPs) in hindlimb motoneurons, together with hindlimb and phrenic nerve discharges. In four of the cats both drives and their voltage-dependent amplification were absent or modest, but in the other three, one or other of these drives was common and the voltage-dependent amplification was frequently strong. Moreover, in these three cats the blood pressure showed marked periodic variation (Mayer waves), with a slow rate (periods 9–104 s, mean 39 ± 17 SD). Profound modulation, synchronized with the Mayer waves was seen in the occurrence and/or in the amplification of the CRDPs or LDPs. In one animal, where CRDPs were present in most cells and the amplification was strong, the CRDP consistently triggered sustained plateaux at one phase of the Mayer wave cycle. In the other two animals, LDPs were common, and the occurrence of the locomotor drive was gated by the Mayer wave cycle, sometimes in alternation with the respiratory drive. Other interactions between the two drives involved respiration providing leading events, including co-activation of flexors and extensors during post-inspiration or a locomotor drive gated or sometimes entrained by respiration. We conclude that the respiratory drive in hindlimb motoneurons is transmitted via elements of the locomotor central pattern generator. The rapid modulation related to Mayer waves suggests the existence of a more direct and specific descending modulatory control than has previously been demonstrated. PMID:25713515

  6. KM3NeT/ARCA sensitivity and discovery potential for neutrino point-like sources

    NASA Astrophysics Data System (ADS)

    Trovato, A.

    2016-04-01

    KM3NeT is a large research infrastructure with a network of deep-sea neutrino telescopes in the abyss of the Mediterranean Sea. Of these, the KM3NeT/ARCA detector, installed in the KM3NeT-It node of the network, is optimised for studying high-energy neutrinos of cosmic origin. Sensitivities to galactic sources such as the supernova remnant RXJ1713.7-3946 and the pulsar wind nebula Vela X are presented as well as sensitivities to a generic point source with an E-2 spectrum which represents an approximation for the spectrum of extragalactic candidate neutrino sources.

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

    PubMed Central

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

    2013-01-01

    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 72 hr 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

  8. Peptide reactivity assay using spectrophotometric method for high-throughput screening of skin sensitization potential of chemical haptens.

    PubMed

    Jeong, Yun Hyeok; An, Susun; Shin, Kyeho; Lee, Tae Ryong

    2013-02-01

    Haptens must react with cellular proteins to be recognized by antigen presenting cells. Therefore, monitoring reactivity of chemicals with peptide/protein has been considered an in vitro skin sensitization testing method. The reactivity of peptides with chemicals (peptide reactivity) has usually been monitored by chromatographic methods like HPLC or LC/MS, which are robust tools for monitoring common chemical reactions but are rather expensive and time consuming. Here, we examined the possibility of using spectrophotometric methods to monitor peptide reactivity. Two synthetic peptides, Ac-RWAACAA and Ac-RWAAKAA, were reacted with 48 chemicals (34 sensitizers and 14 non-sensitizers). Peptide reactivity was measured by monitoring unreacted peptides with UV-Vis spectrophotometer using 5,5'-dithiobis-2-nitrobenzoic acid as a detection reagent for the free thiol group of cysteine-containing peptide or fluorometer using fluorescamine™ as a detection reagent for the free amine group of lysine-containing peptide. Chemicals were categorized as sensitizers when they induced more than 10% depletion of cysteine-containing peptide or 20% depletion of lysine-containing peptide. The sensitivity, specificity, and accuracy of this method were 82.4%, 85.7%, and 83.3%, respectively. These results demonstrate that spectrophotometric methods can be easy, fast, and high-throughput screening tools for the prediction of the skin sensitization potential of chemical haptens.

  9. 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

  10. An Investigation of the Potential of 31-Phosphorus Nuclear Magnetic Resonance Spectroscopy to Predict Radiation Sensitivity

    DTIC Science & Technology

    1988-01-01

    Effectiveness .... 42 E. Clonogenic Assay .......................... 45 1. Description of Technique .............. 45 2. Evaluation of Results...52 3. Anesthesia Effects on Radiation Sensitivity and NMR Parameters ....... 61 B. Fractionated Dose Experiments ............. 65 1...cell proliferation during the treatment period appears to limit the effectiveness of radiotherapy (2). During growth, tumors exhibit gradual 31

  11. Glycogen synthase kinase 3β in the nucleus accumbens core is critical for methamphetamine-induced behavioral sensitization.

    PubMed

    Xu, Chun-Mei; Wang, Jun; Wu, Ping; Xue, Yan-Xue; Zhu, Wei-Li; Li, Qian-Qian; Zhai, Hai-Feng; Shi, Jie; Lu, Lin

    2011-07-01

    As a ubiquitous serine/threonine protein kinase, glycogen synthase kinase 3β (GSK-3β) has been considered to be important in the synaptic plasticity that underlies dopamine-related behaviors and diseases. We recently found that GSK-3β activity in the nucleus accumbens (NAc) core is critically involved in cocaine-induced behavioral sensitization. The present study further explored the association between the changes in GSK-3β activity in the NAc and the chronic administration of methamphetamine. We also examined whether blocking GSK-3β activity in the NAc could alter the initiation and expression of methamphetamine (1 mg/kg, i.p.)-induced locomotor sensitization in rats using systemic administration of lithium chloride (LiCl, 100 mg/kg, i.p) and brain region-specific administration of the GSK-3β inhibitor SB216763 (1 ng/side). We found that GSK-3β activity increased in the NAc core, but not NAc shell, after chronic methamphetamine administration. The initiation and expression of methamphetamine-induced locomotor sensitization was attenuated by systemic administration of LiCl and direct infusion of SB216763 into the NAc core, but not NAc shell. These results indicate that GSK-3β activity in the NAc core mediates the initiation and expression of methamphetamine-induced locomotor sensitization, suggesting that GSK-3β may be a potential target for the treatment of psychostimulant addiction.

  12. Combined use of two membrane-potential-sensitive dyes for determination of the Galvani potential difference across a biomimetic oil/water interface.

    PubMed

    Yoshimura, Tatsuya; Nagatani, Hirohisa; Osakai, Toshiyuki

    2014-05-01

    The fluorescence behavior of anionic membrane-potential-sensitive dyes, bis-(1,3-dibutylbarbituric acid) trimethine oxonol (DiBAC4(3)) and bis-(1,3-diethylthiobarbituric acid)trimethine oxonol (DiSBAC2(3)), at a biomimetic 1,2-dichloroethane (DCE)/water (W) interface was studied by the mean of potential-modulated fluorescence (PMF) spectroscopy. The respective dyes gave a well-defined PMF signal due to the adsorption/desorption at the DCE/W interface. It was also found that the potentials where the two dyes gave the PMF signals were different by about 100 mV. We then attempted a combined use of the two dyes for determination of the Galvani potential difference across the DCE/W interface. When 40 μM DiBAC4(3) and 15 μM DiSBAC2(3) were initially added to the W phase, distinctly different spectra were obtained for different interfacial potentials. The ratio of the PMF signal intensities at 530 and 575 nm (the fluorescence maximum wavelengths for the respective dyes) showed a clear dependence on the interfacial potential. These results suggested the potential utility of the combined use of two dyes for the determination of membrane potentials in vivo.

  13. APC mutations as a potential biomarker for sensitivity to tankyrase inhibitors in colorectal cancer.

    PubMed

    Tanaka, Noritaka; Mashima, Tetsuo; Mizutani, Anna; Sato, Ayana; Aoyama, Aki; Gong, Bo; Yoshida, Haruka; Muramatsu, Yukiko; Nakata, Kento; Matsuura, Masaaki; Katayama, Ryohei; Nagayama, Satoshi; Fujita, Naoya; Sugimoto, Yoshikazu; Seimiya, Hiroyuki

    2017-02-08

    In most colorectal cancers (CRCs), Wnt/β-catenin signaling is activated by loss-of-function mutations in the adenomatous polyposis coli (APC) gene and plays a critical role in tumorigenesis. Tankyrases poly(ADP-ribosyl)ate and destabilize Axins, a negative regulator of β-catenin, and upregulate β-catenin signaling. Tankyrase inhibitors downregulate β-catenin and are expected to be promising therapeutics for CRC. However, CRC cells are not always sensitive to tankyrase inhibitors, and predictive biomarkers for the drug sensitivity remain elusive. Here we demonstrate that the short-form APC mutations predict the sensitivity of CRC cells to tankyrase inhibitors. By using well-established CRC cell lines, we found that tankyrase inhibitors downregulated β-catenin in the drug-sensitive but not resistant CRC cells. The drug-sensitive cells showed higher Tcf/LEF transcriptional activity than the resistant cells and possessed 'short' truncated APCs lacking all seven β-catenin-binding 20-amino-acid repeats (20-AARs). By contrast, the drug-resistant cells possessed 'long' APC retaining two or more 20-AARs. Knockdown of the long APCs with two 20-AARs increased β-catenin, Tcf/LEF transcriptional activity and its target gene AXIN2 expression. Under these conditions, tankyrase inhibitors were able to downregulate β-catenin in the resistant cells. These results indicate that the long APCs are hypomorphic mutants whereas they exert a dominant-negative effect on Axin-dependent β-catenin degradation caused by tankyrase inhibitors. Finally, we established 16 patient-derived CRC cells and confirmed that the tankyrase inhibitor-responsive cells harbor the short-form APC mutations. These observations exemplify the predictive importance of APC mutations, the most common genetic alteration in CRCs, for molecular targeted therapeutics.

  14. 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.

  15. Potential impacts of ambient ozone on wheat rust diseases and the role of plant ozone sensitivity

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The resurgence of rust diseases and the continued rise in tropospheric ozone (O3) levels have the potential to limit global wheat production. We conducted a series of experiments to understand the potential interactions between these two stress factors. Both stem rust and leaf rust were increased o...

  16. Correspondence between the location of evoked potential generators and sites of maximal sensitivity to stimulation.

    PubMed

    Stecker, Mark M

    2005-09-01

    The potential recorded by a set of electrodes as an action potential traverses a small axonal segment is proportional to the transmembrane potential produced during stimulation of that axon segment by the same set of recording electrodes, under certain circumstances. First, the membrane must have a constant thickness which is so small that the difference between the surface area of the inner and outer surfaces is minimal. Second, all media must be linear. Third, there must be a monotonically increasing relation between the mean transmembrane potential induced by a stimulus and the maximum transmembrane potential. Fourth, as each axon segment depolarizes, the transmembrane current and change in membrane potential during this time are same. This principle remains true for magnetic stimulation and recording as long as currents generated at the boundaries between regions of differing conductivity outside the axon contribute minimally to the field at the axon. This allows the identification of the point at which an action potential generates a maximal extracellular potential as the point that is stimulated with the lowest threshold.

  17. Asenapine sensitization from adolescence to adulthood and its potential molecular basis.

    PubMed

    Shu, Qing; Qin, Rongyin; Chen, Yingzhu; Hu, Gang; Li, Ming

    2014-10-15

    Asenapine is a new antipsychotic drug that induces a long-lasting behavioral sensitization in adult rats. The present study investigated the developmental impacts of adolescent asenapine treatment on drug sensitivity and on 3 proteins implicated in the action of antipsychotic drugs (i.e. brain-derived neurotrophic factor (BDNF), dopamine D2 receptor, and ΔFosB) in adulthood. Male adolescent Sprague-Dawley rats (postnatal days, P 43-48) were first treated with asenapine (0.05, 0.10 or 0.20mg/kg, sc) and tested in the conditioned avoidance or PCP (2.0mg/kg, sc)-induced hyperlocomotion tasks for 5 days. After they became adults (∼P 76), asenapine sensitization was assessed in a single avoidance or PCP-induced hyperlocomotion challenge test with all rats being injected with asenapine (0.10mg/kg, sc). Rats were then sacrificed 1 day later and BDNF, D2 and ΔFosB in the prefrontal cortex, striatum and hippocampus were examined using Western blotting. In adolescence, repeated asenapine treatment produced a persistent and dose-dependent inhibition of avoidance response, spontaneous motor activity and PCP-induced hyperlocomotion. In the asenapine challenge test, adult rats treated with asenapine (0.10 and 0.20mg/kg) in adolescence made significantly fewer avoidance responses and showed a stronger inhibition of spontaneous motor activity than those previously treated with saline. However, no group difference in the levels of BDNF, D2 and ΔFosB expression was found. These findings suggest that although adolescent asenapine treatment for a short period of time induces a robust behavioral sensitization that persists into adulthood, such a long-term effect is not likely to be mediated by BDNF, D2 and ΔFosB.

  18. Maternal immune activation in late gestation enhances locomotor response to acute but not chronic amphetamine treatment in male mice offspring: role of the D1 receptor.

    PubMed

    Zager, Adriano; Mennecier, Gregory; Palermo-Neto, João

    2012-06-15

    Exposure to elevated levels of maternal cytokines can lead to functional abnormalities of the dopaminergic system in the adult offspring, including enhanced amphetamine (AMPH)-induced locomotion. Therefore, it seems reasonable to consider that offspring of challenged mothers would behave differently in models of addictive behavior, such as behavioral sensitization. Thus, we sought to evaluate the effects of prenatal exposure to lipopolysaccharide (LPS) on the locomotor response to acute and chronic AMPH treatment in male mice offspring. For this purpose, LPS (Escherichia coli 0127:B8; 120 μg/kg) was administered intraperitoneally to pregnant Swiss mice on gestational day 17. At adulthood, male offspring were studied under one of the following conditions: (1) locomotor response to acute AMPH treatment (2.5 or 5.0 mg/kg) in an open field test; (2) behavioral sensitization paradigm, which consists of a daily injection of AMPH (1.0 mg/kg) for 10 days and observation of locomotion in the open field on days 1, 5, 10 (development phase), 15 and 17 (expression phase). The LPS stimulated offspring showed enhancement of the locomotor-stimulant effect after an acute AMPH challenge in comparison to baseline and saline pre-treated mice. They also showed development of behavioral sensitization earlier than the saline pre-treated group, although no changes between saline and LPS pre-treated groups were observed on development or expression of locomotor behavioral sensitization to AMPH. Furthermore, there was up-regulation of D1 receptor protein level within striatum in the LPS-stimulated offspring which was strongly correlated with increased grooming behavior. Taken together, our results indicate that motor and dopaminergic alterations caused by maternal immune activation are restricted to the acute AMPH challenge, mostly due to up-regulation of the D1 receptor within the mesolimbic and nigrostriatal pathways, but no locomotor differences were observed for behavioral

  19. Radiation sensitivity and EPR dosimetric potential of gallic acid and its esters

    NASA Astrophysics Data System (ADS)

    Tuner, Hasan; Oktay Bal, M.; Polat, Mustafa

    2015-02-01

    In the preset work the radiation sensitivities of Gallic Acid anhydrous and monohydrate, Octyl, Lauryl, and Ethyl Gallate (GA, GAm, OG, LG, and EG) were investigated in the intermediate (0.5-20 kGy) and low radiation (<10 Gy) dose range using Electron Paramagnetic Resonance (EPR) spectroscopy. While OG, LG, and EG are presented a singlet EPR spectra, their radiation sensitivity found to be very different in the intermediate dose range. At low radiation dose range (<10 Gy) only LG is found to be present a signal that easily distinguished from the noise signals. The intermediate and low dose range radiation sensitivities are compared using well known EPR dosimeter alanine. The radiation yields (G) of the interested material were found to be 1.34×10-2, 1.48×10-2, 4.14×10-2, and 6.03×10-2, 9.44×10-2 for EG, GA, GAm, OG, and LG, respectively at the intermediate dose range. It is found that the simple EPR spectra and the noticeable EPR signal of LG make it a promising dosimetric material to be used below 10 Gy of radiation dose.

  20. Synthesis of some new porphyrins and their metalloderivatives as potential sensitizers in photo-dynamic therapy

    PubMed Central

    Rostami, Mahboubeh; Rafiee, Leila; Hassanzadeh, Farshid; Dadrass, Ali Reza; Khodarahmi, Ghadam Ali

    2015-01-01

    Porphyrins are a ubiquitous large class of naturally occurring macrocyclic compounds with many significant biological representatives comprising heme and chlorophyll. Some novel adaptable methods for the synthesis of free-based porphyrins as promising sensitizers for the use in photo-dynamic therapy by the virtue of their known tumor affinity, low dark cytotoxicity, and easy synthesis in good to high yields have already been discussed. In the present study, two new porphyrins including TAPFA, as a novel folic acid targeted porphyrin sensitizer, and TAP-Schiff base, as a novel sensitizer with better light absorption, were prepared for the first time and their structures were confirmed by 1H NMR, 13C NMR, FT-IR and UV-Vis spectroscopy as well as CHNS analysis. The compounds were metalized with Zn(II) and Fe(II) metal ions to study how the metal ions can improve the light absorption wavelength and their water solubility. The structures of metalized compounds were also confirmed by FT-IR and UV-Vis spectroscopy. PMID:26779270

  1. Synthesis of some new porphyrins and their metalloderivatives as potential sensitizers in photo-dynamic therapy.

    PubMed

    Rostami, Mahboubeh; Rafiee, Leila; Hassanzadeh, Farshid; Dadrass, Ali Reza; Khodarahmi, Ghadam Ali

    2015-01-01

    Porphyrins are a ubiquitous large class of naturally occurring macrocyclic compounds with many significant biological representatives comprising heme and chlorophyll. Some novel adaptable methods for the synthesis of free-based porphyrins as promising sensitizers for the use in photo-dynamic therapy by the virtue of their known tumor affinity, low dark cytotoxicity, and easy synthesis in good to high yields have already been discussed. In the present study, two new porphyrins including TAPFA, as a novel folic acid targeted porphyrin sensitizer, and TAP-Schiff base, as a novel sensitizer with better light absorption, were prepared for the first time and their structures were confirmed by (1)H NMR, (13)C NMR, FT-IR and UV-Vis spectroscopy as well as CHNS analysis. The compounds were metalized with Zn(II) and Fe(II) metal ions to study how the metal ions can improve the light absorption wavelength and their water solubility. The structures of metalized compounds were also confirmed by FT-IR and UV-Vis spectroscopy.

  2. Potential sensitivity of photosynthesis and isoprene emission to direct radiative effects of atmospheric aerosol pollution

    NASA Astrophysics Data System (ADS)

    Strada, S.; Unger, N.

    2015-09-01

    A global Earth system model is applied to quantify the impacts of direct anthropogenic aerosol effective radiative forcing on gross primary productivity (GPP) and isoprene emission. The impacts of different pollution aerosol sources (all anthropogenic, biomass burning and non-biomass burning) are investigated by performing sensitivity experiments. On the global scale, our results show that land carbon fluxes (GPP and isoprene emission) are not sensitive to pollution aerosols, even under a global decline in surface solar radiation (direct + diffuse) by ~ 9 %. At the regional scale, plant productivity (GPP) and isoprene emission show a robust but opposite sensitivity to pollution aerosols, in regions where complex canopies dominate. In eastern North America and Europe, anthropogenic pollution aerosols (mainly from non-biomass burning sources) enhance GPP by +8-12 % on an annual average, with a stronger increase during the growing season (> 12 %). In the Amazon basin and central Africa, biomass burning aerosols increase GPP by +2-5 % on an annual average, with a peak in the Amazon basin during the dry-fire season (+5-8 %). In Europe and China, anthropogenic pollution aerosols drive a decrease in isoprene emission of -2 to -12 % on the annual average. Anthropogenic aerosols affect land carbon fluxes via different mechanisms and we suggest that the dominant mechanism varies across regions: (1) light scattering dominates in the eastern US; (2) cooling in the Amazon basin; and (3) reduction in direct radiation in Europe and China.

  3. 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...

  4. 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,...

  5. Unraveling a locomotor network, many neurons at a time.

    PubMed

    Brownstone, Robert M; Stifani, Nicolas

    2015-04-08

    In this issue of Neuron, Bruno et al. (2015) use large-scale recordings in Aplysia, and apply novel dimensionality-reduction techniques to define dynamical building blocks involved in locomotor behavior. These techniques open new avenues to the study of neuronal networks.

  6. 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…

  7. 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…

  8. 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-...

  9. Differing Sensitivity of Photosynthesis to Low Leaf Water Potentials in Corn and Soybean 1

    PubMed Central

    Boyer, J. S.

    1970-01-01

    Rates of net photosynthesis were studied in soil-grown corn (Zea mays) and soybean (Glycine max) plants having various leaf water potentials. Soybean was unaffected by desiccation until leaf water potentials were below −11 bars. Rates of photosynthesis in corn were inhibited whenever leaf water potentials dropped below −3.5 bars. The differences in photosynthetic behavior could be attributed solely to differences in stomatal behavior down to leaf water potentials of −16 bars in soybean and −10 bars in corn. Below these potentials, other factors in addition to stomatal closure caused inhibition, although their effect was relatively small. Corn, which has the C4-dicarboxylic acid pathway for carbon fixation, generally had a higher rate of photosynthesis than soybean during desiccation. Nevertheless, since inhibition of photosynthesis began at higher potentials than in soybean, and since corn was less able to withstand severe desiccation without tissue death, it was concluded that the C4 pathway confers no particular ability to withstand low leaf water potentials. PMID:16657442

  10. Potential Interactions of Calcium-Sensitive Reagents with Zinc Ion in Different Cultured Cells

    PubMed Central

    Fujikawa, Koichi; Fukumori, Ryo; Nakamura, Saki; Kutsukake, Takaya; Takarada, Takeshi; Yoneda, Yukio

    2015-01-01

    Background Several chemicals have been widely used to evaluate the involvement of free Ca2+ in mechanisms underlying a variety of biological responses for decades. Here, we report high reactivity to zinc of well-known Ca2+-sensitive reagents in diverse cultured cells. Methodology/Principal Findings In rat astrocytic C6 glioma cells loaded with the fluorescent Ca2+ dye Fluo-3, the addition of ZnCl2 gradually increased the fluorescence intensity in a manner sensitive to the Ca2+ chelator EGTA irrespective of added CaCl2. The addition of the Ca2+ ionophore A23187 drastically increased Fluo-3 fluorescence in the absence of ZnCl2, while the addition of the Zn2+ ionophore pyrithione rapidly and additionally increased the fluorescence in the presence of ZnCl2, but not in its absence. In cells loaded with the zinc dye FluoZin-3 along with Fluo-3, a similarly gradual increase was seen in the fluorescence of Fluo-3, but not of FluoZin-3, in the presence of both CaCl2 and ZnCl2. Further addition of pyrithione drastically increased the fluorescence intensity of both dyes, while the addition of the Zn2+ chelator N,N,N',N'-tetrakis(2-pyridylmethyl)ethane-1,2-diamine (TPEN) rapidly and drastically decreased FluoZin-3 fluorescence. In cells loaded with FluoZin-3 alone, the addition of ZnCl2 induced a gradual increase in the fluorescence in a fashion independent of added CaCl2 but sensitive to EGTA. Significant inhibition was found in the vitality to reduce 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide in a manner sensitive to TPEN, EDTA and BAPTA in C6 glioma cells exposed to ZnCl2, with pyrithione accelerating the inhibition. Similar inhibition occurred in an EGTA-sensitive fashion after brief exposure to ZnCl2 in pluripotent P19 cells, neuronal Neuro2A cells and microglial BV2 cells, which all expressed mRNA for particular zinc transporters. Conclusions/Significance Taken together, comprehensive analysis is absolutely required for the demonstration of a

  11. Individual differences in cocaine-induced locomotor activity of male Sprague-Dawley rats are not explained by plasma corticosterone levels.

    PubMed

    Nelson, Anna M; Kleschen, Melissa J; Zahniser, Nancy R

    2010-05-26

    Humans differ in their initial response to, and subsequent abuse of, addictive drugs like cocaine. Rodents also exhibit marked individual differences in responsiveness to cocaine. Previously, we classified male Sprague-Dawley rats as either low or high cocaine responders (LCRs or HCRs, respectively), based on their acute low-dose cocaine-induced locomotor activity, and found that with repeated drug exposure LCRs exhibit greater cocaine locomotor sensitization, reward and reinforcement than HCRs. Differential cocaine-induced increases in striatal dopamine help to explain the LCR/HCR phenotypes. Differential levels of stress and/or anxiety could also contribute but have not been explored. Here we measured open-field activity and plasma corticosterone levels both pre- and post-cocaine treatment in LCRs, HCRs, and saline-treated controls. The three groups did not differ in baseline locomotor activity or corticosterone levels. Importantly, LCR/HCR differences in corticosterone levels were also not observed following acute cocaine (10mg/kg, i.p.), when cocaine induced approximately 3.5-fold greater locomotor activity in HCRs than LCRs. Additionally, there were no LCR/HCR differences in plasma corticosterone levels following 5 days of once-daily cocaine, during which time LCRs developed locomotor sensitization such that their cocaine-induced locomotor activity no longer differed from that of HCRs. Likewise, there were no group activity differences in any of four concentric zones within the open-field chamber. In summary, neither plasma corticosterone levels nor thigmotaxis-type anxiety appears to be a factor that contributes to the observed cocaine-induced LCR/HCR behavioral differences.

  12. Dynamic "Range of Motion" Hindlimb Stretching Disrupts Locomotor Function in Rats with Moderate Subacute Spinal Cord Injuries.

    PubMed

    Keller, Anastasia; Rees, Kathlene; Prince, Daniella; Morehouse, Johnny; Shum-Siu, Alice; Magnuson, David

    2017-04-12

    Joint contractures and spasticity are two common secondary complications of a severe spinal cord injury (SCI), which can significantly reduce quality of life, and stretching is one of the top strategies for rehabilitation of these complications. We have previously shown that a daily static stretching protocol administered to rats at either acute or chronic time points after a moderate or moderate-severe T10 SCI significantly disrupts their hindlimb locomotor function. The objective of the current study was to examine the effects of dynamic range of motion (ROM) stretching on the locomotor function of rats with SCI as an alternative to static stretching. Starting at 6 weeks post-injury (T10 moderate contusion) eight adult Sprague-Dawley rats were subjected to hindlimb stretching for 4 weeks. Our standard stretching protocol (six maneuvers to stretch the major hindlimb muscle groups) was modified from 1 min static stretch-and-hold at the end ROM of each stretch position to a dynamic 2 sec hold, 1 sec release rhythm repeated for a duration of 1 min. Four weeks of daily (5 days/week) dynamic stretching led to significant disruption of locomotor function as assessed by the Basso, Beattie, Bresnahan (BBB) Open Field Locomotor Scale and three-dimensional (3D) kinematic and gait analyses. In addition, we identified and analyzed an apparently novel hindlimb response to dynamic stretch that resembles human clonus. The results of the current study extend the observation of the stretching phenomenon to a new modality of stretching that is also commonly used in SCI rehabilitation. Although mechanisms and clinical relevance still need to be established, our findings continue to raise concerns that stretching as a therapy can potentially hinder aspects of locomotor recovery.

  13. Down-regulation of Decapping Protein 2 mediates chronic nicotine exposure-induced locomotor hyperactivity in Drosophila.

    PubMed

    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.

  14. Effects of postweaning social and physical deprivation on locomotor activity patterns and explorative behavior in female CD-1 mice.

    PubMed

    Haupt, Moritz; Schaefers, Andrea T U

    2010-05-01

    Social and physical deprivation during adolescence has detrimental consequences for brain maturation and cognitive functions. To test the hypothesis that social and physical deprivation during mouse adolescence would disrupt activity and exploration behavior, we exposed mice either to deprived or enriched rearing (postnatal days 21-60) and assessed activity and exploration of adult mice individually or in mixed treatment groups. In automated group compartments, deprived-reared mice displayed higher locomotor activity, reduced explorative behavior and shifted activity timing compared to enriched-reared mice. Contrastingly, distance and timing of wheel running were largely unaffected by deprived rearing. Our results demonstrate that postweaning social and physical deprivation has measurable effects on mouse locomotor and exploratory behavior, and that such effects may be discernable depending on the activity type studied. Our results further emphasize the importance of the sensitive postweaning period for shaping adult behavioral profiles.

  15. Effects of pregnancy on body temperature and locomotor performance of velvet geckos.

    PubMed

    Dayananda, Buddhi; Ibargüengoytía, Nora; Whiting, Martin J; Webb, Jonathan K

    2017-04-01

    Pregnancy is a challenging period for egg laying squamates. Carrying eggs can encumber females and decrease their locomotor performance, potentially increasing their risk of predation. Pregnant females can potentially reduce this handicap by selecting higher temperatures to increase their sprint speed and ability to escape from predators, or to speed up embryonic development and reduce the period during which they are burdened with eggs ('selfish mother' hypothesis). Alternatively, females might select more stable body temperatures during pregnancy to enhance offspring fitness ('maternal manipulation hypothesis'), even if the maintenance of such temperatures compromises a female's locomotor performance. We investigated whether pregnancy affects the preferred body temperatures and locomotor performance of female velvet geckos Amalosia lesueurii. We measured running speed of females during late pregnancy, and one week after they laid eggs at four temperatures (20°, 25°, 30° and 35°C). Preferred body temperatures of females were measured in a cost-free thermal gradient during late pregnancy and one week after egg-laying. Females selected higher and more stable set-point temperatures when they were pregnant (mean =29.0°C, Tset =27.8-30.5°C) than when they were non-pregnant (mean =26.2°C, Tset =23.7-28.7°C). Pregnancy was also associated with impaired performance; females sprinted more slowly at all four test temperatures when burdened with eggs. Although females selected higher body temperatures during late pregnancy, this increase in temperature did not compensate for their impaired running performance. Hence, our results suggest that females select higher temperatures during pregnancy to speed up embryogenesis and reduce the period during which they have reduced performance. This strategy may decrease a female's probability of encountering predatory snakes that use the same microhabitats for thermoregulation. Selection of stable temperatures by pregnant

  16. Sensitization and cross-sensitization after chronic treatment with methylphenidate in adolescent Wistar rats.

    PubMed

    Valvassori, Samira S; Frey, Benício N; Martins, Márcio R; Réus, Gislaine Z; Schimidtz, Filipe; Inácio, Cecília G; Kapczinski, Flávio; Quevedo, João

    2007-05-01

    An increasing debate exists about the potential of early exposure to methylphenidate to increase the risk for drug abuse. In addition, little is known about the neurobiological effects of early exposure to methylphenidate. This study was designed to investigate whether chronic treatment with methylphenidate induces behavioral sensitization to subsequent methylphenidate and D-amphetamine challenge in adolescent Wistar rats. Young Wistar rats (P25) were treated with either methylphenidate (1, 2, or 10 mg/kg, intraperitoneally) or saline for 28 days. After 14 days of washout, animals were challenged with methylphenidate 2.5 mg/kg intraperitoneally or D-amphetamine 2 mg/kg intraperitoneally (P67). Locomotor behavior was assessed using the open field test. Rats chronically treated with methylphenidate in the adolescent period showed augmented locomotor sensitization to D-amphetamine but not to methylphenidate in the adult phase. These findings suggest that early exposure do methylphenidate might increase the risk for subsequent D-amphetamine abuse. Further studies focusing on the neurobiological effects of early exposure to methylphenidate are warranted.

  17. Chronic nicotine differentially alters cocaine-induced locomotor activity in adolescent vs. adult male and female rats.

    PubMed

    Collins, Stephanie L; Izenwasser, Sari

    2004-03-01

    Tobacco use is prevalent in the adolescent population. It is a major concern because tobacco is highly addictive and has also been linked to illicit drug use. There is not much research, however, on the interaction between nicotine and other stimulant drugs in animal models of early adolescence. This study examined the effects of chronic nicotine alone and on cocaine-stimulated activity in male and female periadolescent rats compared to male and female adult rats. During the seven-day nicotine pretreatment period, nicotine increased locomotor activity in all groups compared to vehicle controls. Male and female adult rats and female periadolescent rats developed sensitization to the locomotor-activating effects of nicotine over the 7-day treatment period, while male periadolescent rats did not. All groups treated with nicotine, however, exhibited sensitization to nicotine-induced repetitive motion over the 7-day nicotine treatment period. On day 8, male periadolescent rats pretreated with nicotine were more markedly sensitized to the locomotor-activating effects of cocaine than male adult rats, while female rats pretreated with nicotine were not sensitized to cocaine. In contrast, male and female periadolescent rats, but not adult rats, had increased amounts of repetitive beam breaks induced by cocaine after nicotine pretreatment. Overall, it appears that cross-sensitization to cocaine is greater in periadolescent than in adult rats, and that males are more sensitized than females. Thus, it may be that nicotine use during adolescence carries a greater risk than during adulthood and that male adolescents may be particularly vulnerable to the risk of cocaine abuse after nicotine use. This information should be taken into account so as to help us better understand the development of drug addiction in adolescents compared to adults.

  18. 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.

  19. Sensitivity of potential evapotranspiration and simulated flow to varying meteorological inputs, Salt Creek watershed, DuPage County, Illinois

    USGS Publications Warehouse

    Whitbeck, David E.

    2006-01-01

    The Lamoreux Potential Evapotranspiration (LXPET) Program computes potential evapotranspiration (PET) using inputs from four different meteorological sources: temperature, dewpoint, wind speed, and solar radiation. PET and the same four meteorological inputs are used with precipitation data in the Hydrological Simulation Program-Fortran (HSPF) to simulate streamflow in the Salt Creek watershed, DuPage County, Illinois. Streamflows from HSPF are routed with the Full Equations (FEQ) model to determine water-surface elevations. Consequently, variations in meteorological inputs have potential to propagate through many calculations. Sensitivity of PET to variation was simulated by increasing the meteorological input values by 20, 40, and 60 percent and evaluating the change in the calculated PET. Increases in temperatures produced the greatest percent changes, followed by increases in solar radiation, dewpoint, and then wind speed. Additional sensitivity of PET was considered for shifts in input temperatures and dewpoints by absolute differences of ?10, ?20, and ?30 degrees Fahrenheit (degF). Again, changes in input temperatures produced the greatest differences in PET. Sensitivity of streamflow simulated by HSPF was evaluated for 20-percent increases in meteorological inputs. These simulations showed that increases in temperature produced the greatest change in flow. Finally, peak water-surface elevations for nine storm events were compared among unmodified meteorological inputs and inputs with values predicted 6, 24, and 48 hours preceding the simulated peak. Results of this study can be applied to determine how errors specific to a hydrologic system will affect computations of system streamflow and water-surface elevations.

  20. Activation of Neurotensin Receptor Type 1 Attenuates Locomotor Activity

    PubMed Central

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

    2014-01-01

    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 SKF81297 (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

  1. Interpreting locomotor biomechanics from the morphology of human footprints.

    PubMed

    Hatala, Kevin G; Wunderlich, Roshna E; Dingwall, Heather L; Richmond, Brian G

    2016-01-01

    Fossil hominin footprints offer unique direct windows to the locomotor behaviors of our ancestors. These data could allow a clearer understanding of the evolution of human locomotion by circumventing issues associated with indirect interpretations of habitual locomotor patterns from fossil skeletal material. However, before we can use fossil hominin footprints to understand better the evolution of human locomotion, we must first develop an understanding of how locomotor biomechanics are preserved in, and can be inferred from, footprint morphologies. In this experimental study, 41 habitually barefoot modern humans created footprints under controlled conditions in which variables related to locomotor biomechanics could be quantified. Measurements of regional topography (depth) were taken from 3D models of those footprints, and principal components analysis was used to identify orthogonal axes that described the largest proportions of topographic variance within the human experimental sample. Linear mixed effects models were used to quantify the influences of biomechanical variables on the first five principal axes of footprint topographic variation, thus providing new information on the biomechanical variables most evidently expressed in the morphology of human footprints. The footprint's overall depth was considered as a confounding variable, since biomechanics may be linked to the extent to which a substrate deforms. Three of five axes showed statistically significant relationships with variables related to both locomotor biomechanics and substrate displacement; one axis was influenced only by biomechanics and another only by the overall depth of the footprint. Principal axes of footprint morphological variation were significantly related to gait type (walking or running), kinematics of the hip and ankle joints and the distribution of pressure beneath the foot. These results provide the first quantitative framework for developing hypotheses regarding the

  2. Potential sensitivity of photosynthesis and isoprene emission to direct radiative effects of atmospheric aerosol pollution

    NASA Astrophysics Data System (ADS)

    Strada, Susanna; Unger, Nadine

    2016-04-01

    A global Earth system model is applied to quantify the impacts of direct anthropogenic aerosol effective radiative forcing on gross primary productivity (GPP) and isoprene emission. The impacts of different pollution aerosol sources (anthropogenic, biomass burning, and non-biomass burning) are investigated by performing sensitivity experiments. The model framework includes all known light and meteorological responses of photosynthesis, but uses fixed canopy structures and phenology. On a global scale, our results show that global land carbon fluxes (GPP and isoprene emission) are not sensitive to pollution aerosols, even under a global decline in surface solar radiation (direct + diffuse) by ˜ 9 %. At a regional scale, GPP and isoprene emission show a robust but opposite sensitivity to pollution aerosols in regions where forested canopies dominate. In eastern North America and Eurasia, anthropogenic pollution aerosols (mainly from non-biomass burning sources) enhance GPP by +5-8 % on an annual average. In the northwestern Amazon Basin and central Africa, biomass burning aerosols increase GPP by +2-5 % on an annual average, with a peak in the northwestern Amazon Basin during the dry-fire season (+5-8 %). The prevailing mechanism varies across regions: light scattering dominates in eastern North America, while a reduction in direct radiation dominates in Europe and China. Aerosol-induced GPP productivity increases in the Amazon and central Africa include an additional positive feedback from reduced canopy temperatures in response to increases in canopy conductance. In Eurasia and northeastern China, anthropogenic pollution aerosols drive a decrease in isoprene emission of -2 to -12 % on an annual average. Future research needs to incorporate the indirect effects of aerosols and possible feedbacks from dynamic carbon allocation and phenology.

  3. GHRP-6 mimics ghrelin-induced stimulation of food intake and suppression of locomotor activity in goldfish.

    PubMed

    Yahashi, Satowa; Kang, Ki Sung; Kaiya, Hiroyuki; Matsuda, Kouhei

    2012-04-01

    Ghrelin was first identified and characterized from rat stomach as an endogenous ligand for the growth hormone secretagogue (GHS) receptor (GHS-R). Ghrelin also acts as an orexigenic factor and regulates energy balance in rodents. In goldfish, native ghrelin consists of 11 molecular variants, the major form being a 17-residue peptide with n-octanoic acid modification (n-octanoyl ghrelin17), and intraperitoneal (IP) administration of n-octanoyl ghrelin17 induces central actions such as stimulation of food intake and suppression of locomotor activity through capsaicin-sensitive afferents. Four types of GHS-Rs (1a-1, 1a-2, 2a-1 and 2a-2) have been identified in goldfish, and one GHS, GHRP-6, can activate only GHS-R2a-1 in vitro. However, there is no information about the effect of GHRP-6 on food intake and locomotor activity in goldfish in vivo. Therefore, in the present study, we examined whether IP-administered GHRP-6 would mimic the orexigenic action of n-octanoyl ghrelin17 and its suppression of locomotor activity. IP administration of GHRP-6 at 1pmol/g body weight (BW) stimulated food intake, and was equipotent to the orexigenic action of n-octanoyl ghrelin17 at 10 pmol/g BW. IP-injected GHRP-6 at 1 pmol/g BW also induced a significant decrease of locomotor activity, as was the case for IP-injected n-octanoyl ghrelin17 at 10 pmol/g BW. The action of GHRP-6 was blocked by IP-preinjected capsaicin at 160 nmol/g BW. These results suggest that the central action of GHRP-6 might be mediated via the GHS-R2a-1-signaling pathway, and subsequently through capsaicin-sensitive afferents in goldfish.

  4. Chronic nicotine alters cannabinoid-mediated locomotor activity and receptor density in periadolescent but not adult male rats

    PubMed Central

    Werling, Linda L.; Reed, Stephanie Collins; Wade, Dean; Izenwasser, Sari

    2009-01-01

    A significant number of youths use cigarettes, and more than half of the youths who smoke daily also use illicit drugs. The focus of these studies is on how exposure to nicotine affects subsequent responses to both nicotine and cannabinoids in adolescents compared with adults. We have shown previously that chronic treatment with nicotine produces sensitization to its locomotor-activating effects in female and adult rats but not male adolescent rats. To better understand the effects of nicotine on adolescent and adult rats, rats were injected with nicotine or saline for 7 days and, on day 8, either challenged with delta-9-tetrahydrocannabinol (Δ9-THC) or the cannabinoid agonist CP 55,940 and tested for locomotor activity, or the brains were removed for quantitative autoradiography studies of the cannabinoid1 receptor. A separate group of rats was treated with nicotine plus the cannabinoid antagonist AM 251 and then challenged with CP 55,940. In adolescent male rats, nicotine administration led to sensitization to the locomotor-decreasing effects of both Δ9-THC and CP 55,940, but in adult male rats, the response to either drug was unchanged compared to controls. The effect of nicotine on CP 55,940-mediated locomotor activity was blocked by co-administration of AM 251 with the nicotine. Further, cannabinoid receptor density was increased in the prelimbic prefrontal cortex, ventral tegmental area, and select regions of the hippocampus in adolescent male rats pretreated with nicotine compared to vehicle-treated controls. There were no significant changes in cannabinoid receptor binding, however, in any of the brain regions examined in adult males pretreated with nicotine. The prelimbic prefrontal cortex and the hippocampus have been shown previously to be involved in stimulant reinforcement; thus it is possible that these changes contribute to the unique behavioral effects of chronic nicotine and subsequent drug administration in adolescents compared with adults. PMID

  5. 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.

  6. Chronic ultra-mild stress improves locomotor performance of B6D2F1 mice in a motor risk situation.

    PubMed

    Negroni, Julia; Venault, Patrice; Pardon, Marie Christine; Pérez-Diaz, Fernando; Chapouthier, Georges; Cohen-Salmon, Charles

    2004-12-06

    Chronic low grade stress predispose to psychopathological disorders. We consistently showed that chronic ultra-mild stress (CUMS) applied to B6D2F1 female mice induced behavioral disinhibition in several conflict exploration models. Insufficient reactivity to conflicts may be maladaptive and lead to inappropriate appreciation of potential risks and impaired ability to cope with those. Therefore, the purpose of the study was to assess the effect of a CUMS procedure on the behavior of mice in a motor risk situation based on multisensory conflict. Following three weeks exposure to various mild stressors, stressed and control B6D2F1 mice were tested on the rotating beam to determine how CUMS exposure affected balance control, posture stability and locomotor performance in response to a sensory-motor challenge. Detailed behavioral analysis included several parameters, both postural (height of the trunk, tail angle, number of imbalances, falls and head movements) and kinetic (mean velocity on the beam, distance covered with large and small movements, plus time spent in no-motion episodes). Comparisons between control and stressed mice showed that CUMS exposure increased mean velocity and improved locomotor performance in the learning task. In addition, sensitivity to sensory conflict seemed to be reduced in stressed mice, which displayed fewer behavioral adjustments to the increasing difficulty of the test compared to control mice. The results are discussed in terms of the possible influence of disturbances in behavioral and attentional inhibitory processes following CUMS exposure. Whether longer periods of CUMS exposure would shift the performance on the RTB from improvement to deterioration remain to be established.

  7. Evaluation of a High-Throughput Peptide Reactivity Format Assay for Assessment of the Skin Sensitization Potential of Chemicals

    PubMed Central

    Wong, Chin Lin; Lam, Ai-Leen; Smith, Maree T.; Ghassabian, Sussan

    2016-01-01

    The direct peptide reactivity assay (DPRA) is a validated method for in vitro assessment of the skin sensitization potential of chemicals. In the present work, we describe a peptide reactivity assay using 96-well plate format and systematically identified the optimal assay conditions for accurate and reproducible classification of chemicals with known sensitizing capacity. The aim of the research is to ensure that the analytical component of the peptide reactivity assay is robust, accurate, and reproducible in accordance with criteria that are used for the validation of bioanalytical methods. Analytical performance was evaluated using quality control samples (QCs; heptapeptides at low, medium, and high concentrations) and incubation of control chemicals (chemicals with known sensitization capacity, weak, moderate, strong, extreme, and non-sensitizers) with each of three synthetic heptapeptides, viz Cor1-C420 (Ac-NKKCDLF), cysteine- (Ac-RFAACAA), and lysine- (Ac-RFAAKAA) containing heptapeptides. The optimal incubation temperature for all three heptapeptides was 25°C. Apparent heptapeptide depletion was affected by vial material composition. Incubation of test chemicals with Cor1-C420, showed that peptide depletion was unchanged in polypropylene vials over 3-days storage in an autosampler but this was not the case for borosilicate glass vials. For cysteine-containing heptapeptide, the concentration was not stable by day 3 post-incubation in borosilicate glass vials. Although the lysine-containing heptapeptide concentration was unchanged in both polypropylene and borosilicate glass vials, the apparent extent of lysine-containing heptapeptide depletion by ethyl acrylate, differed between polypropylene (24.7%) and glass (47.3%) vials. Additionally, the peptide-chemical complexes for Cor1-C420-cinnamaldehyde and cysteine-containing heptapeptide-2, 4-dinitrochlorobenzene were partially reversible during 3-days of autosampler storage. These observations further highlight

  8. Evaluation of a High-Throughput Peptide Reactivity Format Assay for Assessment of the Skin Sensitization Potential of Chemicals.

    PubMed

    Wong, Chin Lin; Lam, Ai-Leen; Smith, Maree T; Ghassabian, Sussan

    2016-01-01

    The direct peptide reactivity assay (DPRA) is a validated method for in vitro assessment of the skin sensitization potential of chemicals. In the present work, we describe a peptide reactivity assay using 96-well plate format and systematically identified the optimal assay conditions for accurate and reproducible classification of chemicals with known sensitizing capacity. The aim of the research is to ensure that the analytical component of the peptide reactivity assay is robust, accurate, and reproducible in accordance with criteria that are used for the validation of bioanalytical methods. Analytical performance was evaluated using quality control samples (QCs; heptapeptides at low, medium, and high concentrations) and incubation of control chemicals (chemicals with known sensitization capacity, weak, moderate, strong, extreme, and non-sensitizers) with each of three synthetic heptapeptides, viz Cor1-C420 (Ac-NKKCDLF), cysteine- (Ac-RFAACAA), and lysine- (Ac-RFAAKAA) containing heptapeptides. The optimal incubation temperature for all three heptapeptides was 25°C. Apparent heptapeptide depletion was affected by vial material composition. Incubation of test chemicals with Cor1-C420, showed that peptide depletion was unchanged in polypropylene vials over 3-days storage in an autosampler but this was not the case for borosilicate glass vials. For cysteine-containing heptapeptide, the concentration was not stable by day 3 post-incubation in borosilicate glass vials. Although the lysine-containing heptapeptide concentration was unchanged in both polypropylene and borosilicate glass vials, the apparent extent of lysine-containing heptapeptide depletion by ethyl acrylate, differed between polypropylene (24.7%) and glass (47.3%) vials. Additionally, the peptide-chemical complexes for Cor1-C420-cinnamaldehyde and cysteine-containing heptapeptide-2, 4-dinitrochlorobenzene were partially reversible during 3-days of autosampler storage. These observations further highlight

  9. Higher locomotor response to cocaine in female (vs. male) rats selectively bred for high (HiS) and low (LoS) saccharin intake

    PubMed Central

    Carroll, Marilyn E.; Anderson, Marissa M.; Morgan, Andrew D.

    2013-01-01

    Rats selectively bred for high saccharin consumption (HiS) self-administer more oral ethanol and i.v. cocaine than those selectively bred for low saccharin consumption (LoS). Male and female drug-seeking-prone (HiS) and –resistant (LoS) rats were used in the present experiment to test the prediction that cocaine-induced locomotor activity and sensitization varied with sex and their selective breeding status (HiS and LoS). All rats were intermittently exposed over 2 weeks to pairs of sequential saline and cocaine injections, separated by 45 min. The first 5 pairs of injections, each separated by 2-3 days (10-12 days total), were given to examine the development of cocaine-induced locomotor activity and the development of locomotor sensitization, which was determined by comparing the effects of cocaine injection 1 with injection 6, which was given 2 weeks after the 5 pairs of intermittent injections. Results indicated that after the first injection pair (saline, cocaine) the HiS and LoS groups did not differ (saline vs. cocaine) in locomotor activity; however, after cocaine injections 1, 5 and 6, HiS females were more active than HiS males and LoS females. There were also significant phenotype differences (HiS > LoS) in locomotor activity after cocaine injections 5 and 6. There was only a weak sensitization effect in cocaine-induced locomotor activity in HiS females after cocaine injection 5 (compared to 1); however it was not present after injection 6 or in other groups. The lack of a strong sensitization effect under these temporal and dose conditions was inconsistent with previous reports. However, the results showing HiS > LoS and females > males on cocaine-induced activity measures are consistent with several measures of cocaine-seeking behavior (acquisition, maintenance, escalation, extinction, and reinstatement), and they suggest that cocaine-induced locomotor activity and sensitization are behavioral markers of drug-seeking phenotypes. PMID:17707494

  10. Low-dose effect of ethanol on locomotor activity induced by activation of the mesolimbic system.

    PubMed

    Milton, G V; Randall, P K; Erickson, C K

    1995-06-01

    Four experiments were designed to study the ability of 0.5 g/kg ethanol (EtOH) intraperitoneally to modify locomotor activity induced by drugs that interact with different sites in the mesolimbic system (MLS) of male Sprague-Dawley rats. Locomotor activity was measured in a doughnut-shaped circular arena after various treatments. EtOH alone did not alter locomotor activity in any of the experiments. Amphetamine (AMP, intraperitoneally or intraaccumbens) increased locomotor activity in a dose-dependent manner, and the presence of EtOH attenuated AMP-induced locomotor activity. Bilateral infusion of GABAA antagonist picrotoxin (PIC) into the ventral tegmental area also increased locomotor activity in a dose-dependent manner, and the presence of EtOH attenuated PIC-induced locomotor activity. On the other hand, the interaction between bilateral infusion of mu-receptor agonist Tyr-D-Ala-Gly-NMe-Phe-Gly-ol (DAGO) and EtOH on locomotor activity is complex. The highest dose of DAGO that significantly increased locomotor activity was not affected by the presence of EtOH. But, with lower doses of DAGO that either had no effect or a small increase in locomotor activity, the combination of EtOH and DAGO increased and attenuated locomotor activity, respectively. Results from this study support our hypothesis that a low dose of EtOH that does not modify behavior can interact with neurotransmitter systems in the brain and modify drug-induced locomotor activity. Modification of this drug-induced locomotor activity by a low dose of EtOH is dependent on the rate of ongoing locomotor behavior induced by drug and the neurotransmitter substrate that the drug modified to induce locomotor behavior.(ABSTRACT TRUNCATED AT 250 WORDS)

  11. Prostaglandin E2 potentiates a TTX-resistant sodium current in rat capsaicin-sensitive vagal pulmonary sensory neurones.

    PubMed

    Kwong, Kevin; Lee, Lu-Yuan

    2005-04-15

    Capsaicin-sensitive vagal pulmonary neurones (pulmonary C neurones) play an important role in regulating airway function. During airway inflammation, the level of prostaglandin E(2) (PGE(2)) increases in the lungs and airways. PGE(2) has been shown to sensitize isolated pulmonary C neurones. The somatosensory correlate of the pulmonary C neurone, the small-diameter nociceptive neurone of the dorsal root ganglion, contains a high percentage of tetrodotoxin-resistant sodium currents (TTX-R I(Na)). Therefore, this study was carried out to determine whether these channel currents are involved in the PGE(2)-induced sensitization of pulmonary C neurones. We used the perforated patch-clamp technique to study the effects of PGE(2) on the TTX-R I(Na) in acutely cultured capsaicin-sensitive pulmonary neurones that were identified by retrograde labelling with a fluorescent tracer, DiI. We found that the pulmonary neurones sensitive to capsaicin had a higher percentage of TTX-R I(Na) than that of capsaicin-insensitive pulmonary neurones. PGE(2) exposure increased the evoked TTX-R I(Na) when experiments were performed at both room temperature and at 37 degrees C. Furthermore, stimulation of the adenylyl cyclase/protein kinase A pathway with either forskolin or Sp-5,6-DCl-cBiMPS potentiated the TTX-R I(Na) in a manner similar to that of PGE(2). We conclude that these modulatory effects of PGE(2) on TTX-R I(Na) play an important role in the sensitization of pulmonary C neurones.

  12. Conducting Polymer-Based Nanohybrid Transducers: A Potential Route to High Sensitivity and Selectivity Sensors

    PubMed Central

    Park, Seon Joo; Kwon, Oh Seok; Lee, Ji Eun; Jang, Jyongsik; Yoon, Hyeonseok

    2014-01-01

    The development of novel sensing materials provides good opportunities to realize previously unachievable sensor performance. In this review, conducting polymer-based nanohybrids are highlighted as innovative transducers for high-performance chemical and biological sensing devices. Synthetic strategies of the nanohybrids are categorized into four groups: (1) impregnation, followed by reduction; (2) concurrent redox reactions; (3) electrochemical deposition; (4) seeding approach. Nanocale hybridization of conducting polymers with inorganic components can lead to improved sorption, catalytic reaction and/or transport behavior of the material systems. The nanohybrids have thus been used to detect nerve agents, toxic gases, volatile organic compounds, glucose, dopamine, and DNA. Given further advances in nanohybrids synthesis, it is expected that sensor technology will also evolve, especially in terms of sensitivity and selectivity. PMID:24561406

  13. Co-sensitized natural dyes potentially used to enhance light harvesting capability

    NASA Astrophysics Data System (ADS)

    Amelia, R.; Sawitri, D.; Risanti, D. D.

    2015-01-01

    We present the photoelectrochemical properties of dye-sensitized solar cells using natural pigments containing anthocyanins, betalains, and caroteins. The dyes were adsorbed by a photoanode that was fabricated from nanocrystalline TiO2 on transparent conductive glass. TiO2 comprises of 100% anatase and 90:10 anatase:rutile fraction. The dyes extracted from mangosteen pericarp, Musa aromatica pericarp, Celosia cristata flower and red beet root were characterized through UV-vis and IPCE. The effectiveness of the dyes was explained through photocurrent as a function of incident light power. It was found that the cocktail and multilayered dyes comprised of anthocyanins and caroteins is beneficial to obtain high photocurrent, whereas betalains is not recommended to be applied on untreated TiO2. Due to the bandgap properties of rutile and anatase, the presence of 10% rutile in TiO2 is favourable to further enhance the electron transport.

  14. 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

  15. Posttetanic potentiation critically depends on an enhanced Ca2+ sensitivity of vesicle fusion mediated by presynaptic PKC

    PubMed Central

    Korogod, Natalya; Lou, Xuelin; Schneggenburger, Ralf

    2007-01-01

    Activity-dependent enhancement of transmitter release is a common form of presynaptic plasticity, but the underlying signaling mechanisms have remained largely unknown, perhaps because of the inaccessibility of most CNS nerve terminals. Here we investigated the signaling steps that underlie posttetanic potentiation (PTP), a form of presynaptic plasticity found at many CNS synapses. Direct whole-cell recordings from the large calyx of Held nerve terminals with the perforated patch-clamp technique showed that PTP was not mediated by changes in the presynaptic action potential waveform. Ca2+ imaging revealed a slight increase of the presynaptic Ca2+ transient during PTP (≈15%), which, however, was too small to explain a large part of PTP. The presynaptic PKC pathway was critically involved in PTP because (i) PTP was occluded by activation of PKC with phorbol esters, and (ii) PTP was largely (by approximately two-thirds) blocked by the PKC inhibitors, Ro31-8220 or bisindolylmaleimide. Activation of PKC during PTP most likely acts directly on the presynaptic release machinery, because in presynaptic Ca2+ uncaging experiments, activation of PKC by phorbol ester greatly increased the Ca2+ sensitivity of vesicle fusion in a Ro31-8220-sensitive manner (≈300% with small Ca2+ uncaging stimuli), but only slightly increased presynaptic voltage-gated Ca2+ currents (≈15%). We conclude that a PKC-dependent increase in the Ca2+ sensitivity of vesicle fusion is a key step in the enhancement of transmitter release during PTP. PMID:17884983

  16. The influence of chloride on the ouabain-sensitive membrane potential and conductance of crayfish giant axons.

    PubMed

    Lieberman, E M; Nosek, T M

    1976-11-05

    1. Resting potential and current-voltage relation were measured in crayfish giant axons bathed in chloride-free and sodium-free solutions with and without ouabain. 2. Chloride-free solution caused a transient depolarization but did not alter the steady-state membrane potential. Utilizing isethionate as an anion substitute, the membrane resistance increased 12.5%. 3. In the absence of extracellular chloride, ouabain (0.5-1 mM) depolarized the axon 6-7 mV. The shape of the current-voltage relation did not change but the curve was shifted along the current axis. 4. These results indicate that ouabain inhibits a steady-state hyperpolarizing electrogenic pump current of approximately 3 muA/cm2. 5. Extracellular sodium removal from axons equilibrated in chloride-free solutions transiently hyperpolarized the membrane 6-7 mV without a change in membrane resistance. The transient hyperpolarization was ouabain and temperature sensitive. The steady-state potential reached in sodium-free and chloride-free solution was not ouabain sensitive. Temperature sensitivity of the steady-state membrane potential was greatly reduced. 6. The transient hyperpolarization produced by extracellular sodium removal was metabolically driven and may present the expression of a sodium efflux transport current of 7.0-7.5 muA/cm2. 7. Using electrophysiologically measured parameters, sodium and potassium conductance, influx and efflux currents and the coupling ratio for sodium/potassium transport are calculated from a modification of the conductance equation. 8. The sodium/potassium transport coupling ratio for steady-state conditions was estimated at 5:3 (1.67:1).

  17. 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

  18. Diffusion Tensor Imaging as a Predictor of Locomotor Function after Experimental Spinal Cord Injury and Recovery

    PubMed Central

    Kelley, Brian J.; Harel, Noam Y.; Kim, Chang-Yeon; Papademetris, Xenophon; Coman, Daniel; Wang, Xingxing; Hasan, Omar; Kaufman, Adam; Globinsky, Ronen; Staib, Lawrence H.; Cafferty, William B.J.; Hyder, Fahmeed

    2014-01-01

    Abstract Traumatic spinal cord injury (SCI) causes long-term disability with limited functional recovery linked to the extent of axonal connectivity. Quantitative diffusion tensor imaging (DTI) of axonal integrity has been suggested as a potential biomarker for prognostic and therapeutic evaluation after trauma, but its correlation with functional outcomes has not been clearly defined. To examine this application, female Sprague-Dawley rats underwent midthoracic laminectomy followed by traumatic spinal cord contusion of differing severities or laminectomy without contusion. Locomotor scores and hindlimb kinematic data were collected for 4 weeks post-injury. Ex vivo DTI was then performed to assess axonal integrity using tractography and fractional anisotropy (FA), a numerical measure of relative white matter integrity, at the injury epicenter and at specific intervals rostral and caudal to the injury site. Immunohistochemistry for tissue sparing was also performed. Statistical correlation between imaging data and functional performance was assessed as the primary outcome. All injured animals showed some recovery of locomotor function, while hindlimb kinematics revealed graded deficits consistent with injury severity. Standard T2 magnetic resonance sequences illustrated conventional spinal cord morphology adjacent to contusions while corresponding FA maps indicated graded white matter pathology within these adjacent regions. Positive correlations between locomotor (Basso, Beattie, and Bresnahan score and gait kinematics) and imaging (FA values) parameters were also observed within these adjacent regions, most strongly within caudal segments beyond the lesion. Evaluation of axonal injury by DTI provides a mechanism for functional recovery assessment in a rodent SCI model. These findings suggest that focused DTI analysis of caudal spinal cord should be studied in human cases in relationship to motor outcome to augment outcome biomarkers for clinical cases. PMID

  19. Sensitivity of the late positive potentials evoked by emotional pictures to neuroticism during the menstrual cycle.

    PubMed

    Zhang, Wenjuan; Zhou, Renlai; Wang, Qingguo; Zhao, Yan; Liu, Yanfeng

    2013-10-11

    The present event-related potentials (ERPs) study set out to investigate the effect of neuroticism on emotion evaluation during the menstrual cycle, with high and low neuroticism females viewing and evaluating valence and arousal of emotional pictures in the menstruation, late follicular and luteal phases. Behavioral results revealed no group or phase effect. ERPs data showed modulations of the menstrual cycle and neuroticism on the late positive potential (LPP), with the larger LPP (300-1000 ms post-stimulus) during the late follicular phase than that during the luteal phase and larger LPP (1000-3000 ms post-stimulus) in the high neuroticism group than that in the low neuroticism group. Furthermore, significant positive correlations between the LPP amplitudes and valence and arousal evaluations were observed mainly in the high neuroticism group. The present study provides electrophysiological evidences that the LPP evoked by emotional pictures are modulated both by the menstrual cycle and neuroticism.

  20. Functionalized fullerene (C₆₀) as a potential nanomediator in the fabrication of highly sensitive biosensors.

    PubMed

    Afreen, Sadia; Muthoosamy, Kasturi; Manickam, Sivakumar; Hashim, Uda

    2015-01-15

    Designing a biosensor for versatile biomedical applications is a sophisticated task and how dedicatedly functionalized fullerene (C60) can perform on this stage is a challenge for today and tomorrow's nanoscience and nanotechnology. Since the invention of biosensor, many ideas and methods have been invested to upgrade the functionality of biosensors. Due to special physicochemical characteristics, the novel carbon material "fullerene" adds a new dimension to the construction of highly sensitive biosensors. The prominent aspects of fullerene explain its outstanding performance in biosensing devices as a mediator, e.g. fullerene in organic solvents exhibits five stages of reversible oxidation/reduction, and hence fullerene can work either as an electrophile or nucleophile. Fullerene is stable and its spherical structure produces an angle strain which allows it to undergo characteristic reactions of addition to double bonds (hybridization which turns from sp(2) to sp(3)). Research activities are being conducted worldwide to invent a variety of methods of fullerene functionalization with a purpose of incorporating it effectively in biosensor devices. The different types of functionalization methods include modification of fullerene into water soluble derivatives and conjugation with enzymes and/or other biomolecules, e.g. urease, glucose oxidase, hemoglobin, myoglobin (Mb), conjugation with metals e.g. gold (Au), chitosan (CS), ferrocene (Fc), etc. to enhance the sensitivity of biosensors. The state-of-the-art research on fullerene functionalization and its application in sensor devices has proven that fullerene can be implemented successfully in preparing biosensors to detect glucose level in blood serum, urea level in urine solution, hemoglobin, immunoglobulin, glutathione in real sample for pathological purpose, to identify doping abuse, to analyze pharmaceutical preparation and even to detect cancer and tumor cells at an earlier stage. Employing fullerene

  1. Distinct sets of locomotor modules control the speed and modes of human locomotion

    PubMed Central

    Yokoyama, Hikaru; Ogawa, Tetsuya; Kawashima, Noritaka; Shinya, Masahiro; Nakazawa, Kimitaka

    2016-01-01

    Although recent vertebrate studies have revealed that different spinal networks are recruited in locomotor mode- and speed-dependent manners, it is unknown whether humans share similar neural mechanisms. Here, we tested whether speed- and mode-dependence in the recruitment of human locomotor networks exists or not by statistically extracting locomotor networks. From electromyographic activity during walking and running over a wide speed range, locomotor modules generating basic patterns of muscle activities were extracted using non-negative matrix factorization. The results showed that the number of modules changed depending on the modes and speeds. Different combinations of modules were extracted during walking and running, and at different speeds even during the same locomotor mode. These results strongly suggest that, in humans, different spinal locomotor networks are recruited while walking and running, and even in the same locomotor mode different networks are probably recruited at different speeds. PMID:27805015

  2. Capsaicin-sensitive C- and A-fibre nociceptors control long-term potentiation-like pain amplification in humans.

    PubMed

    Henrich, Florian; Magerl, Walter; Klein, Thomas; Greffrath, Wolfgang; Treede, Rolf-Detlef

    2015-09-01

    Long-term potentiation in the spinal dorsal horn requires peptidergic C-fibre activation in animals. Perceptual correlates of long-term potentiation following high-frequency electrical stimulation in humans include increased sensitivity to electrical stimuli at the high frequency stimulation site (homotopic pain-long-term potentiation) and increased sensitivity to pinprick surrounding the high frequency stimulation site (heterotopic pain-long-term potentiation, equivalent to secondary hyperalgaesia). To characterize the peripheral fibre populations involved in induction of pain-long-term potentiation, we performed two selective nerve block experiments in 30 healthy male volunteers. Functional blockade of TRPV1-positive nociceptors by high-concentration capsaicin (verified by loss of heat pain) significantly reduced pain ratings to high frequency stimulation by 47% (P < 0.001), homotopic pain-long-term potentiation by 71% (P < 0.01), heterotopic pain-long-term potentiation by 92% (P < 0.001) and the area of secondary hyperalgesia by 76% (P < 0.001). The selective blockade of A-fibre conduction by nerve compression (verified by loss of first pain to pinprick) significantly reduced pain ratings to high frequency stimulation by 37% (P < 0.01), but not homotopic pain-long-term potentiation (-5%). It had a marginal effect on heterotopic pain-long-term potentiation (-35%, P = 0.059), while the area of secondary hyperalgesia remained unchanged (-2%, P = 0.88). In conclusion, all nociceptor subclasses contribute to high frequency stimulation-induced pain (with a relative contribution of C > Aδ fibres, and an equal contribution of TRPV1-positive and TRPV1-negative fibres). TRPV1-positive C-fibres are the main inducers of both homotopic and heterotopic pain-long-term potentiation. TRPV1-positive A-fibres contribute substantially to the induction of heterotopic pain-long-term potentiation. TRPV1-negative C-fibres induce a component of homotopic self-facilitation but not

  3. Ethanol induces locomotor activating effects in preweanling Sprague-Dawley rats

    PubMed Central

    Arias, Carlos; Mlewski, Cecilia E.; Molina, Juan Carlos; Spear, Norman E.

    2009-01-01

    Drugs of abuse exert biphasic motor activity effects, which seem to be associated with their motivational effects. In the case of ethanol, heterogenous rat strains appear to be particularly sensitive to the sedative effects of the drug. In contrast, ethanol’s activating effects have been consistently reported in rats genetically selected for ethanol affinity. Heightened ethanol affinity and sensitivity to ethanol’s reinforcement are also observed in non-selected rats during early ontogeny. In the present study we examined psychomotor effects of ethanol (1.25 and 2.5 g/kg) in 8, 12 and 15-day-old pups. Motor activity in a novel environment was assessed 5–10 or 15–20 minutes following drug treatment. Rectal temperatures and latency to exhibit the righting reflex were recorded immediately after locomotor activity assessment. Ethanol exerted clear activating effects at 8 and 12 days of age (Experiments 1a and 1b) and to a lesser extent at 15 days. At this age ethanol enhanced locomotor activity in the first testing interval (Experiment 1b) and suppressed locomotion at 15–20 minutes (Experiment 1a). Ethanol-mediated motor impairment was more pronounced in the youngest group (PD 8) than in the older ones. Blood ethanol concentrations were equivalent in all age groups. The present study indicates that preweanling rats are sensitive to ethanol’s stimulating effects during the second postnatal week, and suggest that specific periods during early ontogeny of the rat can provide a valuable framework for the study of mechanisms underlying ethanol’s stimulation and reinforcement effects. PMID:19185206

  4. Synthesis of pH sensitive gold nanoparticles for potential application in radiosensitization.

    PubMed

    Das, Abhishek; Chadha, Ridhima; Maiti, Nandita; Kapoor, Sudhir

    2015-10-01

    Synthesis of gold nanoparticles (GNPs) for in-vivo applications involves reduction of chloroauric acid by a biologically important molecule which itself undergoes redox reaction during physiological processes in human body. But the GNPs often prepared by this method are not stable enough. In order to stabilize these particles, surfactants are used which may or may not be compatible for in-vivo applications. Is there any other way to stabilize these particles in solution? In this work, the answer to this question is explored and a detailed study of the mechanism of the formation of GNPs is done to understand the basis of stabilization of nanoparticles without using a stabilizer. Chloroauric acid is reduced by L-tryptophan (Trp) in buffered medium and the formation mechanism is studied both visually and by UV-vis spectroscopy. The pH dependent structure of Trp was found to play an important role not only in the formation of stable GNPs but also in the stabilization of redispersed nanoparticles. pH sensitive property of the synthesized GNPs was utilized to make the GNPs accumulate at polar-non-polar liquid-liquid interface similar to hypoxic tumor tissue environment. Mechanistic study of the formation of GNPs by gas chromatography throws light on intermediate decarboxylation process. On the other hand, fluorescence study gives information about the interaction of Trp with GNPs.

  5. Sensitization potential of dental resins: 2-hydroxyethyl methacrylate and its water-soluble oligomers have immunostimulatory effects.

    PubMed

    Fukumoto, Izumi; Tamura, Atsushi; Matsumura, Mitsuaki; Miura, Hiroyuki; Yui, Nobuhiko

    2013-01-01

    The immunostimulatory effects of the representative dental resin monomer 2-hydroxyethyl methacrylate (HEMA), a HEMA derivative that does not contain a double bond (2-hydroxyethyl isobutyrate, HEIB), and polymerized water-soluble oligomers of HEMA (PHEMA) were investigated. It is known that expression levels of either or both of CD54 and CD86 in THP-1 cells are increased by exposure to sensitizing substances. In this study, the expression levels of CD54 and CD86, the production of reactive oxygen species (ROS), and the viability of the cells were measured after 24 h of incubation with these materials at different concentrations. The concentrations of the materials that induced the expression of both CD54 and CD86 were low in the following order: NiSO4, HEMA, and methyl methacrylate (MMA). These results indicate that these dental resin monomers have lower sensitizing potentials than NiSO4. Although HEIB, which lacks a double bond, resulted in negligible ROS production and reduced cytotoxicity than HEMA, it induced the expression of CD54 and CD86. Comparison of the results for HEMA and HEIB indicates that dental resin monomer-induced sensitization may be related not only to the oxidative stress related to the methacryloyl group but also to the structures of these compounds. Of particular interest is the result that a water-soluble PHEMA oligomer with a relatively high-molecular weight also exhibited negligible cytotoxicity, whereas the expression level of CD54 increased after exposure to PHEMA at a high concentration. This result serves as a warning that polymerized substances also have the potential to induce sensitization. This study provides insight into the nature of allergic responses to dental resin materials in clinical use and may facilitate the development of more biocompatible restorative materials in the future.

  6. Effects of repeated exposure to malathion on growth, food consumption, and locomotor performance of the western fence lizard (Sceloporus occidentalis).

    PubMed

    Holem, Ryan R; Hopkins, William A; Talent, Larry G

    2008-03-01

    Effects of repeated pollutant exposure on growth, locomotor performance, and behavior have rarely been evaluated in reptiles. We administered three doses of malathion (2.0, 20, or 100mg/kg body weight) to western fence lizards (Sceloporus occidentalis) over an 81day period. Eight and 23% mortality occurred at 20 and 100mg/kg (p=0.079) and 85% of lizards in the 100mg/kg group exhibited clinical symptoms of poisoning. Growth, food consumption, body condition index, and terrestrial locomotor performance were not significantly influenced by malathion. However, arboreal sprint velocity was significantly reduced in lizards receiving 100mg/kg. Fifty percent of lizards in the 100mg/kg group also refused to sprint in the arboreal setting (p=0.085). Based on these results, arboreal locomotor performance was the most sensitive metric of exposure we evaluated. Further study of compounds such as malathion is warranted due to highly variable application rates and exposure scenarios.

  7. Insulin Signaling in Bupivacaine-induced Cardiac Toxicity: Sensitization during Recovery and Potentiation by Lipid Emulsion

    PubMed Central

    Fettiplace, Michael R.; Kowal, Katarzyna; Ripper, Richard; Young, Alexandria; Lis, Kinga; Rubinstein, Israel; Bonini, Marcelo; Minshall, Richard; Weinberg, Guy

    2015-01-01

    Background The impact of local anesthetics on regulation of glucose homeostasis by protein kinase B (Akt) and 5’-Adenosine monophosphate activated protein kinase (AMPK) is unclear but important because of the implications for both local anesthetic toxicity and its reversal by intravenous lipid emulsion (ILE). Methods Sprague-Dawley rats received 10mg/kg bupivacaine over 20 seconds followed by nothing or 10mL/kg ILE (or ILE without bupivacaine). At key time points, heart and kidney were excised. Glycogen content and phosphorylation levels of Akt, p70s6k, s6, IRS1, GSK-3β, AMPK, ACC, TSC2 were quantified. Three animals received Wortmannin to irreversibily inhibit phosphoinositide-3-kinase (Pi3k) signaling. Isolated heart studies were conducted with bupivacaine and LY294002—a reversible Pi3K inhibitor. Results Bupivacaine cardiotoxicity rapidly de-phosphorylated Akt at S473 to 63 ± 5% of baseline and phosphorylated AMPK to 151 ± 19%. AMPK activation inhibited targets downstream of mTORC1 via TSC2. Feedback dephosphorylation of IRS1 to 31 ± 8% of baseline sensitized Akt signaling in hearts resulting in hyper-phosphorylation of Akt at T308 and GSK-3β to 390 ± 64% and 293 ± 50% of baseline respectively. Glycogen accumulated to 142 ± 7% of baseline. Irreversible inhibition of Pi3k upstream of Akt exacerbated bupivacaine cardiotoxicity, while pretreating with a reversible inhibitor delayed onset of toxicity. ILE rapidly phosphorylated Akt at S473 and T308 to 150 ± 23% and 167 ± 10% of baseline, respectively but did not interfere with AMPK or targets of mTORC1. Conclusion Glucose handling by Akt and AMPK is integral to recovery from bupivacaine cardiotoxicity and modulation of these pathways by ILE contributes to lipid resuscitation. PMID:26646023

  8. Aquifer heterogeneity characterization with oscillatory pumping: Sensitivity analysis and imaging potential

    NASA Astrophysics Data System (ADS)

    Cardiff, M.; Bakhos, T.; Kitanidis, P. K.; Barrash, W.

    2013-09-01

    Periodic pumping tests, in which a fluid is extracted during half a period, then reinjected, have been used historically to estimate effective aquifer properties. In this work, we suggest a modified approach to periodic pumping test analysis in which one uses several periodic pumping signals of different frequencies as stimulation, and responses are analyzed through inverse modeling using a "steady-periodic" model formulation. We refer to this strategy as multifrequency oscillatory hydraulic imaging. Oscillating pumping tests have several advantages that have been noted, including no net water extraction during testing and robust signal measurement through signal processing. Through numerical experiments, we demonstrate additional distinct advantages that multifrequency stimulations have, including: (1) drastically reduced computational cost through use of a steady-periodic numerical model and (2) full utilization of the aquifer heterogeneity information provided by responses at different frequencies. We first perform fully transient numerical modeling for heterogeneous aquifers and show that equivalent results are obtained using a faster steady-periodic heterogeneous numerical model of the wave phasor. The sensitivities of observed signal response to aquifer heterogeneities are derived using an adjoint state-based approach, which shows that different frequency stimulations provide complementary information. Finally, we present an example 2-D application in which sinusoidal signals at multiple frequencies are used as a data source and are inverted to obtain estimates of aquifer heterogeneity. These analyses show the different heterogeneity information that can be obtained from different stimulation frequencies, and that data from several sinusoidal pumping tests can be rapidly inverted using the steady-periodic framework.

  9. Potential targets by pentacyclic triterpenoids from Callicarpa farinosa against methicillin-resistant and sensitive Staphylococcus aureus.

    PubMed

    Chung, Pooi Yin; Chung, Lip Yong; Navaratnam, Parasakthi

    2014-04-01

    The evolution of antibiotic resistance in Staphylococcus aureus showed that there is no long-lasting remedy against this pathogen. The limited number of antibacterial classes and the common occurrence of cross-resistance within and between classes reinforce the urgent need to discover new compounds targeting novel cellular functions not yet targeted by currently used drugs. One of the experimental approaches used to discover novel antibacterials and their in vitro targets is natural product screening. Three known pentacyclic triterpenoids were isolated for the first time from the bark of Callicarpa farinosa Roxb. (Verbenaceae) and identified as α-amyrin [3β-hydroxy-urs-12-en-3-ol], betulinic acid [3β-hydroxy-20(29)-lupaene-28-oic acid], and betulinaldehyde [3β-hydroxy-20(29)-lupen-28-al]. These compounds exhibited antimicrobial activities against reference and clinical strains of methicillin-resistant (MRSA) and methicillin-sensitive S. aureus (MSSA), with minimum inhibitory concentration (MIC) ranging from 2 to 512 μg/mL. From the genome-wide transcriptomic analysis to elucidate the antimicrobial effects of these compounds, multiple novel cellular targets in cell division, two-component system, ABC transporters, fatty acid biosynthesis, peptidoglycan biosynthesis, aminoacyl-tRNA synthetases, ribosomes and β-lactam resistance pathways are affected, resulting in destabilization of the bacterial cell membrane, halt in protein synthesis, and inhibition of cell growth that eventually lead to cell death. The novel targets in these essential pathways could be further explored in the development of therapeutic compounds for the treatment of S. aureus infections and help mitigate resistance development due to target alterations.

  10. The peacock train does not handicap cursorial locomotor performance

    PubMed Central

    Thavarajah, Nathan K.; Tickle, Peter G.; Nudds, Robert L.; Codd, Jonathan R.

    2016-01-01

    Exaggerated traits, like the peacock train, are recognized as classic examples of sexual selection. The evolution of sexual traits is often considered paradoxical as, although they enhance reproductive success, they are widely presumed to hinder movement and survival. Many exaggerated traits represent an additional mechanical load that must be carried by the animal and therefore may influence the metabolic cost of locomotion and constrain locomotor performance. Here we conducted respirometry experiments on peacocks and demonstrate that the exaggerated sexually selected train does not compromise locomotor performance in terms of the metabolic cost of locomotion and its kinematics. Indeed, peacocks with trains had a lower absolute and mass specific metabolic cost of locomotion. Our findings suggest that adaptations that mitigate any costs associated with exaggerated morphology are central in the evolution of sexually selected traits. PMID:27805067

  11. Adenosine deaminase complexing protein (ADCP): a transformation sensitive protein with potentials of a cancer marker.

    PubMed

    Herbschleb-Voogt, E; Ten Kate, J; Meera Khan, P

    1983-01-01

    Several observations by independent investigators in the past have indicated that adenosine deaminase complexing protein (ADCP), present in considerable quantities in certain human tissues, was absent or decreased in the cancers originated from them. During the present study, electrophoretic analysis of adenosine deaminase (ADA) isozymes and radioimmunoassay for ADCP in the primary fibroblasts and the transformed as well as certain tumor derived cell lines have demonstrated that ADCP present in large quantities in the primary cells was absent or nearly absent in the transformed or tumor-derived cell lines. Though the mechanisms involved are not yet clear, the above observations indicate that ADCP has the potentials of a useful marker in the studies on transformed cells and cancer tissues.

  12. Organization of mammalian locomotor rhythm and pattern generation

    PubMed Central

    McCrea, David A.; Rybak, Ilya A.

    2008-01-01

    Central pattern generators (CPGs) located in the spinal cord produce the coordinated activation of flexor and extensor motoneurons during locomotion. Previously proposed architectures for the spinal locomotor CPG have included the classical half-center oscillator and the unit burst generator (UBG) comprised of multiple coupled oscillators. We have recently proposed another organization in which a two-level CPG has a common rhythm generator (RG) that controls the operation of the pattern formation (PF) circuitry responsible for motoneuron activation. These architectures are discussed in relation to recent data obtained during fictive locomotion in the decerebrate cat. The data show that the CPG can maintain the period and phase of locomotor oscillations both during spontaneous deletions of motoneuron activity and during sensory stimulation affecting motoneuron activity throughout the limb. The proposed two-level CPG organization has been investigated with a computational model which incorporates interactions between the CPG, spinal circuits and afferent inputs. The model includes interacting populations of spinal interneurons and motoneurons modeled in the Hodgkin-Huxley style. Our simulations demonstrate that a relatively simple CPG with separate RG and PF networks can realistically reproduce many experimental phenomena including spontaneous deletions of motoneuron activity and a variety of effects of afferent stimulation. The model suggests plausible explanations for a number of features of real CPG operation that would be difficult to explain in the framework of the classical single-level CPG organization. Some modeling predictions and directions for further studies of locomotor CPG organization are discussed. PMID:17936363

  13. 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.

  14. 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

  15. Fast calcium and voltage-sensitive dye imaging in enteric neurones reveal calcium peaks associated with single action potential discharge.

    PubMed

    Michel, K; Michaelis, M; Mazzuoli, G; Mueller, K; Vanden Berghe, P; Schemann, M

    2011-12-15

    Slow changes in [Ca(2+)](i) reflect increased neuronal activity. Our study demonstrates that single-trial fast [Ca(2+)](i) imaging (≥200 Hz sampling rate) revealed peaks each of which are associated with single spike discharge recorded by consecutive voltage-sensitive dye (VSD) imaging in enteric neurones and nerve fibres. Fast [Ca(2+)](i) imaging also revealed subthreshold fast excitatory postsynaptic potentials. Nicotine-evoked [Ca(2+)](i) peaks were reduced by -conotoxin and blocked by ruthenium red or tetrodotoxin. Fast [Ca(2+)](i) imaging can be used to directly record single action potentials in enteric neurones. [Ca(2+)](i) peaks required opening of voltage-gated sodium and calcium channels as well as Ca(2+) release from intracellular stores.

  16. Irritant and Sensitizing Potential of Some Common Indian Cact' Succulents, Lichens and Aquatic Plants.

    PubMed

    Bhalme, Abhay Y; Pasricha, J S

    1986-01-01

    Irritant potential of 3 cacti, Opuntia dilenii, Rhispalis baccifera and Cereus Peruvians, and 4 succulents, Euphorbia royleana, Euphorbia antiquorum,Sansevieria zeyilanica and Agave sisalana was tested by rubbing their freshly exposed pulp 10 times on the forearm skin of 10 human voluntrees. Opuntia dilenii, Euphorbia antiquorum, Rhispalis baccifera and Agave sisalana produced transitory itching and burning or dermatitis in only one patient each, indicating that these plants are not highly irritant. Patch tests undertaken with the juice, pulp or other components of these plants as well as those of 5 lichens, Parmelia trichotera, Parmelia sulcata, Parmelia quercina, Parmelia furfuracea and Parmelia verrucifera, and 6 aquatic plants Nelumbo nucifera, Eichnornia crassipes, Trapa natans, Anabaena, Salvinia auriculata and Ceratophyllam demeusam in 10 cases each revealed positive reaction with Opuntia Dilenil, Rhispalis baccifera, Cereus Peruvians, Parmelia verrucifera, Nelumbo nucifera, Trapa natans, Salvinia auriculata and Ceratophyllum demeusum in one case each. Agava sisalana and Sensevieria zeylanica in 2 cases each. Euphorbia antiquorym, Parmelia trichotera ' Parmelia quercina, Parmelia furfuracea and Eichhornia crassipes in 3 cases each and Euphorbia royleana and Parmelia sulcata in 4 cases each.

  17. P-glycoprotein inhibitors of natural origin as potential tumor chemo-sensitizers: A review

    PubMed Central

    Abdallah, Hossam M.; Al-Abd, Ahmed M.; El-Dine, Riham Salah; El-Halawany, Ali M.

    2014-01-01

    Resistance of solid tumors to treatment is significantly attributed to pharmacokinetic reasons at both cellular and multi-cellular levels. Anticancer agent must be bio-available at the site of action in a cytotoxic concentration to exert its proposed activity. P-glycoprotein (P-gp) is a member of the ATP-dependent membrane transport proteins; it is known to pump substrates out of cells in ATP-dependent mechanism. The over-expression of P-gp in tumor cells reduces the intracellular drug concentrations, which decreases the cytotoxicity of a broad spectrum of antitumor drugs. Accordingly, P-gp inhibitors/blockers are potential enhancer for the cellular bioavailability of several clinically important anticancer drugs such as, anthracyclines, taxanes, vinca alkaloids, and podophyllotoxins. Besides several chemically synthesized P-gp inhibitors/blockers, some naturally occurring compounds and plant extracts were reported for their modulation of multidrug resistance; however, this review will focus only on major classes of naturally occurring inhibitors viz., flavonoids, coumarins, terpenoids, alkaloids and saponins. PMID:25685543

  18. Temperature-sensitive transient receptor potential channels in corneal tissue layers and cells.

    PubMed

    Mergler, Stefan; Valtink, Monika; Takayoshi, Sumioka; Okada, Yuka; Miyajima, Masayasu; Saika, Shizuya; Reinach, Peter S

    2014-01-01

    We here provide a brief summary of the characteristics of transient receptor potential channels (TRPs) identified in corneal tissue layers and cells. In general, TRPs are nonselective cation channels which are Ca(2+) permeable. Most TRPs serve as thermosensitive molecular sensors (thermo-TRPs). Based on their functional importance, the possibilities are described for drug-targeting TRP activity in a clinical setting. TRPs are expressed in various tissues of the eye including both human corneal epithelial and endothelial layers as well as stromal fibroblasts and stromal nerve fibers. TRP vanilloid type 1 (TRPV1) heat receptor, also known as capsaicin receptor, along with TRP melastatin type 8 (TRPM8) cold receptor, which is also known as menthol receptor, are prototypes of the thermo-TRP family. The TRPV1 functional channel is the most investigated TRP channel in these tissues, owing to its contribution to maintaining tissue homeostasis as well as eliciting wound healing responses to injury. Other thermo-TRP family members identified in these tissues are TRPV2, 3 and 4. Finally, there is the TRP ankyrin type 1 (TRPA1) cold receptor. All of these thermo-TRPs can be activated within specific temperature ranges and transduce such inputs into chemical and electrical signals. Although several recent studies have begun to unravel complex roles for thermo-TRPs such as TRPV1 in corneal layers and resident cells, additional studies are needed to further elucidate their roles in health and disease.

  19. Increasing sensitivity to DNA damage is a potential driver for human ovarian cancer

    PubMed Central

    Jin, Yimei; Xu, Xin; Wang, Xuemeng; Kuang, Henry; Osterman, Michael; Feng, Shi; Han, Deqiang; Wu, Yu; Li, Mo; Guo, Hongyan

    2016-01-01

    Ovarian cancer is one of the most common cancers among women, accounting for more deaths than any other gynecological diseases. However, the survival rate for ovarian cancer has not essentially improved over the past thirty years. Thus, to understand the molecular mechanism of ovarian tumorigenesis is important for optimizing the early diagnosis and treating this disease. In this study, we observed obvious DNA lesions, especially DNA double strand breaks (DSBs) accompanying cell cycle checkpoint activation, in the human epithelial ovarian cancer samples, which could be due to the impaired DNA response machinery. Following this line, we found that these DNA damage response-deficient primary cancer cells were hypersensitive to DNA damage and lost their ability to repair the DNA breaks, leading to genomic instability. Of note, three key DNA damage response factors, RNF8, Ku70, and FEN1 exhibited dramatically decreased expression level, implying the dysfunctional DNA repair pathways. Re-expression of wild type RNF8, Ku70, or FEN1 in these cells restored the DNA lesions and also partially rescued the cells from death. Our current study therefore proposes that accumulated DNA lesions might be a potential driver of ovarian cancer and the impaired DNA damage responders could be the targets for clinical treatment. PMID:27391345

  20. Circadian locomotor rhythms in the cricket, Gryllodes sigillatus. II. Interactions between bilaterally paired circadian pacemakers.

    PubMed

    Ushirogawa, H; Abe, Y; Tomioka, K

    1997-10-01

    The optic lobe is essential for circadian locomotor rhythms in the cricket, Gryllodes sigillatus. We examined potential interactions between the bilaterally paired optic lobes in circadian rhythm generation. When one optic lobe was removed, the free-running period of the locomotor rhythm slightly but significantly lengthened. When exposed to light-dark cycles (LD) with 26 hr period, intact and sham operated animals were clearly entrained to the light cycle, but a large number of animals receiving unilateral optic nerve severance showed rhythm dissociation. In the dissociation, two rhythmic components appeared; one was readily entrained to the given LD and the other free-ran with a period shorter than 24 hr, and activity was expressed only when they were inphase. The period of the free-running component was significantly longer than that of the animals with a single blinded pacemaker kept in LD13:13, suggesting that the pacemaker on the intact side had some influence on the blinded pacemaker even in the dissociated state. The ratio of animals with rhythm dissociation was greater with the lower light intensity of the LD. The results suggest that the bilaterally distributed pacemakers are only weakly coupled to one another but strongly suppress the activity driven by the partner pacemaker during their subjective day. The strong suppression of activity would be advantageous to keep a stable nocturnality for this cricket living indoors.

  1. Activation of the GABA(B) Receptor Prevents Nicotine-Induced Locomotor Stimulation in Mice.

    PubMed

    Lobina, Carla; Carai, Mauro A M; Froestl, Wolfgang; Mugnaini, Claudia; Pasquini, Serena; Corelli, Federico; Gessa, Gian Luigi; Colombo, Giancarlo

    2011-01-01

    Recent studies demonstrated that activation of the GABA(B) receptor, either by means of orthosteric agonists or positive allosteric modulators (PAMs), inhibited different nicotine-related behaviors, including intravenous self-administration and conditioned place preference, in rodents. The present study investigated whether the anti-nicotine effects of the GABA(B) receptor agonist, baclofen, and GABA(B) PAMs, CGP7930, and GS39783, extend to nicotine stimulant effects. To this end, CD1 mice were initially treated with baclofen (0, 1.25, and 2.5 mg/kg, i.p.), CGP7930 (0, 25, and 50 mg/kg, i.g.), or GS39783 (0, 25, and 50 mg/kg, i.g.), then treated with nicotine (0 and 0.05 mg/kg, s.c.), and finally exposed to an automated apparatus for recording of locomotor activity. Pretreatment with doses of baclofen, CGP7930, or GS39783 that did not alter locomotor activity when given with nicotine vehicle fully prevented hyperlocomotion induced by 0.05 mg/kg nicotine. These data extend to nicotine stimulant effects the capacity of baclofen and GABA(B) PAMs to block the reinforcing, motivational, and rewarding properties of nicotine. These data strengthen the hypothesis that activation of the GABA(B) receptor may represent a potentially useful, anti-smoking therapeutic strategy.

  2. Sensitivity to the photoperiod and potential migratory features of neuroblasts in the adult sheep hypothalamus.

    PubMed

    Batailler, Martine; Derouet, Laura; Butruille, Lucile; Migaud, Martine

    2016-07-01

    Adult neurogenesis, a process that consists in the generation of new neurons from adult neural stem cells, represents a remarkable illustration of the brain structural plasticity abilities. The hypothalamus, a brain region that plays a key role in the neuroendocrine regulations including reproduction, metabolism or food intake, houses neural stem cells located within a hypothalamic neurogenic niche. In adult sheep, a seasonal mammalian species, previous recent studies have revealed photoperiod-dependent changes in the hypothalamic cell proliferation rate. In addition, doublecortin (DCX), a microtubule-associated protein expressed in immature migrating neurons, is highly present in the vicinity of the hypothalamic neurogenic niche. With the aim to further explore the mechanism underlying adult sheep hypothalamic neurogenesis, we first show that new neuron production is also seasonally regulated since the density of DCX-positive cells changes according to the photoperiodic conditions at various time points of the year. We then demonstrate that cyclin-dependant kinase-5 (Cdk5) and p35, two proteins involved in DCX phosphorylation and known to be critically involved in migration processes, are co-expressed with DCX in young hypothalamic neurons and are capable of in vivo interaction. Finally, to examine the migratory potential of these adult-born neurons, we reveal the rostro-caudal extent of DCX labeling on hypothalamic sagittal planes. DCX-positive cells are found in the most rostral nuclei of the hypothalamus, including the preoptic area many of which co-expressed estrogen receptor-α. Thus, beyond the confirmation of the high level of neuron production during short photoperiod in sheep, our results bring new and compelling elements in support of the existence of a hypothalamic migratory path that is responsive to seasonal stimuli.

  3. An event-related potential component sensitive to images of the human body.

    PubMed

    Thierry, Guillaume; Pegna, Alan J; Dodds, Chris; Roberts, Mark; Basan, Sébastien; Downing, Paul

    2006-08-15

    One of the critical functions of vision is to provide information about other individuals. Neuroimaging experiments examining the cortical regions that analyze the appearance of other people have found partially overlapping networks that respond selectively to human faces and bodies. In event-related potential (ERP) studies, faces systematically elicit a negative component peaking 170 ms after presentation - the N170. To characterize the electrophysiological response to human bodies, we compared the ERPs elicited by faces, bodies and various control stimuli. In Experiment 1, a comparison of ERPs elicited by faces, bodies, objects and places showed that pictures of the human body (without the head) elicit a negative component peaking at 190 ms (an N190). While broadly similar to the N170, the N190 differs in both spatial distribution and amplitude from the N1 components elicited by faces, objects and scenes and peaks significantly later than the N170. The difference between N190 and N170 was further supported using topographic analyses of ERPs and source localization techniques. A unique, stable map topography was found to characterize human bodies between 130 and 230 ms. In Experiment 2, we tested the four conditions from Experiment 1, as well as intact and scrambled silhouettes and stick figures of the human body. We found that intact silhouettes and stick figures elicited significantly greater N190 amplitudes than their scrambled counterparts. Thus, the N190 generalizes to some degree to schematic depictions of the human form. Overall, our findings are consistent with intertwined, but functionally distinct, neural representations of the human face and body.

  4. Increased nasal potential difference and amiloride sensitivity in neonates with cystic fibrosis.

    PubMed

    Gowen, C W; Lawson, E E; Gingras-Leatherman, J; Gatzy, J T; Boucher, R C; Knowles, M R

    1986-04-01

    Patients with cystic fibrosis (CF) have an increased nasal transepithelial potential difference (PD) which reflects increased sodium absorption across epithelium relatively impermeable to chloride. To evaluate nasal epithelial function in neonates with CF, the PD was recorded and the voltage response to superfusion of 10(-5M) amiloride, an inhibitor of sodium transport, measured between a Ringer perfused bridge on the nasal mucosa and a reference electrode in the subcutaneous space. We studied three neonates with CF with meconium ileus and compared the results with those in 24 term healthy neonates, including one obligate heterozygote for CF, and 27 control neonates with disease. All three CF neonates had raised sweat chloride values (mean 100 mEq/L) at 2 months. The CF neonates had higher PDs (-64.0 +/- 8.4 mV) than those in normal (-24.4 +/- 2.0 mV) or control (-25.8 +/- 2.0 mV) neonates. Superfusion with amiloride induced a 72% reduction in PD in the CF neonates as compared with healthy (37.5 +/- 1.0%) and diseased (36.0 +/- 1.3%) neonates. The PD and amiloride response in CF neonates are similar to those in CF infants (2.24 months), older CF children (greater than 6 years), and CF adults (-64.9 +/- 9.3 mV; 77.7 +/- 1.8%, n = 51). These results suggest that (1) nasal epithelial dysfunction is present in patients with CF shortly after birth, and (2) the nasal PD may be a diagnostic adjunct to the sweat test in the early diagnosis of CF.

  5. Properties of recombinant human N1-acetylpolyamine oxidase (hPAO): potential role in determining drug sensitivity.

    PubMed

    Wang, Yanlin; Hacker, Amy; Murray-Stewart, Tracy; Frydman, Benjamin; Valasinas, Aldonia; Fraser, Alison V; Woster, Patrick M; Casero, Robert A

    2005-07-01

    The recent cloning of the mammalian gene coding for N(1)-acetylpolyamine oxidase (PAO) provides the opportunity to directly examine the role of human PAO (hPAO) in polyamine homeostasis as well as its potential role in determining cellular response to antitumor polyamine analogues. To facilitate the study of this enzyme, the production, purification, and characterization of the recombinant hPAO is reported. hPAO oxidizes N(1)-acetylspermidine (K(m)=2.1 microM, K(cat)=15.0 s(-1)) and has very high affinity for N(1)-acetylspermine (K(m)=0.85 microM, K(cat)=31.7 s(-1)). The recombinant hPAO does not efficiently oxidize spermine, thereby demonstrating a significant difference in substrate specificity from the previously described human spermine oxidase PAOh1/SMO. Importantly, hPAO demonstrates the ability to oxidize a subset of antitumor polyamine analogues, suggesting that this oxidase activity could have a significant effect on determining tumor sensitivity to these or similar agents. Transfection of A549 human lung cancer cells with an hPAO-expressing plasmid leads to a profound decrease in sensitivity to those analogues which act as substrates, confirming its potential to alter drug response. One similarity that hPAO shares with human PAOh1/SMO, is that certain oligoamine analogues are potent inhibitors of its oxidase activity. The results of these studies demonstrate how changes in polyamine catabolism may affect drug response.

  6. Sensory-evoked perturbations of locomotor activity by sparse sensory input: a computational study

    PubMed Central

    Brownstone, Robert M.

    2015-01-01

    Sensory inputs from muscle, cutaneous, and joint afferents project to the spinal cord, where they are able to affect ongoing locomotor activity. Activation of sensory input can initiate or prolong bouts of locomotor activity depending on the identity of the sensory afferent activated and the timing of the activation within the locomotor cycle. However, the mechanisms by which afferent activity modifies locomotor rhythm and the distribution of sensory afferents to the spinal locomotor networks have not been determined. Considering the many sources of sensory inputs to the spinal cord, determining this distribution would provide insights into how sensory inputs are integrated to adjust ongoing locomotor activity. We asked whether a sparsely distributed set of sensory inputs could modify ongoing locomotor activity. To address this question, several computational models of locomotor central pattern generators (CPGs) that were mechanistically diverse and generated locomotor-like rhythmic activity were developed. We show that sensory inputs restricted to a small subset of the network neurons can perturb locomotor activity in the same manner as seen experimentally. Furthermore, we show that an architecture with sparse sensory input improves the capacity to gate sensory information by selectively modulating sensory channels. These data demonstrate that sensory input to rhythm-generating networks need not be extensively distributed. PMID:25673740

  7. Comparative Sensitivity of Intraoperative Motor Evoked Potential Monitoring in Predicting Postoperative Neurologic Deficits: Nondegenerative versus Degenerative Myelopathy

    PubMed Central

    Clark, Aaron J.; Safaee, Michael; Chou, Dean; Weinstein, Philip R.; Molinaro, Annette M.; Clark, John P.; Mummaneni, Praveen V.

    2015-01-01

    Study Design  Retrospective review. Objective  Intraoperative motor evoked potential (MEP) monitoring in spine surgery may assist surgeons in taking corrective measures to prevent neurologic deficits. The efficacy of monitoring MEPs intraoperatively in patients with myelopathy from nondegenerative causes has not been quantified. We compared the sensitivity and specificity of intraoperative MEP monitoring in patients with myelopathy caused by nondegenerative processes to patients with degenerative cervicothoracic spondylotic myelopathy (CSM). Methods  We retrospectively reviewed our myelopathy surgical cases during a 1-year period to identify patients with degenerative CSM and CSM of nondegenerative causes and collected data on intraoperative MEP changes and postoperative new deficits. Categorical variables were analyzed by Fisher exact test. Receiver operator curves assessed intraoperative MEP monitoring performance in the two groups. Results  In all, 144 patients were identified: 102 had degenerative CSM and 42 had CSM of nondegenerative causes (24 extra-axial tumors, 12 infectious processes, 5 traumatic fractures, and 1 rheumatoid arthritis). For degenerative CSM, there were 11 intraoperative MEP alerts and 7 new deficits (p < 0.001). The corresponding sensitivity was 71% and the specificity was 94%. In the nondegenerative group, there were 11 intraoperative MEP alerts and 3 deficits, which was not significant (p > 0.99). The sensitivity (33%) and specificity (74%) were lower. Among patients with degenerative CSM, the model performed well for predicting postoperative deficits (area under the curve [AUC] 0.826), which appeared better than the nondegenerative group, although it did not reach statistical significance (AUC 0.538, p = 0.16). Conclusions  Based on this large retrospective analysis, intraoperative MEP monitoring in surgery for nondegenerative CSM cases appears to be less sensitive to cord injury and less predictive of postoperative

  8. Assessment of the Potential Impacts of Wheat Plant Traits across Environments by Combining Crop Modeling and Global Sensitivity Analysis

    PubMed Central

    Casadebaig, Pierre; Zheng, Bangyou; Chapman, Scott; Huth, Neil; Faivre, Robert; Chenu, Karine

    2016-01-01

    A crop can be viewed as a complex system with outputs (e.g. yield) that are affected by inputs of genetic, physiology, pedo-climatic and management information. Application of numerical methods for model exploration assist in evaluating the major most influential inputs, providing the simulation model is a credible description of the biological system. A sensitivity analysis was used to assess the simulated impact on yield of a suite of traits involved in major processes of crop growth and development, and to evaluate how the simulated value of such traits varies across environments and in relation to other traits (which can be interpreted as a virtual change in genetic background). The study focused on wheat in Australia, with an emphasis on adaptation to low rainfall conditions. A large set of traits (90) was evaluated in a wide target population of environments (4 sites × 125 years), management practices (3 sowing dates × 3 nitrogen fertilization levels) and CO2 (2 levels). The Morris sensitivity analysis method was used to sample the parameter space and reduce computational requirements, while maintaining a realistic representation of the targeted trait × environment × management landscape (∼ 82 million individual simulations in total). The patterns of parameter × environment × management interactions were investigated for the most influential parameters, considering a potential genetic range of +/- 20% compared to a reference cultivar. Main (i.e. linear) and interaction (i.e. non-linear and interaction) sensitivity indices calculated for most of APSIM-Wheat parameters allowed the identification of 42 parameters substantially impacting yield in most target environments. Among these, a subset of parameters related to phenology, resource acquisition, resource use efficiency and biomass allocation were identified as potential candidates for crop (and model) improvement. PMID:26799483

  9. Assessment of the Potential Impacts of Wheat Plant Traits across Environments by Combining Crop Modeling and Global Sensitivity Analysis.

    PubMed

    Casadebaig, Pierre; Zheng, Bangyou; Chapman, Scott; Huth, Neil; Faivre, Robert; Chenu, Karine

    2016-01-01

    A crop can be viewed as a complex system with outputs (e.g. yield) that are affected by inputs of genetic, physiology, pedo-climatic and management information. Application of numerical methods for model exploration assist in evaluating the major most influential inputs, providing the simulation model is a credible description of the biological system. A sensitivity analysis was used to assess the simulated impact on yield of a suite of traits involved in major processes of crop growth and development, and to evaluate how the simulated value of such traits varies across environments and in relation to other traits (which can be interpreted as a virtual change in genetic background). The study focused on wheat in Australia, with an emphasis on adaptation to low rainfall conditions. A large set of traits (90) was evaluated in a wide target population of environments (4 sites × 125 years), management practices (3 sowing dates × 3 nitrogen fertilization levels) and CO2 (2 levels). The Morris sensitivity analysis method was used to sample the parameter space and reduce computational requirements, while maintaining a realistic representation of the targeted trait × environment × management landscape (∼ 82 million individual simulations in total). The patterns of parameter × environment × management interactions were investigated for the most influential parameters, considering a potential genetic range of +/- 20% compared to a reference cultivar. Main (i.e. linear) and interaction (i.e. non-linear and interaction) sensitivity indices calculated for most of APSIM-Wheat parameters allowed the identification of 42 parameters substantially impacting yield in most target environments. Among these, a subset of parameters related to phenology, resource acquisition, resource use efficiency and biomass allocation were identified as potential candidates for crop (and model) improvement.

  10. Mental practice for relearning locomotor skills.

    PubMed

    Malouin, Francine; Richards, Carol L

    2010-02-01

    Over the past 2 decades, much work has been carried out on the use of mental practice through motor imagery for optimizing the retraining of motor function in people with physical disabilities. Although much of the clinical work with mental practice has focused on the retraining of upper-extremity tasks, this article reviews the evidence supporting the potential of motor imagery for retraining gait and tasks involving coordinated lower-limb and body movements. First, motor imagery and mental practice are defined, and evidence from physiological and behavioral studies in healthy individuals supporting the capacity to imagine walking activities through motor imagery is examined. Then the effects of stroke, spinal cord injury, lower-limb amputation, and immobilization on motor imagery ability are discussed. Evidence of brain reorganization in healthy individuals following motor imagery training of dancing and of a foot movement sequence is reviewed, and the effects of mental practice on gait and other tasks involving coordinated lower-limb and body movements in people with stroke and in people with Parkinson disease are examined. Lastly, questions pertaining to clinical assessment of motor imagery ability and training strategies are discussed.

  11. Nicotine-induced place conditioning and locomotor activity in an adolescent animal model of attention deficit/hyperactivity disorder (ADHD).

    PubMed

    Watterson, Elizabeth; Daniels, Carter W; Watterson, Lucas R; Mazur, Gabriel J; Brackney, Ryan J; Olive, M Foster; Sanabria, Federico

    2015-09-15

    Attention deficit/hyperactivity disorder (ADHD) is a risk factor for tobacco use and dependence. This study examines the responsiveness to nicotine of an adolescent model of ADHD, the spontaneously hypertensive rat (SHR). The conditioned place preference (CPP) procedure was used to assess nicotine-induced locomotion and conditioned reward in SHR and the Wistar Kyoto (WKY) control strain over a range of nicotine doses (0.0, 0.1, 0.3 and 0.6 mg/kg). Prior to conditioning, SHRs were more active and less biased toward one side of the CPP chamber than WKY rats. Following conditioning, SHRs developed CPP to the highest dose of nicotine (0.6 mg/kg), whereas WKYs did not develop CPP to any nicotine dose tested. During conditioning, SHRs displayed greater locomotor activity in the nicotine-paired compartment than in the saline-paired compartment across conditioning trials. SHRs that received nicotine (0.1, 0.3, 0.6 mg/kg) in the nicotine-paired compartment showed an increase in locomotor activity between conditioning trials. Nicotine did not significantly affect WKY locomotor activity. These findings suggest that the SHR strain is a suitable model for studying ADHD-related nicotine use and dependence, but highlights potential limitations of the WKY control strain and the CPP procedure for modeling ADHD-related nicotine reward.

  12. Actions of incretin metabolites on locomotor activity, cognitive function and in vivo hippocampal synaptic plasticity in high fat fed mice.

    PubMed

    Porter, David; Faivre, Emilie; Flatt, Peter R; Hölscher, Christian; Gault, Victor A

    2012-05-01

    The incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) improve markers of cognitive function in obesity-diabetes, however, both are rapidly degraded to their major metabolites, GLP-1(9-36)amide and GIP(3-42), respectively. Therefore, the present study investigated effects of GLP-1(9-36)amide and GIP(3-42) on locomotor activity, cognitive function and hippocampal synaptic plasticity in mice with diet-induced obesity and insulin resistance. High-fat fed Swiss TO mice treated with GLP-1(9-36)amide, GIP(3-42) or exendin(9-39)amide (twice-daily for 60 days) did not exhibit any changes in bodyweight, non-fasting plasma glucose and plasma insulin concentrations or glucose tolerance compared with high-fat saline controls. Similarly, locomotor and feeding activity, O(2) consumption, CO(2) production, respiratory exchange ratio and energy expenditure were not altered by chronic treatment with incretin metabolites. Administration of the truncated metabolites did not alter general behavior in an open field test or learning and memory ability as recorded during an object recognition test. High-fat mice exhibited a significant impairment in hippocampal long-term potentiation (LTP) which was not affected by treatment with incretin metabolites. These data indicate that incretin metabolites do not influence locomotor activity, cognitive function and hippocampal synaptic plasticity when administered at pharmacological doses to mice fed a high-fat diet.

  13. Degradation of mouse locomotor pattern in the absence of proprioceptive sensory feedback.

    PubMed

    Akay, Turgay; Tourtellotte, Warren G; Arber, Silvia; Jessell, Thomas M

    2014-11-25

    Mammalian locomotor programs are thought to be directed by the actions of spinal interneuron circuits collectively referred to as "central pattern generators." The contribution of proprioceptive sensory feedback to the coordination of locomotor activity remains less clear. We have analyzed changes in mouse locomotor pattern under conditions in which proprioceptive feedback is attenuated genetically and biomechanically. We find that locomotor pattern degrades upon elimination of proprioceptive feedback from muscle spindles and Golgi tendon organs. The degradation of locomotor pattern is manifest as the loss of interjoint coordination and alternation of flexor and extensor muscles. Group Ia/II sensory feedback from muscle spindles has a predominant influence in patterning the activity of flexor muscles, whereas the redundant activities of group Ia/II and group Ib afferents appear to determine the pattern of extensor muscle firing. These findings establish a role for proprioceptive feedback in the control of fundamental aspects of mammalian locomotor behavior.

  14. TEA-sensitive currents contribute to membrane potential of organ surface primo-node cells in rats.

    PubMed

    Choi, Jae-Hong; Lim, Chae Jeong; Han, Tae Hee; Lee, Seul Ki; Lee, So Yeong; Ryu, Pan Dong

    2011-02-01

    The primo-vascular (Bonghan) tissue has been identified in most tissues in the body, but its structure and functions are not yet well understood. We characterized electrophysiological properties of the cells of the primo-nodes (PN) on the surface of abdominal organs using a slice patch clamp technique. The most abundant were small round cells (~10 μm) without processes. These PN cells exhibited low resting membrane potential (-36 mV) and did not fire action potentials. On the basis of the current-voltage (I-V) relationships and kinetics of outward currents, the PN cells can be grouped into four types. Among these, type I cells were the majority (69%); they showed strong outward rectification in I-V relations. The outward current was activated rapidly and sustained without decay. Tetraethylammonium (TEA) dose-dependently blocked both outward and inward current (IC(50), 4.3 mM at ± 60 mV). In current clamp conditions, TEA dose-dependently depolarized the membrane potential (18.5 mV at 30 mM) with increase in input resistance. The tail current following a depolarizing voltage step was reversed at -27 mV, and transient outward current like A-type K(+) current was not expressed at holding potential of -80 mV. Taken together, the results demonstrate for the first time that the small round PN cells are heterogenous, and that, in type I cells, TEA-sensitive current with limited selectivity to K(+) contributed to resting membrane potential of these cells.

  15. Assessment of Potential Yield andClimate Change Sensitivity of Peanut Crop in Cagayan Valley, Philippines using DSSAT Simulation Model

    NASA Astrophysics Data System (ADS)

    Balderama, O. F.

    2013-12-01

    Peanut is a major upland crop in Cagayan Valley and a leguminous crop that requires less water and therefore, considered an important crop in improving productivity of upland and rainfed areas. However, little information is available on the potential productivity of the crop and analysis on the production constraints including climate change sensitivity. This study was aimed to determine yield potential and production constraints of peanut crop in Cagayan Valley through the use of Decision Support System for Agrotechnology Transfer (DSSAT) simulation modeling; analyze yield gaps between simulated and actual yield levels and to provide decision support to further optimize peanut production under climate change condition. Site of experiment for model calibration and validation was located on-station at Isabela State University, Echague, Isabela. Rainfall and other climatic variables were monitored using a HOBO weather station (Automatic Weather Station) which is strategically installed inside experimental zone.The inputs required to run the CSM model include information on soil and weather conditions, crop management practices and cultivar specific genetic coefficients. In the first step,a model calibration was conducted to determine the cultivar coefficients for certain peanut cultivar that are normally grown in Cagayan Valley. Crop growth and yield simulation modeling was undertaken using the Decision Support System for Agro-Technology Transfer (DSSAT) for small seeded peanut (Pn9). An evaluation of the CSM-CROPGRO-peanut model was performed with data sets from peanut experiment conducted from December 2011 to April 2012. The model was evaluated in the estimation of potential yield of peanut under rainfed condition and low-nitrogen application. Yield potential for peanut limited only by temperature and solar radiation and no-water and nutrient stress, ranged from 3274 to 4805 kg per hectare for six planting dates (October 1, October 15, November 1, November 15

  16. Short-term Cortical Plasticity Associated With Feedback-Error Learning After Locomotor Training in a Patient With Incomplete Spinal Cord Injury

    PubMed Central

    Peters, Sue; Borich, Michael R.; Boyd, Lara A.; Lam, Tania

    2015-01-01

    Background and Purpose For rehabilitation strategies to be effective, training should be based on principles of motor learning, such as feedback-error learning, that facilitate adaptive processes in the nervous system by inducing errors and recalibration of sensory and motor systems. This case report suggests that locomotor resistance training can enhance somatosensory and corticospinal excitability and modulate resting-state brain functional connectivity in a patient with motor-incomplete spinal cord injury (SCI). Case Description The short-term cortical plasticity of a 31-year-old man who had sustained an incomplete SCI 9.5 years previously was explored in response to body-weight–supported treadmill training with velocity-dependent resistance applied with a robotic gait orthosis. The following neurophysiological and neuroimaging measures were recorded before and after training. Sensory evoked potentials were elicited by electrical stimulation of the tibial nerve and recorded from the somatosensory cortex. Motor evoked potentials were generated with transcranial magnetic stimulation applied over the tibialis anterior muscle representation in the primary motor cortex. Resting-state functional magnetic resonance imaging was performed to evaluate short-term changes in patterns of brain activity associated with locomotor training. Outcomes Somatosensory excitability and corticospinal excitability were observed to increase after locomotor resistance training. Motor evoked potentials increased (particularly at higher stimulation intensities), and seed-based resting-state functional magnetic resonance imaging analyses revealed increased functional connectivity strength in the motor cortex associated with the less affected side after training. Discussion The observations suggest evidence of short-term cortical plasticity in 3 complementary neurophysiological measures after one session of locomotor resistance training. Future investigation in a sample of people with

  17. CNGA3 achromatopsia-associated mutation potentiates the phosphoinositide sensitivity of cone photoreceptor CNG channels by altering intersubunit interactions

    PubMed Central

    Dai, Gucan

    2013-01-01

    Cyclic nucleotide-gated (CNG) channels are critical for sensory transduction in retinal photoreceptors and olfactory receptor cells; their activity is modulated by phosphoinositides (PIPn) such as phosphatidylinositol 4,5-bisphosphate (PIP2) and phosphatidylinositol 3,4,5-trisphosphate (PIP3). An achromatopsia-associated mutation in cone photoreceptor CNGA3, L633P, is located in a carboxyl (COOH)-terminal leucine zipper domain shown previously to be important for channel assembly and PIPn regulation. We determined the functional consequences of this mutation using electrophysiological recordings of patches excised from cells expressing wild-type and mutant CNG channel subunits. CNGA3-L633P subunits formed functional channels with or without CNGB3, producing an increase in apparent cGMP affinity. Surprisingly, L633P dramatically potentiated PIPn inhibition of apparent cGMP affinity for these channels. The impact of L633P on PIPn sensitivity depended on an intact amino (NH2) terminal PIPn regulation module. These observations led us to hypothesize that L633P enhances PIPn inhibition by altering the coupling between NH2- and COOH-terminal regions of CNGA3. A recombinant COOH-terminal fragment partially restored normal PIPn sensitivity to channels with COOH-terminal truncation, but L633P prevented this effect. Furthermore, coimmunoprecipitation of channel fragments, and thermodynamic linkage analysis, also provided evidence for NH2-COOH interactions. Finally, tandem dimers of CNGA3 subunits that specify the arrangement of subunits containing L633P and other mutations indicated that the putative interdomain interaction occurs between channel subunits (intersubunit) rather than exclusively within the same subunit (intrasubunit). Collectively, these studies support a model in which intersubunit interactions control the sensitivity of cone CNG channels to regulation by phosphoinositides. Aberrant channel regulation may contribute to disease progression in patients with the

  18. Inactivation of the Class II PI3K-C2β Potentiates Insulin Signaling and Sensitivity

    PubMed Central

    Alliouachene, Samira; Bilanges, Benoit; Chicanne, Gaëtan; Anderson, Karen E.; Pearce, Wayne; Ali, Khaled; Valet, Colin; Posor, York; Low, Pei Ching; Chaussade, Claire; Scudamore, Cheryl L.; Salamon, Rachel S.; Backer, Jonathan M.; Stephens, Len; Hawkins, Phill T.; Payrastre, Bernard; Vanhaesebroeck, Bart

    2015-01-01

    Summary In contrast to the class I phosphoinositide 3-kinases (PI3Ks), the organismal roles of the kinase activity of the class II PI3Ks are less clear. Here, we report that class II PI3K-C2β kinase-dead mice are viable and healthy but display an unanticipated enhanced insulin sensitivity and glucose tolerance, as well as protection against high-fat-diet-induced liver steatosis. Despite having a broad tissue distribution, systemic PI3K-C2β inhibition selectively enhances insulin signaling only in metabolic tissues. In a primary hepatocyte model, basal PI3P lipid levels are reduced by 60% upon PI3K-C2β inhibition. This results in an expansion of the very early APPL1-positive endosomal compartment and altered insulin receptor trafficking, correlating with an amplification of insulin-induced, class I PI3K-dependent Akt signaling, without impacting MAPK activity. These data reveal PI3K-C2β as a critical regulator of endosomal trafficking, specifically in insulin signaling, and identify PI3K-C2β as a potential drug target for insulin sensitization. PMID:26655903

  19. Temperature-sensitive polymer-coated magnetic nanoparticles as a potential drug delivery system for targeted therapy of thyroid cancer.

    PubMed

    Koppolu, Bhanuprasanth; Bhavsar, Zarna; Wadajkar, Aniket S; Nattama, Sivaniarvindpriya; Rahimi, Maham; Nwariaku, Fiemu; Nguyen, Kytai T

    2012-12-01

    The objective of this work was to develop and investigate temperature-sensitive poly(N-isopropylacrylamide-acrylamide-allylamine)-coated iron oxide magnetic nanoparticles (TPMNPs) as possible targeted drug carriers for treatments of advanced thyroid cancer (ATC). These nanoparticles were prepared by free radical polymerization of monomers on the surface of silane-coupled iron oxide nanoparticles. In vitro studies demonstrated that TPMNPs were cytocompatible and effectively taken up by cancer cells in a dose-dependent manner. An external magnetic field significantly increased nanoparticle uptake, especially when cells were exposed to physiological flow conditions. Drug loading and release studies using doxorubicin confirmed the temperature-responsive release of drugs from nanoparticles. In addition, doxorubicin-loaded nanoparticles significantly killed ATC cells when compared to free doxorubicin. The in vitro results indicate that TPMNPs have potential as targeted and controlled drug carriers for thyroid cancer treatment.

  20. Lymphocyte phenotypes in wild-caught rats suggest potential mechanisms underlying increased immune sensitivity in post-industrial environments

    PubMed Central

    Trama, Ashley M; Holzknecht, Zoie E; Thomas, Anitra D; Su, Kuei-Ying; Lee, Sean M; Foltz, Emily E; Perkins, Sarah E; Lin, Shu S; Parker, William

    2012-01-01

    The immune systems of wild rats and of laboratory rats can been utilized as models of the human immune system in pre-industrial and post-industrial societies, respectively. In this study, lymphocyte phenotypes in wild rats were broadly characterized, and the results were compared to those obtained by us and by others using cells derived from various strains of laboratory rats. Although not expected, the production of regulatory T cells was not apparently different in wild rats compared to laboratory rats. On the other hand, differences in expression of markers involved in complement regulation, adhesion, signaling and maturation suggest increased complement regulation and decreased sensitivity in wild-caught rats compared to laboratory rats, and point toward complex differences between the maturation of T cells. The results potentially lend insight into the pathogenesis of post-industrial epidemics of allergy and autoimmune disease. PMID:22327212

  1. Monitoring Locomotor Load in Soccer: Is Metabolic Power, Powerful?

    PubMed

    Buchheit, M; Manouvrier, C; Cassirame, J; Morin, J-B

    2015-12-01

    The aim of the present study was to examine the validity and reliability of metabolic power (P) estimated from locomotor demands during soccer-specific drills. 14 highly-trained soccer players performed a soccer-specific circuit with the ball (3×1-min bouts, interspersed with 30-s passive recovery) on 2 different occasions. Locomotor activity was monitored with 4-Hz GPSs, while oxygen update (VO2) was collected with a portable gas analyzer. P was calculated using either net VO2 responses and traditional calorimetry principles (PVO2, W.kg(-1)) or locomotor demands (PGPS, W.kg(-1)). Distance covered into different speed, acceleration and P zones was recorded. While PGPS was 29±10% lower than PVO2 (d<- 3) during the exercise bouts, it was 85±7% lower (d<- 8) during recovery phases. The typical error between PGPS vs. PVO2 was moderate: 19.8%, 90% confidence limits: (18.4;21.6). The correlation between both estimates of P was small: 0.24 (0.14;0.33). Very large day-to-day variations were observed for acceleration, deceleration and > 20 W.kg(-1) distances (all CVs > 50%), while average Po2 and PGPS showed CVs < 10%. ICC ranged from very low- (acceleration and > 20 W.kg(-1) distances) to-very high (PVO2). PGPS largely underestimates the energy demands of soccer-specific drills, especially during the recovery phases. The poor reliability of PGPS >20 W.kg(-1) questions its value for monitoring purposes in soccer.

  2. Locomotor energetics and leg length in hominid bipedality.

    PubMed

    Kramer, P A; Eck, G G

    2000-05-01

    Because bipedality is the quintessential characteristic of Hominidae, researchers have compared ancient forms of bipedality with modern human gait since the first clear evidence of bipedal australopithecines was unearthed over 70 years ago. Several researchers have suggested that the australopithecine form of bipedality was transitional between the quadrupedality of the African apes and modern human bipedality and, consequently, inefficient. Other researchers have maintained that australopithecine bipedality was identical to that of Homo. But is it reasonable to require that all forms of hominid bipedality must be the same in order to be optimized? Most attempts to evaluate the locomotor effectiveness of the australopithecines have, unfortunately, assumed that the locomotor anatomy of modern humans is the exemplar of consummate bipedality. Modern human anatomy is, however, the product of selective pressures present in the particular milieu in which Homo arose and it is not necessarily the only, or even the most efficient, bipedal solution possible. In this report, we investigate the locomotion of Australopithecus afarensis, as represented by AL 288-1, using standard mechanical analyses. The osteological anatomy of AL 288-1 and movement profiles derived from modern humans are applied to a dynamic model of a biped, which predicts the mechanical power required by AL 288-1 to walk at various velocities. This same procedure is used with the anatomy of a composite modern woman and a comparison made. We find that AL 288-1 expends less energy than the composite woman when locomoting at walking speeds. This energetic advantage comes, however, at a price: the preferred transition speed (from a walk to a run) of AL 288-1 was lower than that of the composite woman. Consequently, the maximum daily range of AL 288-1 may well have been substantially smaller than that of modern people. The locomotor anatomy of A. afarensis may have been optimized for a particular ecological niche

  3. Differential effects of serotonin (5-HT)2 receptor-targeting ligands on locomotor responses to nicotine-repeated treatment.

    PubMed

    Zaniewska, Magdalena; McCreary, Andrew C; Wydra, Karolina; Filip, Małgorzata

    2010-07-01

    We verified the hypothesis that serotonin (5-HT)(2) receptors control the locomotor effects of nicotine (0.4 mg kg(-1)) in rats by using the 5-HT(2A) receptor antagonist M100907, the preferential 5-HT(2A) receptor agonist DOI, the 5-HT(2C) receptor antagonist SB 242084, and the 5-HT(2C) receptor agonists Ro 60-0175 and WAY 163909. Repeated pairings of a test environment with nicotine for 5 days, on Day 10 significantly augmented the locomotor activity following nicotine administration. Of the investigated 5-HT(2) receptor ligands, M100907 (2 mg kg(-1)) or DOI (1 mg kg(-1)) administered during the first 5 days in combination with nicotine attenuated or enhanced, respectively, the development of nicotine sensitization. Given acutely on Day 10, M100907 (2 mg kg(-1)), Ro 60-0175 (1 mg kg(-1)), and WAY 163909 (1.5 mg kg(-1)) decreased the expression of nicotine sensitization. In another set of experiments, where the nicotine challenge test was performed on Day 15 in animals treated repeatedly (Days: 1-5, 10) with nicotine, none of 5-HT(2) receptor ligands administered during the second withdrawal period (Days: 11-14) to nicotine-treated rats altered the sensitizing effect of nicotine given on Day 15. Our data indicate that 5-HT(2A) receptors (but not 5-HT(2C) receptors) play a permissive role in the sensitizing effects of nicotine, while stimulation of 5-HT(2A) receptors enhances the development of nicotine sensitization and activation of 5-HT(2C) receptors is essential for the expression of nicotine sensitization. Repeated treatment with the 5-HT(2) receptor ligands within the second nicotine withdrawal does not inhibit previously established sensitization.

  4. Predictive Measures of Locomotor Performance on an Unstable Walking Surface

    NASA Technical Reports Server (NTRS)

    Bloomberg, J. J.; Peters, B. T.; Mulavara, A. P.; Caldwell, E. E.; Batson, C. D.; De Dios, Y. E.; Gadd, N. E.; Goel, R.; Wood, S. J.; Cohen, H. S.; Oddsson, L. I.; Seidler, R. D.

    2016-01-01

    Locomotion requires integration of visual, vestibular, and somatosensory information to produce the appropriate motor output to control movement. The degree to which these sensory inputs are weighted and reorganized in discordant sensory environments varies by individual and may be predictive of the ability to adapt to novel environments. The goals of this project are to: 1) develop a set of predictive measures capable of identifying individual differences in sensorimotor adaptability, and 2) use this information to inform the design of training countermeasures designed to enhance the ability of astronauts to adapt to gravitational transitions improving balance and locomotor performance after a Mars landing and enhancing egress capability after a landing on Earth.

  5. Locomotor Dysfunction after Spaceflight: Characterization and Countermeasure Development

    NASA Technical Reports Server (NTRS)

    Mulavara, A. P.; Cohen, H. S.; Peters, B. T.; Miller, C. A.; Brady, R.; Bloomberg, Jacob J.

    2007-01-01

    Astronauts returning from space flight show disturbances in locomotor control manifested by changes in various sub-systems including head-trunk coordination, dynamic visual acuity, lower limb muscle activation patterning and kinematics (Glasauer, et al., 1995; Bloomberg, et al., 1997; McDonald, et al., 1996; 1997; Layne, et al., 1997; 1998, 2001, 2004; Newman, et al., 1997; Bloomberg and Mulavara, 2003). These post flight changes in locomotor performance, due to neural adaptation to the microgravity conditions of space flight, affect the ability of crewmembers especially after a long duration mission to egress their vehicle and perform extravehicular activities soon after landing on Earth or following a landing on the surface of the Moon or Mars. At present, no operational training intervention is available pre- or in- flight to mitigate post flight locomotor disturbances. 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. 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 sensorimotor sub-systems to achieve safe and effective locomotion as soon as possible after space flight. We have previously confirmed that subjects participating in adaptive generalization training programs, using a variety of visuomotor distortions and different motor tasks from throwing to negotiating an obstacle course as the dependent measure, can learn to enhance their ability to adapt to a

  6. Modular functional organisation of the axial locomotor system in salamanders.

    PubMed

    Cabelguen, Jean-Marie; Charrier, Vanessa; Mathou, Alexia

    2014-02-01

    Most investigations on tetrapod locomotion have been concerned with limb movements. However, there is compelling evidence that the axial musculoskeletal system contributes to important functions during locomotion. Adult salamanders offer a remarkable opportunity to examine these functions because these amphibians use axial undulations to propel themselves in both aquatic and terrestrial environments. In this article, we review the currently available biological data on axial functions during various locomotor modes in salamanders. We also present data showing the modular organisation of the neural networks that generate axial synergies during locomotion. The functional implication of this modular organisation is discussed.

  7. A Locomotor Deficit Induced by Sublethal Doses of Pyrethroid and Neonicotinoid Insecticides in the Honeybee Apis mellifera.

    PubMed

    Charreton, Mercédès; Decourtye, Axel; Henry, Mickaël; Rodet, Guy; Sandoz, Jean-Christophe; Charnet, Pierre; Collet, Claude

    2015-01-01

    The toxicity of pesticides used in agriculture towards non-targeted organisms and especially pollinators has recently drawn the attention from a broad scientific community. Increased honeybee mortality observed worldwide certainly contributes to this interest. The potential role of several neurotoxic insecticides in triggering or potentiating honeybee mortality was considered, in particular phenylpyrazoles and neonicotinoids, given that they are widely used and highly toxic for insects. Along with their ability to kill insects at lethal doses, they can compromise survival at sublethal doses by producing subtle deleterious effects. In this study, we compared the bee's locomotor ability, which is crucial for many tasks within the hive (e.g. cleaning brood cells, feeding larvae…), before and after an acute sublethal exposure to one insecticide belonging to the two insecticide classes, fipronil and thiamethoxam. Additionally, we examined the locomotor ability after exposure to pyrethroids, an older chemical insecticide class still widely used and known to be highly toxic to bees as well. Our study focused on young bees (day 1 after emergence) since (i) few studies are available on locomotion at this stage and (ii) in recent years, pesticides have been reported to accumulate in different hive matrices, where young bees undergo their early development. At sublethal doses (SLD48h, i.e. causing no mortality at 48 h), three pyrethroids, namely cypermethrin (2.5 ng/bee), tetramethrin (70 ng/bee), tau-fluvalinate (33 ng/bee) and the neonicotinoid thiamethoxam (3.8 ng/bee) caused a locomotor deficit in honeybees. While the SLD48h of fipronil (a phenylpyrazole, 0.5 ng/bee) had no measurable effect on locomotion, we observed high mortality several days after exposure, an effect that was not observed with the other insecticides. Although locomotor deficits observed in the sublethal range of pyrethroids and thiamethoxam would suggest deleterious effects in the field, the case of

  8. A Locomotor Deficit Induced by Sublethal Doses of Pyrethroid and Neonicotinoid Insecticides in the Honeybee Apis mellifera

    PubMed Central

    Charreton, Mercédès; Decourtye, Axel; Henry, Mickaël; Rodet, Guy; Sandoz, Jean-Christophe; Charnet, Pierre; Collet, Claude

    2015-01-01

    The toxicity of pesticides used in agriculture towards non-targeted organisms and especially pollinators has recently drawn the attention from a broad scientific community. Increased honeybee mortality observed worldwide certainly contributes to this interest. The potential role of several neurotoxic insecticides in triggering or potentiating honeybee mortality was considered, in particular phenylpyrazoles and neonicotinoids, given that they are widely used and highly toxic for insects. Along with their ability to kill insects at lethal doses, they can compromise survival at sublethal doses by producing subtle deleterious effects. In this study, we compared the bee’s locomotor ability, which is crucial for many tasks within the hive (e.g. cleaning brood cells, feeding larvae…), before and after an acute sublethal exposure to one insecticide belonging to the two insecticide classes, fipronil and thiamethoxam. Additionally, we examined the locomotor ability after exposure to pyrethroids, an older chemical insecticide class still widely used and known to be highly toxic to bees as well. Our study focused on young bees (day 1 after emergence) since (i) few studies are available on locomotion at this stage and (ii) in recent years, pesticides have been reported to accumulate in different hive matrices, where young bees undergo their early development. At sublethal doses (SLD48h, i.e. causing no mortality at 48h), three pyrethroids, namely cypermethrin (2.5 ng/bee), tetramethrin (70 ng/bee), tau-fluvalinate (33 ng/bee) and the neonicotinoid thiamethoxam (3.8 ng/bee) caused a locomotor deficit in honeybees. While the SLD48h of fipronil (a phenylpyrazole, 0.5 ng/bee) had no measurable effect on locomotion, we observed high mortality several days after exposure, an effect that was not observed with the other insecticides. Although locomotor deficits observed in the sublethal range of pyrethroids and thiamethoxam would suggest deleterious effects in the field, the case

  9. Three-axis optical force plate for studies in small animal locomotor mechanics

    SciTech Connect

    Hsieh, S. Tonia

    2006-05-15

    The use of force plates to measure whole-body locomotor mechanics is a well-established technique. However, commercially available force plates are not sensitive enough for use on small-bodied vertebrates or invertebrates. The standard design for single- and multiple-axis, high-sensitivity force plates built by individual research groups uses semiconductor foil strain gauges to measure deflections; yet foil strain gauges are highly temperature and position sensitive, resulting in a drifting base line and nonlinear responses. I present here a design for a three-axis optical force plate that was successfully calibrated to measure forces as small as 1.5 mN and is capable of determining the position of center of pressure with a mean error of 0.07 cm along the X axis and 0.13 cm along the Y axis. Using optical sensors instead of foil strain gauges to measure deflection, this force plate is not subject to temperature-related drift and is more robust against slight positioning inaccuracies. This force plate was used to measure forces produced by amphibious fishes weighing less than 2 g as they jumped off the force platform.

  10. Hyperglycemia Potentiates H2O2 Production in Adipocytes and Enhances Insulin Signal Transduction: Potential Role for Oxidative Inhibition of Thiol-Sensitive Protein-Tyrosine Phosphatases

    PubMed Central

    WU, XIANGDONG; ZHU, LI; ZILBERING, ASSAF; MAHADEV, KALYANKAR; MOTOSHIMA, HIROYUKI; YAO, JUNLI; GOLDSTEIN, BARRY J.

    2006-01-01

    Insulin signal transduction in adipocytes is accompanied by a burst of cellular hydrogen peroxide (H2O2 facilitates insulin signaling by inhibiting thiol-dependent protein-tyrosine phosphatases (PTPs)) that are negative regulators of insulin action. As hyperglycemia is associated with increased cellular reactive oxygen species, we postulated that high glucose conditions might potentiate the H2O2 generated by insulin and modulate insulin-stimulated protein phosphorylation. Basal H2O2 generation was increased threefold in differentiated 3T3-L1 adipocytes by growth in 25 mM glucose versus 5 mM glucose. High glucose increased the sensitivity of the insulin-stimulated H2O2 signal to lower concentrations of insulin. Basal endogenous total PTP activity and the activity of PTP1B, a PTP implicated in the negative regulation of insulin signaling, were reduced in high glucose conditions, and their further reduction by insulin stimulation was more enhanced in high versus low glucose medium. Phosphorylation of the insulin receptor, IRS-1, and Akt in response to insulin was also significantly enhanced in high glucose conditions, especially at submaximal insulin concentrations. In primary rat adipocytes, high glucose increased insulin-stimulated H2O2 the oxidative inhibition of total PTP production and potentiated and PTP1B activity; however, insulin signaling was not enhanced in the primary cells in high glucose apparently due to cross-regulation of insulin-stimulated protein phosphorylation by activation of protein kinase C (PKC). These studies indicate that high glucose can enhance insulin-stimulated H2O2 generation and augment oxidative PTP inhibition in cultured and primary adipocytes, but the overall balance of insulin signal transduction is determined by additional signal effects in high glucose, including the activation of PKC. PMID:15889998

  11. Activation of steroid-sensitive TRPM3 channels potentiates glutamatergic transmission at cerebellar Purkinje neurons from developing rats.

    PubMed

    Zamudio-Bulcock, Paula A; Everett, Julie; Harteneck, Christian; Valenzuela, C Fernando

    2011-11-01

    The functional implications of transient receptor potential melastatin 3 (TRPM3) activation, the most recently described member of the melastatin subfamily of cation permeable TRP channels, have begun to be elucidated in recent years. The discovery of TRPM3 activation by the steroid pregnenolone sulfate (PregS) has shed new light on the physiological role of this channel. For example, TRPM3 activation enhances insulin secretion from β pancreatic cells, induces contraction of vascular smooth muscle, and is also involved in the detection of noxious heat. Although TRPM3 expression has been detected in several regions of the developing and mature brain, little is known about the roles of TRPM3 in brain physiology. In this study, we demonstrate the abundant expression of TRPM3 steroid-sensitive channels in the developing cerebellar cortex. We also show that TRPM3-like channels are expressed at glutamatergic synapses in neonatal Purkinje cells. We recently showed that PregS potentiates spontaneous glutamate release onto neonatal Purkinje cells during a period of active glutamatergic synapse formation; we now show that this effect of PregS is mediated by TRPM3-like channels. Mefenamic acid, a recently discovered TRPM3 antagonist, blocked the effect of PregS on glutamate release. The PregS effect on glutamate release was mimicked by other TRPM3 agonists (nifedipine and epipregnanolone sulfate) but not by a TRMP3-inactive steroid (progesterone). Our findings identify TRPM3 channels as novel modulators of glutamatergic transmission in the developing brain.

  12. Potential sensitivity of warm season precipitation to urbanization extents: Modeling study in Beijing-Tianjin-Hebei urban agglomeration in China

    NASA Astrophysics Data System (ADS)

    Wang, Jun; Feng, Jinming; Yan, Zhongwei

    2015-09-01

    In this study, we investigated how different degrees of urbanization affect local and regional rainfall using high-resolution simulations based on the Weather Research and Forecasting Model. The extreme rainfall event of 21 July 2012 in Beijing was simulated for three representative urban land use distributions (no urbanization, early urbanization level of 1980, and recent urbanization level of 2009). Results suggest that urban modification of rainfall is potentially sensitive to urban land use condition. Rainfall was increased significantly over the downwind Beijing metropolis because of the effects of early urbanization; however, recent conditions of high urban development caused no significant increase. Further comparative analysis revealed that positive urban thermodynamical effects (i.e., urban warming, increased sensible heat transportation, and enhanced convergence and vertical motions) play major roles in urban modification of rainfall during the early urbanization stage. However, after cities expand to a certain extent (i.e., urban agglomeration), the regional moisture depression induced by the prevalence of impervious urban land has an effect on atmospheric instability energy, which might negate the city's positive impact on regional rainfall. Additional results from regional climate simulations for 10 Julys confirm this supposition. Given the explosive urban population growth and increasing demand for freshwater in cities, the potential negative effects of the urban environment on precipitation are worth investigation, particularly in rapidly developing countries and regions.

  13. Scaling Behavior of Human Locomotor Activity Amplitude: Association with Bipolar Disorder

    PubMed Central

    Indic, Premananda; Salvatore, Paola; Maggini, Carlo; Ghidini, Stefano; Ferraro, Gabriella; Baldessarini, Ross J.; Murray, Greg

    2011-01-01

    Scale invariance is a feature of complex biological systems, and abnormality of multi-scale behaviour may serve as an indicator of pathology. The hypothalamic suprachiasmatic nucleus (SCN) is a major node in central neural networks responsible for regulating multi-scale behaviour in measures of human locomotor activity. SCN also is implicated in the pathophysiology of bipolar disorder (BD) or manic-depressive illness, a severe, episodic disorder of mood, cognition and behaviour. Here, we investigated scaling behaviour in actigraphically recorded human motility data for potential indicators of BD, particularly its manic phase. A proposed index of scaling behaviour (Vulnerability Index [VI]) derived from such data distinguished between: [i] healthy subjects at high versus low risk of mood disorders; [ii] currently clinically stable BD patients versus matched controls; and [iii] among clinical states in BD patients. PMID:21655197

  14. Locomotor stimulant and discriminative stimulus effects of 'bath salt' cathinones.

    PubMed

    Gatch, Michael B; Taylor, Cynthia M; Forster, Michael J

    2013-09-01

    A number of psychostimulant-like cathinone compounds are being sold as 'legal' alternatives to methamphetamine or cocaine. The purpose of these experiments was to determine whether cathinone compounds stimulate motor activity and have discriminative stimulus effects similar to those of cocaine and/or methamphetamine. 3,4-Methylenedioxypyrovalerone (MDPV), methylone, mephedrone, naphyrone, flephedrone, and butylone were tested for locomotor stimulant effects in mice and subsequently for substitution in rats trained to discriminate cocaine (10 mg/kg, intraperitoneally) or methamphetamine (1 mg/kg, intraperitoneally) from saline. All compounds fully substituted for the discriminative stimulus effects of cocaine and methamphetamine. Several commonly marketed cathinones produce discriminative stimulus effects comparable with those of cocaine and methamphetamine, which suggests that these compounds are likely to have similar abuse liabilities. MDPV and naphyrone produced locomotor stimulant effects that lasted much longer than those of cocaine or methamphetamine and therefore may be of particular concern, particularly because MDPV is one of the most commonly found substances associated with emergency room visits because of adverse effects of taking 'bath salts'.

  15. Nasal oxytocin administration reduces food intake without affecting locomotor activity and glycemia with c-Fos induction in limited brain areas.

    PubMed

    Maejima, Yuko; Rita, Rauza Sukma; Santoso, Putra; Aoyama, Masato; Hiraoka, Yuichi; Nishimori, Katsuhiko; Gantulga, Darambazar; Shimomura, Kenju; Yada, Toshihiko

    2015-01-01

    Recent studies have considered oxytocin (Oxt) as a possible medicine to treat obesity and hyperphagia. To find the effective and safe route for Oxt treatment, we compared the effects of its nasal and intraperitoneal (IP) administration on food intake, locomotor activity, and glucose tolerance in mice. Nasal Oxt administration decreased food intake without altering locomotor activity and increased the number of c-Fos-immunoreactive (ir) neurons in the paraventricular nucleus (PVN) of the hypothalamus, the area postrema (AP), and the dorsal motor nucleus of vagus (DMNV) of the medulla. IP Oxt administration decreased food intake and locomotor activity and increased the number of c-Fos-ir neurons not only in the PVN, AP, and DMNV but also in the nucleus of solitary tract of the medulla and in the arcuate nucleus of the hypothalamus. In IP glucose tolerance tests, IP Oxt injection attenuated the rise of blood glucose, whereas neither nasal nor intracerebroventricular Oxt affected blood glucose. In isolated islets, Oxt administration potentiated glucose-induced insulin secretion. These results indicate that both nasal and IP Oxt injections reduce food intake to a similar extent and increase the number of c-Fos-ir neurons in common brain regions. IP Oxt administration, in addition, activates broader brain regions, reduces locomotor activity, and affects glucose tolerance possibly by promoting insulin secretion from pancreatic islets. In comparison with IP administration, the nasal route of Oxt administration could exert a similar anorexigenic effect with a lesser effect on peripheral organs.

  16. Tolerance to the locomotor-activating effects of 3,4-methylenedioxymethamphetamine (MDMA) predicts escalation of MDMA self-administration and cue-induced reinstatement of MDMA seeking in rats.

    PubMed

    Ball, Kevin T; Slane, Mylissa

    2014-11-01

    Pre-clinical studies of individual differences in addiction vulnerability have been increasing over recent years, but the amphetamine derivative 3,4-methylenedioxymethamphetamine (MDMA; ecstasy) has received relatively little attention in this regard. Previously, we reported large individual differences both in rats' initial behavioral response to experimenter-administered MDMA and their degree of behavioral sensitization to repeated administration. To determine whether these differences could predict subsequent patterns of MDMA-taking or -seeking behaviors we used the self-administration-extinction-reinstatement model to examine addiction-like behavior (i.e., escalation of MDMA self-administration and cue-induced reinstatement of MDMA seeking) in rats a priori characterized for either locomotor sensitization or tolerance to MDMA. Rats that developed tolerance to the locomotor-activating effects of MDMA had a significantly larger locomotor response to the first MDMA injection relative to rats that developed sensitization. Importantly, rats that developed tolerance subsequently displayed an escalation of MDMA self-administration over days, as well as clear cue-induced reinstatement of MDMA seeking following extinction. Conversely, rats that developed locomotor sensitization to MDMA subsequently maintained relatively stable levels of MDMA self-administration over days and showed no cue-induced reinstatement of MDMA seeking. These results show that differences in the level of psychomotor activation following acute and repeated MDMA administration can reliably predict two important addiction-like behaviors in rats, which may have implications in the prediction of compulsive MDMA use in humans.

  17. Impact loading and locomotor-respiratory coordination significantly influence breathing dynamics in running humans.

    PubMed

    Daley, Monica A; Bramble, Dennis M; Carrier, David R

    2013-01-01

    Locomotor-respiratory coupling (LRC), phase-locking between breathing and stepping rhythms, occurs in many vertebrates. When quadrupedal mammals gallop, 1∶1 stride per breath coupling is necessitated by pronounced mechanical interactions between locomotion and ventilation. Humans show more flexibility in breathing patterns during locomotion, using LRC ratios of 2∶1, 2.5∶1, 3∶1, or 4∶1 and sometimes no coupling. Previous studies provide conflicting evidence on the mechanical significance of LRC in running humans. Some studies suggest LRC improves breathing efficiency, but others suggest LRC is mechanically insignificant because 'step-driven flows' (ventilatory flows attributable to step-induced forces) contribute a negligible fraction of tidal volume. Yet, although step-driven flows are brief, they cause large fluctuations in ventilatory flow. Here we test the hypothesis that running humans use LRC to minimize antagonistic effects of step-driven flows on breathing. We measured locomotor-ventilatory dynamics in 14 subjects running at a self-selected speed (2.6±0.1 ms(-1)) and compared breathing dynamics in their naturally 'preferred' and 'avoided' entrainment patterns. Step-driven flows occurred at 1-2X step frequency with peak magnitudes of 0.97±0.45 Ls(-1) (mean ±S.D). Step-driven flows varied depending on ventilatory state (high versus low lung volume), suggesting state-dependent changes in compliance and damping of thoraco-abdominal tissues. Subjects naturally preferred LRC patterns that minimized antagonistic interactions and aligned ventilatory transitions with assistive phases of the step. Ventilatory transitions initiated in 'preferred' phases within the step cycle occurred 2x faster than those in 'avoided' phases. We hypothesize that humans coordinate breathing and locomotion to minimize antagonistic loading of respiratory muscles, reduce work of breathing and minimize rate of fatigue. Future work could address the potential consequences of

  18. Locomotor Tests Predict Community Mobility in Children and Youth with Cerebral Palsy

    ERIC Educational Resources Information Center

    Ferland, Chantale; Moffet, Helene; Maltais, Desiree

    2012-01-01

    Ambulatory children and youth with cerebral palsy have limitations in locomotor capacities and in community mobility. The ability of three locomotor tests to predict community mobility in this population (N = 49, 27 boys, 6-16 years old) was examined. The tests were a level ground walking test, the 6-min-Walk-Test (6MWT), and two tests of advanced…

  19. Treadmill training promotes spinal changes leading to locomotor recovery after partial spinal cord injury in cats.

    PubMed

    Martinez, Marina; Delivet-Mongrain, Hugo; Rossignol, Serge

    2013-06-01

    After a spinal hemisection at thoracic level in cats, the paretic hindlimb progressively recovers locomotion without treadmill training but asymmetries between hindlimbs persist for several weeks and can be seen even after a further complete spinal transection at T13. To promote optimal locomotor recovery after hemisection, such asymmetrical changes need to be corrected. In the present study we determined if the locomotor deficits induced by a spinal hemisection can be corrected by locomotor training and, if so, whether the spinal stepping after the complete spinal cord transection is also more symmetrical. This would indicate that locomotor training in the hemisected period induces efficient changes in the spinal cord itself. Sixteen adult cats were first submitted to a spinal hemisection at T10. One group received 3 wk of treadmill training, whereas the second group did not. Detailed kinematic and electromyographic analyses showed that a 3-wk period of locomotor training was sufficient to improve the quality and symmetry of walking of the hindlimbs. Moreover, after the complete spinal lesion was performed, all the trained cats reexpressed bilateral and symmetrical hindlimb locomotion within 24 h. By contrast, the locomotor pattern of the untrained cats remained asymmetrical, and the hindlimb on the side of the hemisection was still deficient. This study highlights the beneficial role of locomotor training in facilitating bilateral and symmetrical functional plastic changes within the spinal circuitry and in promoting locomotor recovery after an incomplete spinal cord injury.

  20. Evaluation of an in vitro assay system as a potential alternative to current histamine sensitization test for acellular pertussis vaccines.

    PubMed

    Xing, Dorothy; Yuen, Chun-Ting; Asokanathan, Catpagavalli; Rigsby, Peter; Horiuchi, Yoshinobu

    2012-11-01

    The histamine sensitization test (HIST) is a lethal test for batch release of acellular pertussis or its combination vaccines (ACV). Large numbers of animals have been used and it is difficult to standardize. Therefore there is an urgent need to develop an in vitro alternative to HIST. An in vitro test system has been developed as a potential alternative to HIST, to examine both the functional domains of PT based on a combination of enzyme coupled-HPLC (E-HPLC) and carbohydrate binding assays. We describe here an international collaborative study, which involved sixteen laboratories from 9 countries to assess the methodology transferability of the in vitro test system and its suitability for the testing of three different types of ACV products that are currently used worldwide. This study also evaluated further the relationship between the in vivo activity by HIST and the in vitro assay system. The results showed that the methodology of the E-HPLC and carbohydrate binding assays are transferable between laboratories worldwide and is suitable for the three types of ACV products included in the study. Although direct correlation between the in vitro assay system and the in vivo HIST (temperature reduction assay) for each individual vaccine lot cannot be established due to the large variation in the HIST results, the observation that the mean estimates of the in vitro and in vivo activities gave the same rank order of the three vaccine types included in the study is encouraging. The in vitro systems provide reproducible product specific profiles which supports their use as a potential alternative to the HIST.

  1. An intravenous exposure mouse model for prediction of potential drug-sensitization using reporter antigens popliteal lymph node assay.

    PubMed

    Lin, Mingbao; Sun, Wei; Wang, Yingchao; Li, Xiang; Jin, Yecheng; Gong, Wan; Fan, Xiaohui; Wang, Yi

    2012-06-01

    Immune-mediated drug hypersensitivity is a particularly concerning health-safety issue among clinicians given its unpredictability and potentially life-threatening effects, especially with exposure to intravenous drugs. Therefore, the development of intravenous drug-exposure models for drug-hazard assessments has garnered increasing interest in recent years. In this study, we used reporter antigens popliteal lymph node assay to investigate the potential value of intravenous exposure to a selected variety of allergenic compounds, including ovalbumin (OVA), concanavalin A (ConA) and diclofenac. The trinitrophenyl (TNP)-specific antibody-forming cells were used to assess the systemic immune responses to a bystander antigen. Mice were subsequently sensitized by TNP-OVA, and then intravenous exposure to one of the selective compounds. As expected, all positive compounds induced significant popliteal lymph node (PLN) proliferation compared with the control. OVA significantly increased Cluster of Differentiation 4 receptors (CD⁴)⁺ interleukin-4 (IL-4)⁺ T-helper 2 (Th2) cells and, consequently, increased the ratios of IL-4/interferon-γ (IFN-γ) antibody-forming cells (AFCs) in PLNs, while bringing about a dose-dependent increase in immunoglobulin G1 (IgG1) AFCs; these findings indicate that a Th2 hypersensitivity response was induced. A Th2 response was also observed in diclofenac sodium-treated groups, and for ConA, a more mixed Th1/Th2 immune response appeared to be induced. In addition, there was no marked reaction with the negative compound. Together, it seems likely that the intravenous exposure model may be useful for drug-induced systemic hypersensitivity assessments.

  2. Neurotensin and bombesin, a relationship between their effects on body temperature and locomotor activity?

    PubMed

    van Wimersma Greidanus, T B; Schijff, J A; Noteboom, J L; Spit, M C; Bruins, L; van Zummeren, B M; Rinkel, G J

    1984-08-01

    Neurotensin and bombesin have been tested for their effects on body temperature and locomotor activity in an open field. Both peptides induce hypothermia and suppress ambulation and rearing. The time curves of the hypothermic effects of both peptides appear to be rather similar, although bombesin is a more potent hypothermic agent than neurotensin. The time curves of the effects on locomotor activity appear to be quite different. The suppressive effect of neurotensin on locomotor activity is relatively short lasting and reaches its maximum at approximately 32 minutes. The effect of bombesin follows a different time curve and shows two peaks, suggesting that two different mechanisms are involved in the suppressive action of bombesin on locomotor activity. Calculation of the correlation coefficients between the effects of neurotensin and of bombesin on body temperature and on locomotor activity (ambulation) suggest that a causal relationship between these two effects is not likely, in particular for neurotensin.

  3. A new hyaluronic acid pH sensitive derivative obtained by ATRP for potential oral administration of proteins.

    PubMed

    Fiorica, Calogero; Pitarresi, Giovanna; Palumbo, Fabio Salvatore; Di Stefano, Mauro; Calascibetta, Filippo; Giammona, Gaetano

    2013-11-30

    Atom transfer radical polymerization (ATRP) has been successfully employed to obtain a new derivative of hyaluronic acid (HA) able to change its solubility as a function of external pH and then to be potentially useful for intestinal release of bioactive molecules, included enzymes and proteins. In particular, a macroinitiator has been prepared by linking 2-bromo-2-methypropionic acid (BMP) to the amino groups of ethylenediamino derivative of tetrabutyl ammonium salt of HA (HA-TBA-EDA). This macroinititor, named HA-TBA-EDA-BMP has been used for the ATRP of sodium methacrylate (MANa) using a complex of Cu(I) and 2,2'-bipyridyl (Byp) as a catalyst. The resulting copolymer, named HA-EDA-BMP-MANa, has been characterized by (1)H NMR and size exclusion chromatography (SEC) analyses. A turbidimetric analysis has showed its pH sensitive behavior, being insoluble in simulated gastric fluid but soluble when pH increases more than 2.5. To confirm the ability of HA-EDA-BMP-MANa in protecting peptides or proteins from denaturation in acidic medium, α-chymotrypsin has been chosen as a model of protein molecule and its activity has been evaluated after entrapment into HA-EDA-BMP-MANa chains and treatment under simulated gastric conditions. Finally, cell compatibility has been evaluated by performing a MTS assay on murine dermal fibroblasts cultured with HA-EDA-BMP-MANa solutions.

  4. Differential sensitivity of osteoblasts and bacterial pathogens to 405-nm light highlighting potential for decontamination applications in orthopedic surgery

    NASA Astrophysics Data System (ADS)

    Ramakrishnan, Praveen; Maclean, Michelle; MacGregor, Scott J.; Anderson, John G.; Grant, M. Helen

    2014-10-01

    Healthcare associated infections pose a major threat to patients admitted to hospitals and infection rates following orthopedic arthroplasty surgery are as high as 4%. A 405-nm high-intensity narrow spectrum light has been proven to reduce environmental contamination in hospital isolation rooms, and there is potential to develop this technology for application in arthroplasty surgery. Cultured rat osteoblasts were exposed to varying light intensities and it was found that exposures of up to a dose of 36 J/cm2 had no significant effect on cell viability [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay], function (alkaline phosphatase activity), and proliferation rate (BrdU cell proliferation assay). High irradiance exposures (54 J/cm2) significantly affected the cell viability indicating that the effects of 405-nm light on osteoblasts are dose dependent. Additionally, exposure of a variety of clinically related bacteria to a dose of 36 J/cm2 resulted in up to 100% kill. These results demonstrating the differential sensitivity of osteoblasts and bacteria to 405-nm light are an essential step toward developing the technique for decontamination in orthopedic surgery.

  5. Optimization of absorption bands of dye-sensitized and perovskite tandem solar cells based on loss-in-potential values.

    PubMed

    Sobuś, Jan; Ziółek, Marcin

    2014-07-21

    A numerical study of optimal bandgaps of light absorbers in tandem solar cell configurations is presented with the main focus on dye-sensitized solar cells (DSSCs) and perovskite solar cells (PSCs). The limits in efficiency and the expected improvements of tandem structures are investigated as a function of total loss-in-potential (V(L)), incident photon to current efficiency (IPCE) and fill factor (FF) of individual components. It is shown that the optimal absorption onsets are significantly smaller than those derived for multi-junction devices. For example, for double-cell devices the onsets are at around 660 nm and 930 nm for DSSCs with iodide based electrolytes and at around 720 nm and 1100 nm for both DSSCs with cobalt based electrolytes and PSCs. Such configurations can increase the total sunlight conversion efficiency by about 35% in comparison to single-cell devices of the same VL, IPCE and FF. The relevance of such studies for tandem n-p DSSCs and for a proposed new configuration for PSCs is discussed. In particular, it is shown that maximum total losses of 1.7 V for DSSCs and 1.4 V for tandem PSCs are necessary to give any efficiency improvement with respect to the single bandgap device. This means, for example, a tandem n-p DSSC with TiO2 and NiO porous electrodes will hardly work better than the champion single DSSC. A source code of the program used for calculations is also provided.

  6. The canonical transient receptor potential 6 (TRPC6) channel is sensitive to extracellular pH in mouse platelets.

    PubMed

    Berna-Erro, Alejandro; Albarran, Letizia; Dionisio, Natalia; Redondo, Pedro C; Alonso, Nieves; Gomez, Luis J; Salido, Gines M; Rosado, Juan A

    2014-01-01

    The canonical transient receptor potential-6 (TRPC6) is a receptor-activated non-selective Ca(2+) channel regulated by a variety of modulators such as diacylglycerol, Ca(2+)/calmodulin or phosphorylation. The present study is aimed to investigate whether different situations, such as acidic pH, exposure to reactive oxygen species (ROS) or hypoxic-like conditions modulate TRPC6 channel function. Here we show normal aggregation and Ca(2+) mobilization stimulated by thrombin in TRPC6 KO platelets; however, OAG (1-oleoyl-2-acetyl-sn-glycerol)-evoked Ca(2+) entry was attenuated in the absence of TRPC6. Exposure of mouse platelets to acidic pH resulted in abolishment of thrombin-evoked aggregation and attenuated platelet aggregation induced by thapsigargin (TG) or OAG. Both OAG-induced Ca(2+) entry and platelet aggregation were greatly attenuated in cells expressing TRPC6 channels. Exposure of platelets to H2O2 or deferoxamine did not clearly alter thrombin, TG or OAG-induced platelet aggregation. Our results indicate that TRPC6 is sensitive to acidic pH but not to exposure to ROS or hypoxic-like conditions, which might be involved in the pathogenesis of the altered platelet responsiveness to DAG-generating agonists in disorders associated to acidic pH.

  7. Sensitization of a stray-field NMR to vibrations: a potential for MR elastometry with a portable NMR sensor.

    PubMed

    Mastikhin, Igor; Barnhill, Marie

    2014-11-01

    An NMR signal from a sample in a constant stray field of a portable NMR sensor is sensitized to vibrations. The CPMG sequence is synchronized to vibrations so that the constant gradient becomes an "effective" square-wave gradient, leading to the vibration-induced phase accumulation. The integrating nature of the spot measurement, combined with the phase distribution due to a non-uniform gradient and/or a wave field, leads to a destructive interference, the drop in the signal intensity and changes in the echo train shape. Vibrations with amplitudes as small as 140 nm were reliably detected with the permanent gradient of 12.4 T/m. The signal intensity depends on the phase offset between the vibrations and the pulse sequence. This approach opens the way for performing elastometry and micro-rheology measurements with portable NMR devices beyond the walls of a laboratory. Even without synchronization, if a vibration frequency is comparable to 1/2TE of the CPMG sequence, the signal can be severely affected, making it important for potential industrial applications of stray-field NMR.

  8. Locomotor Trajectories of Stroke Patients during Oriented Gait and Turning

    PubMed Central

    Van Hamme, Angele; Bensmail, Djamel

    2016-01-01

    Background The Timed Up and Go (TUG) test is widely used to assess locomotion in patients with stroke and is considered to predict the risk of falls. The analysis of locomotor trajectories during the TUG appears pertinent in stroke patients. The aims of this study were i) to analyze locomotor trajectories in patients with stroke during the walking and turning sub-tasks of the TUG, and to compare them with healthy subjects, ii) to determine whether trajectory parameters provide additional information to that provided by the conventional measure (performance time), iii) to compare the trajectory parameters of fallers and non-fallers with stroke and of patients with right and left hemisphere stroke, and iv) to evaluate correlations between trajectory parameters and Berg Balance Scale scores. Methods 29 patients with stroke (mean age 54.2±12.2 years, 18 men, 8 fallers) and 25 healthy subjects (mean age 51.6±8.7 years, 11 men) underwent three-dimensional analysis of the TUG. The trajectory of the center of mass was analyzed by calculation of the global trajectory length, Hausdorff distance and Dynamic Time Warping. The parameters were compared with a reference trajectory during the total task and each sub-task (Go, Turn, Return) of the TUG. Results Values of trajectory parameters were significantly higher for the stroke group during the total TUG and the Go and Turn sub-tasks (p<0.05). Moreover, logistic regression indicated that these parameters better discriminated stroke patients and healthy subjects than the conventional timed performance during the Go sub-task. In addition, fallers were distinguished by higher Dynamic Time Warping during the Go (p<0.05). There were no differences between patients with right and left hemisphere stroke. Discussion and Conclusion The trajectories of the stroke patients were longer and more deviated during the turn and the preceding phase. Trajectory parameters provided additional information to timed performance of this locomotor

  9. Training Enhances Both Locomotor and Cognitive Adaptability to a Novel Sensory Environment

    NASA Technical Reports Server (NTRS)

    Bloomberg, J. J.; Peters, B. T.; Mulavara, A. P.; Brady, R. A.; Batson, C. D.; Ploutz-Snyder, R. J.; Cohen, H. S.

    2010-01-01

    During adaptation to novel gravitational environments, sensorimotor disturbances have the potential to disrupt the ability of astronauts to perform required mission tasks. The goal of this project is to develop a sensorimotor adaptability (SA) training program to facilitate rapid adaptation. We have developed a unique training system comprised of a treadmill placed on a motion-base facing a virtual visual scene that provides an unstable walking surface combined with incongruent visual flow designed to enhance sensorimotor adaptability. The goal of our present study was to determine if SA training improved both the locomotor and cognitive responses to a novel sensory environment and to quantify the extent to which training would be retained. Methods: Twenty subjects (10 training, 10 control) completed three, 30-minute training sessions during which they walked on the treadmill while receiving discordant support surface and visual input. Control subjects walked on the treadmill but did not receive any support surface or visual alterations. To determine the efficacy of training all subjects performed the Transfer Test upon completion of training. For this test, subjects were exposed to novel visual flow and support surface movement, not previously experienced during training. The Transfer Test was performed 20 minutes, 1 week, 1, 3 and 6 months after the final training session. Stride frequency, auditory reaction time, and heart rate data were collected as measures of postural stability, cognitive effort and anxiety, respectively. Results: Using mixed effects regression methods we determined that subjects who received SA training showed less alterations in stride frequency, auditory reaction time and heart rate compared to controls. Conclusion: Subjects who received SA training improved performance across a number of modalities including enhanced locomotor function, increased multi-tasking capability and reduced anxiety during adaptation to novel discordant sensory

  10. Effects of reduced plantar cutaneous afferent feedback on locomotor adjustments in dynamic stability during perturbed walking.

    PubMed

    Höhne, Angela; Stark, Christian; Brüggemann, Gert-Peter; Arampatzis, Adamantios

    2011-08-11

    This study examined the effects of reduced plantar cutaneous afferent feedback on predictive and feedback adaptive locomotor adjustments in dynamic stability during perturbed walking. Twenty-two matched participants divided between an experimental-group and a control-group performed a gait protocol, which included surface alterations to one covered exchangeable gangway-element (hard/soft). In the experimental-group, cutaneous sensation in both foot soles was reduced to the level of sensory peripheral neuropathy by means of intradermal injections of an anaesthetic solution, without affecting foot proprioception or muscles. The gait protocol consisted of baseline trials on a uniformly hard surface and an adaptation phase consisting of nineteen trials incorporating a soft gangway-element, interspersed with three trials using the hard surface-element (2nd, 8th and 19th). Dynamic stability was assessed by quantifying the margin of stability (MS), which was calculated as the difference between the base of support (BS) and the extrapolated centre of mass (CM). The horizontal velocity of the CM and its vertical projection in the anterior-posterior direction and the eigenfrequency of an inverted pendulum determine the extrapolated-CM. Both groups increased the BS at the recovery step in response to the first unexpected perturbation. These feedback corrections were used more extensively in the experimental-group, which led to a higher MS compared to the control-group, i.e. a more stable body-position. In the adaptation phase the MS returned to baseline similarly in both groups. In the trial on the hard surface directly after the first perturbation, both groups increased the MS at touchdown of the disturbed leg compared to baseline trials, indicating rapid predictive adjustments irrespective of plantar cutaneous input. Our findings demonstrate that the locomotor adaptational potential does not decrease due to the loss of plantar sensation.

  11. Anatomical and functional evidence for trace amines as unique modulators of locomotor function in the mammalian spinal cord

    PubMed Central

    Gozal, Elizabeth A.; O'Neill, Brannan E.; Sawchuk, Michael A.; Zhu, Hong; Halder, Mallika; Chou, Ching-Chieh; Hochman, Shawn

    2014-01-01

    The trace amines (TAs), tryptamine, tyramine, and β-phenylethylamine, are synthesized from precursor amino acids via aromatic-L-amino acid decarboxylase (AADC). We explored their role in the neuromodulation of neonatal rat spinal cord motor circuits. We first showed that the spinal cord contains the substrates for TA biosynthesis (AADC) and for receptor-mediated actions via trace amine-associated receptors (TAARs) 1 and 4. We next examined the actions of the TAs on motor activity using the in vitro isolated neonatal rat spinal cord. Tyramine and tryptamine most consistently increased motor activity with prominent direct actions on motoneurons. In the presence of N-methyl-D-aspartate, all applied TAs supported expression of a locomotor-like activity (LLA) that was indistinguishable from that ordinarily observed with serotonin, suggesting that the TAs act on common central pattern generating neurons. The TAs also generated distinctive complex rhythms characterized by episodic bouts of LLA. TA actions on locomotor circuits did not require interaction with descending monoaminergic projections since evoked LLA was maintained following block of all Na+-dependent monoamine transporters or the vesicular monoamine transporter. Instead, TA (tryptamine and tyramine) actions depended on intracellular uptake via pentamidine-sensitive Na+-independent membrane transporters. Requirement for intracellular transport is consistent with the TAs having much slower LLA onset than serotonin and for activation of intracellular TAARs. To test for endogenous actions following biosynthesis, we increased intracellular amino acid levels with cycloheximide. LLA emerged and included distinctive TA-like episodic bouts. In summary, we provided anatomical and functional evidence of the TAs as an intrinsic spinal monoaminergic modulatory system capable of promoting recruitment of locomotor circuits independent of the descending monoamines. These actions support their known sympathomimetic function

  12. Cool running: locomotor performance at low body temperature in mammals

    PubMed Central

    Rojas, A. Daniella; Körtner, Gerhard; Geiser, Fritz

    2012-01-01

    Mammalian torpor saves enormous amounts of energy, but a widely assumed cost of torpor is immobility and therefore vulnerability to predators. Contrary to this assumption, some small marsupial mammals in the wild move while torpid at low body temperatures to basking sites, thereby minimizing energy expenditure during arousal. Hence, we quantified how mammalian locomotor performance is affected by body temperature. The three small marsupial species tested, known to use torpor and basking in the wild, could move while torpid at body temperatures as low as 14.8–17.9°C. Speed was a sigmoid function of body temperature, but body temperature effects on running speed were greater than those in an ectothermic lizard used for comparison. We provide the first quantitative data of movement at low body temperature in mammals, which have survival implications for wild heterothermic mammals, as directional movement at low body temperature permits both basking and predator avoidance. PMID:22675136

  13. Cool running: locomotor performance at low body temperature in mammals.

    PubMed

    Rojas, A Daniella; Körtner, Gerhard; Geiser, Fritz

    2012-10-23

    Mammalian torpor saves enormous amounts of energy, but a widely assumed cost of torpor is immobility and therefore vulnerability to predators. Contrary to this assumption, some small marsupial mammals in the wild move while torpid at low body temperatures to basking sites, thereby minimizing energy expenditure during arousal. Hence, we quantified how mammalian locomotor performance is affected by body temperature. The three small marsupial species tested, known to use torpor and basking in the wild, could move while torpid at body temperatures as low as 14.8-17.9°C. Speed was a sigmoid function of body temperature, but body temperature effects on running speed were greater than those in an ectothermic lizard used for comparison. We provide the first quantitative data of movement at low body temperature in mammals, which have survival implications for wild heterothermic mammals, as directional movement at low body temperature permits both basking and predator avoidance.

  14. Age-Related Differences in Locomotor Strategies During Adaptive Walking.

    PubMed

    Lowry, Kristin A; Sebastian, Katherine; Perera, Subashan; Van Swearingen, Jessie; Smiley-Oyen, Ann L

    2016-11-21

    Simultaneous control of lower limb stepping movements and trunk motion is important for skilled walking; adapting gait to environmental constraints requires frequent alternations in stepping and trunk motion. These alterations provide a window into the locomotor strategies adopted by the walker. The authors examined gait strategies in young and healthy older adults when manipulating step width. Anteroposterior (AP) and mediolateral (ML) smoothness (quantified by harmonic ratios) and stepping consistency (quantified by gait variability) were analyzed during narrow and wide walking while controlling cadence to preferred pace. Results indicated older adults preserved ML smoothness at the expense of AP smoothness, shortened their steps, and exhibited reduced stepping consistency. The authors conclude that older adults prioritized ML control over forward progression during adaptive walking challenges.

  15. Tarsier-like locomotor specializations in the Oligocene primate Afrotarsius

    PubMed Central

    Rasmussen, D. Tab; Conroy, Glenn C.; Simons, Elwyn L.

    1998-01-01

    Tarsiers and extinct tarsier-like primates have played a central role in views of primate phylogeny and evolution for more than a century. Because of the importance of tarsiers in so many primatological problems, there has been particular interest in questions about the origin of tarsier specializations and the biogeography of early tarsioid radiations. We report on a new fossil of rare Afrotarsius that shows near identity to modern Tarsius in unique specializations of the leg, which provides information about the locomotor behavior and clarifies the phylogenetic position of this previously controversial primate. These specializations constitute evidence that Afrotarsius is a tarsiid, closely related to extant Tarsius; hence, it is now excluded from being a generalized sister taxon to Anthropoidea. PMID:9843978

  16. Suprachiasmatic vasopressin and the circadian regulation of voluntary locomotor behavior.

    PubMed

    Cormier, Holly C; Della-Maggiore, Valeria; Karatsoreos, Ilia N; Koletar, Margaret M; Ralph, Martin R

    2015-01-01

    A role for arginine vasopressin in the circadian regulation of voluntary locomotor behavior (wheel running activity) was investigated in the golden hamster, Mesocricetus auratus. Spontaneous nocturnal running was suppressed in a dose-dependent manner by systemic injections of vasopressin, and also in a concentration-dependent manner by microinjections directly into the hypothalamic suprachiasmatic nucleus. Pre-injections of a vasopressin V1 receptor antagonist into the nucleus reduced the suppression of behavior by vasopressin. Ethogram analyses revealed that peripheral drug injections predominantly increased grooming, flank marking, and sleep-related behaviors. Central injections did not induce sleep, but increased grooming and periods of 'quiet vigilance' (awake but not moving). Nocturnal behavioral profiles following either peripheral or central injections were similar to those shown by untreated animals in the hour prior to the onset of nocturnal wheel running. Site control vasopressin injections into the medial preoptic area or periaqueductal gray increased flank marking and grooming, but had no significant effect on locomotion, suggesting behavioral specificity of a vasopressin target near the suprachiasmatic nucleus. Both peripheral and central administration increased FOS-like immunoreactivity in the retinorecipient core of the suprachiasmatic nucleus. The distribution of FOS-positive cells overlapped the calbindin subregion, but was more extensive, and most calbindin-positive cells did not co-express FOS. We propose a model of temporal behavioral regulation wherein voluntary behavior, such as nocturnal locomotor activity, is inhibited by the activity of neurons in the suprachiasmatic ventrolateral core that project to the posterior hypothalamus and are driven by rhythmic vasopressin input from the dorsomedial shell.

  17. What does autonomic arousal tell us about locomotor learning?

    PubMed

    Green, D A; Bunday, K L; Bowen, J; Carter, T; Bronstein, A M

    2010-09-29

    Walking onto a stationary sled previously experienced as moving induces locomotor aftereffects (LAE, or "broken escalator phenomenon"). This particular form of aftereffect can develop after a single adaptation trial and occurs despite subjects being fully aware that the sled will not move. Here, we investigate whether such strong LAE expression may relate to arousal or fear related to instability during the gait adaptation process. Forty healthy subjects were allocated to three sled velocity groups; SLOW (0.6 m/s), MEDIUM (1.3 m/s), or FAST (2.0 m/s). Subjects walked onto the stationary sled for five trials (BEFORE), then onto the moving sled for 15 trials (adaptation or MOVING trials) and, finally, again onto the stationary sled for five trials (AFTER). Explicit warning regarding sled status was given. Trunk position, foot-sled contact timing, autonomic markers (electrodermal activity [EDA], ECG, respiratory movements) in addition to self-reported task-related confidence and state/trait anxiety were recorded. Trunk sway, EDA, and R-R interval shortening were greatest during the first MOVING trial (MOVING_1), progressively attenuating during subsequent MOVING trials. A LAE, recorded as increased gait velocity and trunk sway during AFTER_1, occurred in both MEDIUM and FAST sled velocity groups. The amplitude of forward trunk sway in AFTER_1 (an indicator of aftereffect magnitude) was related to EDA during the final adaptation trial (MOVING_15). AFTER_1 gait velocity (also an indicator of aftereffect magnitude) was related to MOVING_1 trunk sway. Hence, gait velocity and trunk sway components of the LAE are differentially related to kinematic and autonomic parameters during the early and late adaptation phase. The finding that EDA is a predictor of LAE expression indicates that autonomic arousal or fear-based mechanisms can promote locomotor learning. This could in turn explain some unusual characteristics of this LAE, namely its resistance to explicit knowledge and

  18. Melatonin and locomotor activity in the fiddler crab Uca pugilator.

    PubMed

    Tilden, Andrea R; Shanahan, J Kearney; Khilji, Zahra S; Owen, Jeffrey G; Sterio, Thomas W; Thurston, Kristy T

    2003-05-01

    The influence of melatonin on locomotor activity levels was measured in the fiddler crab Uca pugilator. First, activity in untreated, laboratory-acclimated crabs was measured over 48 hours in a 12L:12D photoperiod; this study showed a nocturnal increase in activity. In eyestalk-ablated crabs, overall activity was significantly reduced, and no significant activity pattern occurred. Next, crabs were injected with melatonin or saline (controls) at various times during the 12L:12D photoperiod (0900h, 1200h, and twice at 2100h; each trial was separated by 3-4 days) and monitored for 3 hr post-injection. Control crabs had low activity during early photophase, high at mid-photophase, increasing activity during the first scotophase trial, and decreasing activity during the second scotophase trial. Melatonin had no significant influence on activity when injected during the early-photophase activity trough or early-scotophase activity decline, but significantly increased activity when injected during the mid-photophase activity peak and early-scotophase activity incline. Next, crabs were injected during an early scotophase activity trough and monitored throughout the twelve-hour scotophase. Melatonin did not increase activity until the mid-scotophase activity increase, approximately 6 hours later, showing that the pharmacological dosage persisted in the crabs' systems and had later effects during the incline and peak of activity but not the trough. Eyestalk-ablated crabs were injected with melatonin or saline during early photo- and scotophase. Melatonin significantly increased activity in the photophase but not the scotophase trial, indicating that the responsiveness to melatonin continues following eyestalk removal, but the timing may not match that of intact crabs. Melatonin may be involved in the transmission of environmental timing information from the eyestalks to locomotor centers in U. pugilator.

  19. Immature Spinal Locomotor Output in Children with Cerebral Palsy

    PubMed Central

    Cappellini, Germana; Ivanenko, Yury P.; Martino, Giovanni; MacLellan, Michael J.; Sacco, Annalisa; Morelli, Daniela; Lacquaniti, Francesco

    2016-01-01

    Detailed descriptions of gait impairments have been reported in cerebral palsy (CP), but it is still unclear how maturation of the spinal motoneuron output is affected. Spatiotemporal alpha-motoneuron activation during walking can be assessed by mapping the electromyographic activity profiles from several, simultaneously recorded muscles onto the anatomical rostrocaudal location of the motoneuron pools in the spinal cord, and by means of factor analysis of the muscle activity profiles. Here, we analyzed gait kinematics and EMG activity of 11 pairs of bilateral muscles with lumbosacral innervation in 35 children with CP (19 diplegic, 16 hemiplegic, 2–12 years) and 33 typically developing (TD) children (1–12 years). TD children showed a progressive reduction of EMG burst durations and a gradual reorganization of the spatiotemporal motoneuron output with increasing age. By contrast, children with CP showed very limited age-related changes of EMG durations and motoneuron output, as well as of limb intersegmental coordination and foot trajectory control (on both sides for diplegic children and the affected side for hemiplegic children). Factorization of the EMG signals revealed a comparable structure of the motor output in children with CP and TD children, but significantly wider temporal activation patterns in children with CP, resembling the patterns of much younger TD infants. A similar picture emerged when considering the spatiotemporal maps of alpha-motoneuron activation. Overall, the results are consistent with the idea that early injuries to developing motor regions of the brain substantially affect the maturation of the spinal locomotor output and consequently the future locomotor behavior. PMID:27826251

  20. Novel locomotor muscle design in extreme deep-diving whales.

    PubMed

    Velten, B P; Dillaman, R M; Kinsey, S T; McLellan, W A; Pabst, D A

    2013-05-15

    Most marine mammals are hypothesized to routinely dive within their aerobic dive limit (ADL). Mammals that regularly perform deep, long-duration dives have locomotor muscles with elevated myoglobin concentrations that are composed of predominantly large, slow-twitch (Type I) fibers with low mitochondrial volume densities (V(mt)). These features contribute to extending ADL by increasing oxygen stores and decreasing metabolic rate. Recent tagging studies, however, have challenged the view that two groups of extreme deep-diving cetaceans dive within their ADLs. Beaked whales (including Ziphius cavirostris and Mesoplodon densirostris) routinely perform the deepest and longest average dives of any air-breathing vertebrate, and short-finned pilot whales (Globicephala macrorhynchus) perform high-speed sprints at depth. We investigated the locomotor muscle morphology and estimated total body oxygen stores of several species within these two groups of cetaceans to determine whether they (1) shared muscle design features with other deep divers and (2) performed dives within their calculated ADLs. Muscle of both cetaceans displayed high myoglobin concentrations and large fibers, as predicted, but novel fiber profiles for diving mammals. Beaked whales possessed a sprinter's fiber-type profile, composed of ~80% fast-twitch (Type II) fibers with low V(mt). Approximately one-third of the muscle fibers of short-finned pilot whales were slow-twitch, oxidative, glycolytic fibers, a rare fiber type for any mammal. The muscle morphology of beaked whales likely decreases the energetic cost of diving, while that of short-finned pilot whales supports high activity events. Calculated ADLs indicate that, at low metabolic rates, both beaked and short-finned pilot whales carry sufficient onboard oxygen to aerobically support their dives.

  1. AltitudeOmics: on the consequences of high-altitude acclimatization for the development of fatigue during locomotor exercise in humans

    PubMed Central

    Goodall, Stuart; Twomey, Rosie; Subudhi, Andrew W.; Lovering, Andrew T.; Roach, Robert C.

    2013-01-01

    The development of muscle fatigue is oxygen (O2)-delivery sensitive [arterial O2 content (CaO2) × limb blood flow (QL)]. Locomotor exercise in acute hypoxia (AH) is, compared with sea level (SL), associated with reduced CaO2 and exaggerated inspiratory muscle work (Winsp), which impairs QL, both of which exacerbate fatigue individually by compromising O2 delivery. Since chronic hypoxia (CH) normalizes CaO2 but exacerbates Winsp, we investigated the consequences of a 14-day exposure to high altitude on exercise-induced locomotor muscle fatigue. Eight subjects performed the identical constant-load cycling exercise (138 ± 14 W; 11 ± 1 min) at SL (partial pressure of inspired O2, 147.1 ± 0.5 Torr), in AH (73.8 ± 0.2 Torr), and in CH (75.7 ± 0.1 Torr). Peripheral fatigue was expressed as pre- to postexercise percent reduction in electrically evoked potentiated quadriceps twitch force (ΔQtw,pot). Central fatigue was expressed as the exercise-induced percent decrease in voluntary muscle activation (ΔVA). Resting CaO2 at SL and CH was similar, but CaO2 in AH was lower compared with SL and CH (17.3 ± 0.5, 19.3 ± 0.7, 20.3 ± 1.3 ml O2/dl, respectively). Winsp during exercise increased with acclimatization (SL: 387 ± 36, AH: 503 ± 53, CH: 608 ± 67 cmH2O·s−1·min−1; P < 0.01). Exercise at SL did not induce central or peripheral fatigue. ΔQtw,pot was significant but similar in AH and CH (21 ± 2% and 19 ± 3%; P = 0.24). ΔVA was significant in both hypoxic conditions but smaller in CH vs. AH (4 ± 1% vs. 8 ± 2%; P < 0.05). In conclusion, acclimatization to severe altitude does not attenuate the substantial impact of hypoxia on the development of peripheral fatigue. In contrast, acclimatization attenuates, but does not eliminate, the exacerbation of central fatigue associated with exercise in severe AH. PMID:23813531

  2. AltitudeOmics: on the consequences of high-altitude acclimatization for the development of fatigue during locomotor exercise in humans.

    PubMed

    Amann, Markus; Goodall, Stuart; Twomey, Rosie; Subudhi, Andrew W; Lovering, Andrew T; Roach, Robert C

    2013-09-01

    The development of muscle fatigue is oxygen (O2)-delivery sensitive [arterial O2 content (CaO2) × limb blood flow (QL)]. Locomotor exercise in acute hypoxia (AH) is, compared with sea level (SL), associated with reduced CaO2 and exaggerated inspiratory muscle work (Winsp), which impairs QL, both of which exacerbate fatigue individually by compromising O2 delivery. Since chronic hypoxia (CH) normalizes CaO2 but exacerbates Winsp, we investigated the consequences of a 14-day exposure to high altitude on exercise-induced locomotor muscle fatigue. Eight subjects performed the identical constant-load cycling exercise (138 ± 14 W; 11 ± 1 min) at SL (partial pressure of inspired O2, 147.1 ± 0.5 Torr), in AH (73.8 ± 0.2 Torr), and in CH (75.7 ± 0.1 Torr). Peripheral fatigue was expressed as pre- to postexercise percent reduction in electrically evoked potentiated quadriceps twitch force (ΔQtw,pot). Central fatigue was expressed as the exercise-induced percent decrease in voluntary muscle activation (ΔVA). Resting CaO2 at SL and CH was similar, but CaO2 in AH was lower compared with SL and CH (17.3 ± 0.5, 19.3 ± 0.7, 20.3 ± 1.3 ml O2/dl, respectively). Winsp during exercise increased with acclimatization (SL: 387 ± 36, AH: 503 ± 53, CH: 608 ± 67 cmH2O·s(-1)·min(-1); P < 0.01). Exercise at SL did not induce central or peripheral fatigue. ΔQtw,pot was significant but similar in AH and CH (21 ± 2% and 19 ± 3%; P = 0.24). ΔVA was significant in both hypoxic conditions but smaller in CH vs. AH (4 ± 1% vs. 8 ± 2%; P < 0.05). In conclusion, acclimatization to severe altitude does not attenuate the substantial impact of hypoxia on the development of peripheral fatigue. In contrast, acclimatization attenuates, but does not eliminate, the exacerbation of central fatigue associated with exercise in severe AH.

  3. Chronic preexposure to methylphenidate cross-sensitizes methamphetamine in male Japanese quail.

    PubMed

    Rosine, Bobbi Jo; Levi Bolin, B; Akins, Chana K

    2009-07-01

    An increasing debate exists about the potential of exposure to methylphenidate increasing later risk of drug abuse. The objective of this study was to investigate whether chronic preexposure to methylphenidate would induce cross-sensitization to a subsequent methamphetamine challenge in male Japanese quail. Male quail were treated intraperitoneally with either 5, 10, or 20 mg/kg methylphenidate or saline for 14 days. After a 14-day washout period, birds were challenged with 5.6 mg/kg of methamphetamine. Methylphenidate-induced behavioral sensitization was not evident after 14 days of preexposure. However, locomotor activity was greater during the methamphetamine challenge in birds that were preexposed to a high dose of methylphenidate. The findings suggest that chronic preexposure to methylphenidate may be sufficient to alter later responding to methamphetamine, regardless of whether preexposure resulted in behavioral sensitization.

  4. Altered brainstem auditory evoked potentials in a rat central sensitization model are similar to those in migraine.

    PubMed

    Arakaki, Xianghong; Galbraith, Gary; Pikov, Victor; Fonteh, Alfred N; Harrington, Michael G

    2014-05-14

    Migraine symptoms often include auditory discomfort. Nitroglycerin (NTG)-triggered central sensitization (CS) provides a rodent model of migraine, but auditory brainstem pathways have not yet been studied in this example. Our objective was to examine brainstem auditory evoked potentials (BAEPs) in rat CS as a measure of possible auditory abnormalities. We used four subdermal electrodes to record horizontal (h) and vertical (v) dipole channel BAEPs before and after injection of NTG or saline. We measured the peak latencies (PLs), interpeak latencies (IPLs), and amplitudes for detectable waveforms evoked by 8, 16, or 32 kHz auditory stimulation. At 8 kHz stimulation, vertical channel positive PLs of waves 4, 5, and 6 (vP4, vP5, and vP6), and related IPLs from earlier negative or positive peaks (vN1-vP4, vN1-vP5, vN1-vP6; vP3-vP4, vP3-vP6) increased significantly 2h after NTG injection compared to the saline group. However, BAEP peak amplitudes at all frequencies, PLs and IPLs from the horizontal channel at all frequencies, and the vertical channel stimulated at 16 and 32 kHz showed no significant/consistent change. For the first time in the rat CS model, we show that BAEP PLs and IPLs ranging from putative bilateral medial superior olivary nuclei (P4) to the more rostral structures such as the medial geniculate body (P6) were prolonged 2h after NTG administration. These BAEP alterations could reflect changes in neurotransmitters and/or hypoperfusion in the midbrain. The similarity of our results with previous human studies further validates the rodent CS model for future migraine research.

  5. Early differential sensitivity of evoked-potentials to local and global shape during the perception of three-dimensional objects.

    PubMed

    Leek, E Charles; Roberts, Mark; Oliver, Zoe J; Cristino, Filipe; Pegna, Alan J

    2016-08-01

    Here we investigated the time course underlying differential processing of local and global shape information during the perception of complex three-dimensional (3D) objects. Observers made shape matching judgments about pairs of sequentially presented multi-part novel objects. Event-related potentials (ERPs) were used to measure perceptual sensitivity to 3D shape differences in terms of local part structure and global shape configuration - based on predictions derived from hierarchical structural description models of object recognition. There were three types of different object trials in which stimulus pairs (1) shared local parts but differed in global shape configuration; (2) contained different local parts but shared global configuration or (3) shared neither local parts nor global configuration. Analyses of the ERP data showed differential amplitude modulation as a function of shape similarity as early as the N1 component between 146-215ms post-stimulus onset. These negative amplitude deflections were more similar between objects sharing global shape configuration than local part structure. Differentiation among all stimulus types was reflected in N2 amplitude modulations between 276-330ms. sLORETA inverse solutions showed stronger involvement of left occipitotemporal areas during the N1 for object discrimination weighted towards local part structure. The results suggest that the perception of 3D object shape involves parallel processing of information at local and global scales. This processing is characterised by relatively slow derivation of 'fine-grained' local shape structure, and fast derivation of 'coarse-grained' global shape configuration. We propose that the rapid early derivation of global shape attributes underlies the observed patterns of N1 amplitude modulations.

  6. Potentially avoidable and ambulatory care sensitive hospitalisations among forced migrants: a protocol for a systematic review and meta-analysis

    PubMed Central

    Lichtl, Célina; Gewalt, Sandra Claudia; Noest, Stefan; Szecsenyi, Joachim; Bozorgmehr, Kayvan

    2016-01-01

    Introduction There is an increasing number of forced migrants globally, including refugees, asylum seekers, internally displaced persons and undocumented migrants. According to international law, forced migrants should enjoy access to health services free of discrimination equivalent to the host population, but they face barriers to healthcare worldwide. This may lead to a delay in care and result in preventable hospital treatment, referred to as potentially preventable hospitalisation (PPH) or ambulatory care sensitive hospitalisation (ACSH). There is as yet no overview of the prevalence of PPH in different countries and groups of forced migrants, and it is unknown whether the concept has been used among these migrant groups. We aim to systematically review the evidence (1) on the prevalence of PPH among forced migrants and (2) on differences in the prevalence of PPH between forced migrants and the general host population. Methods and analysis A systematic review will be conducted searching databases (PubMed/MEDLINE, Web of Science/Knowledge, Cochrane Library, CINAHL, Google Scholar) and the internet (Google). Inclusion criteria: observational studies on forced migrants reporting PPH or ACSH with or without comparison groups published in the English or German language. Exclusion criteria: studies on general migrant groups or hospitalisations without clear reference to avoidability. Study selection: titles, abstracts and full texts will be screened in duplicate for eligibility. Data on the prevalence of PPH/ACSH among forced migrants, as well as any reported prevalence differences between host populations, will be systematically extracted. Quality appraisal will be performed using standardised checklists. The evidence will be synthesised in tabular form and by means of forest plots. A meta-analysis will be performed only among homogeneous studies (in terms of design and population). Ethics and dissemination Ethical clearance is not necessary (secondary research

  7. A novel high-throughput screening assay for HCN channel blocker using membrane potential-sensitive dye and FLIPR.

    PubMed

    Vasilyev, Dmitry V; Shan, Qin J; Lee, Yan T; Soloveva, Veronica; Nawoschik, Stanley P; Kaftan, Edward J; Dunlop, John; Mayer, Scott C; Bowlby, Mark R

    2009-10-01

    Hyperpolarization-activated cation nonselective (HCN) channels represent an interesting group of targets for drug development. In this study, the authors report the development of a novel membrane potential-sensitive dye (MPSD) assay for HCN channel modulators that has been miniaturized into 384-well fluorescent imaging plate reader (FLIPR) high-throughput screening (HTS) format. When optimized (by cell plating density, plate type, cell recovery from cryopreservation), the well-to-well signal variability was low, with a Z' = 0.73 and coefficient of variation = 6.4%, whereas the MPSD fluorescence signal amplitude was -23,700 +/- 1500 FLIPR(3) relative fluorescence units (a linear relationship was found between HCN1 MPSD fluorescence signal and the cell plating density) and was completely blocked by 30 microM ZD7288. The assay tolerated up to 1% DMSO, inclusion of which did not significantly change the signal kinetics or amplitude. A single-concentration screening of an ion channel-focused library composed of 4855 compounds resulted in 89 HCN1 blocker hits, 51 of which were subsequently analyzed with an 8-point concentration-response analysis on the IonWorks HT electrophysiology platform. The correlation between MPSD and the electrophysiology assay was moderate, as shown by the linear regression analysis (r(2) = 0.56) between the respective IC(50)s obtained using these 2 assays. The reported HTS-compatible HCN channel blocker assay can serve as a tool in drug discovery in the pursuit of HCN channel isoform-selective small molecules that could be used in the development of clinically relevant compounds.

  8. Overexpressed transient receptor potential vanilloid 3 ion channels in skin keratinocytes modulate pain sensitivity via prostaglandin E2.

    PubMed

    Huang, Susan M; Lee, Hyosang; Chung, Man-Kyo; Park, Una; Yu, Yin Yin; Bradshaw, Heather B; Coulombe, Pierre A; Walker, J Michael; Caterina, Michael J

    2008-12-17

    The ability to sense changes in the environment is essential for survival because it permits responses such as withdrawal from noxious stimuli and regulation of body temperature. Keratinocytes, which occupy much of the skin epidermis, are situated at the interface between the external environment and the body's internal milieu, and have long been appreciated for their barrier function against external insults. The recent discovery of temperature-sensitive transient receptor potential vanilloid (TRPV) ion channels in keratinocytes has raised the possibility that these cells also actively participate in acute temperature and pain sensation. To address this notion, we generated and characterized transgenic mice that overexpress TRPV3 in epidermal keratinocytes under the control of the keratin 14 promoter. Compared with wild-type controls, keratinocytes overexpressing TRPV3 exhibited larger currents as well as augmented prostaglandin E(2) (PGE(2)) release in response to two TRPV3 agonists, 2-aminoethoxydiphenyl borate (2APB) and heat. Thermal selection behavior and heat-evoked withdrawal behavior of naive mice overexpressing TRPV3 were not consistently altered. Upon selective pharmacological inhibition of TRPV1 with JNJ-17203212 [corrected], however, the keratinocyte-specific TRPV3 transgenic mice showed increased escape responses to noxious heat relative to their wild-type littermates. Coadministration of the cyclooxygenase inhibitor, ibuprofen, with the TRPV1 antagonist decreased inflammatory thermal hyperalgesia in transgenic but not wild-type animals. Our results reveal a previously undescribed mechanism for keratinocyte participation in thermal pain transduction through keratinocyte TRPV3 ion channels and the intercellular messenger PGE(2).

  9. Transient receptor potential ankyrin 1 activation enhances hapten sensitization in a T-helper type 2-driven fluorescein isothiocyanate-induced contact hypersensitivity mouse model

    SciTech Connect

    Shiba, Takahiro; Tamai, Takuma; Sahara, Yurina; Kurohane, Kohta; Watanabe, Tatsuo; Imai, Yasuyuki

    2012-11-01

    Some chemicals contribute to the development of allergies by increasing the immunogenicity of other allergens. We have demonstrated that several phthalate esters, including dibutyl phthalate (DBP), enhance skin sensitization to fluorescein isothiocyanate (FITC) in a mouse contact hypersensitivity model, in which the T-helper type 2 (Th2) response is essential. On the other hand, some phthalate esters were found to activate transient receptor potential ankyrin 1 (TRPA1) cation channels on sensory neurons. We then found a positive correlation between the enhancing effects of several types of phthalate esters on skin sensitization to FITC and their ability to activate TRPA1. Here we examined the involvement of TRPA1 in sensitization to FITC by using TRPA1 agonists other than phthalate esters. During skin sensitization to FITC, the TRPA1 agonists (menthol, carvacrol, cinnamaldehyde and DBP) augmented the ear-swelling response as well as trafficking of FITC-presenting dendritic cells to draining lymph nodes. We confirmed that these TRPA1 agonists induced calcium influx into TRPA1-expressing Chinese hamster ovary (CHO) cells. We also found that TRPA1 antagonist HC-030031 inhibited DBP-induced calcium influx into TRPA1-expressing CHO cells. After pretreatment with this antagonist upon skin sensitization to FITC, the enhancing effect of DBP on sensitization was suppressed. These results suggest that TRPA1 activation will become a useful marker to find chemicals that facilitate sensitization in combination with other immunogenic haptens. -- Highlights: ► Role of TRPA1 activation was revealed in a mouse model of skin sensitization to FITC. ► TRPA1 agonists enhanced skin sensitization as well as dendritic cell trafficking. ► Dibutyl phthalate (DBP) has been shown to enhance skin sensitization to FITC. ► TRPA1 activation by DBP was inhibited by a selective antagonist, HC-030031. ► HC-030031 inhibited the enhancing effect of DBP on skin sensitization to FITC.

  10. Gradual training reduces practice difficulty while preserving motor learning of a novel locomotor task.

    PubMed

    Sawers, Andrew; Hahn, Michael E

    2013-08-01

    Motor learning strategies that increase practice difficulty and the size of movement errors are thought to facilitate motor learning. In contrast to this, gradual training minimizes movement errors and reduces practice difficulty by incrementally introducing task requirements, yet remains as effective as sudden training and its large movement errors for learning novel reaching tasks. While attractive as a locomotor rehabilitation strategy, it remains unknown whether the efficacy of gradual training extends to learning locomotor tasks and their unique requirements. The influence of gradual vs. sudden training on learning a locomotor task, asymmetric split belt treadmill walking, was examined by assessing whole body sagittal plane kinematics during 24 hour retention and transfer performance following either gradual or sudden training. Despite less difficult and less specific practice for the gradual cohort on day 1, gradual training resulted in equivalent motor learning of the novel locomotor task as sudden training when assessed by retention and transfer a day later. This suggests that large movement errors and increased practice difficulty may not be necessary for learning novel locomotor tasks. Further, gradual training may present a viable locomotor rehabilitation strategy avoiding large movement errors that could limit or impair improvements in locomotor performance.

  11. Evaluation of the interaction of mu and kappa opioid agonists on locomotor behavior in the horse.

    PubMed Central

    Mama, K R; Pascoe, P J; Steffey, E P

    1993-01-01

    This study was designed to determine the interactive effects of mu and kappa opioid agonists on locomotor behavior in the horse. Three doses of a mu agonist, fentanyl (5, 10, 20 micrograms/kg) and a kappa agonist U50,488H (30, 60, 120 micrograms/kg) were administered in a random order to six horses. Locomotor activity was measured using a two minute footstep count. Each dose of U50,488H was then combined with 20 micrograms/kg of fentanyl to determine the interactive effects of the drugs on locomotor activity. A significant increase in locomotor activity was seen with 20 micrograms/kg of fentanyl and all the drug combinations. The combination of U50,488H with fentanyl resulted in an earlier onset of locomotor activity. At the highest doses of the combination (U50,488H 120 micrograms/kg, fentanyl 20 micrograms/kg), the duration of locomotor activity was significantly increased when compared to the other doses. We conclude that locomotor activity is maintained or enhanced in horses when a receptor specific kappa agonist is combined with a mu receptor agonist. PMID:8490803

  12. Locomotor recovery after spinal cord contusion injury in rats is improved by spontaneous exercise.

    PubMed

    Van Meeteren, Nico L U; Eggers, Ruben; Lankhorst, Alex J; Gispen, Willem Hendrik; Hamers, Frank P T

    2003-10-01

    We have recently shown that enriched environment (EE) housing significantly enhances locomotor recovery following spinal cord contusion injury (SCI) in rats. As the type and intensity of locomotor training with EE housing are rather poorly characterized, we decided to compare the effectiveness of EE housing with that of voluntary wheel running, the latter of which is both well characterized and easily quantified. Female Wistar rats were made familiar with three types of housing conditions, social housing (nine together) in an EE (EHC), individual housing in a running wheel cage (RUN, n = 8), and standard housing two together (CON, n = 10). Subsequently, a 12.5 gcm SCI at Th8 was produced and animals were randomly divided over the three housing conditions. Locomotor function was measured regularly, once a week by means of the BBB score, BBB sub score, TLH test, Gridwalk test, and CatWalk test. In the RUN group, daily distance covered was also measured. Locomotor recovery in the EHC and the RUN groups was equal and significantly better than in the CON group. The extent of recovery at 8 weeks post injury in the RUN group did not correlate with distance covered. We conclude that locomotor training needs to exceed a given threshold in order to be effective in enhancing locomotor recovery in this experimental model, but that once this threshold is exceeded no further improvement occurs, and that the specificity of locomotor training plays little role.

  13. High-speed video gait analysis reveals early and characteristic locomotor phenotypes in mouse models of neurodegenerative movement disorders.

    PubMed

    Preisig, Daniel F; Kulic, Luka; Krüger, Maik; Wirth, Fabian; McAfoose, Jordan; Späni, Claudia; Gantenbein, Pascal; Derungs, Rebecca; Nitsch, Roger M; Welt, Tobias

    2016-09-15

    Neurodegenerative diseases of the central nervous system frequently affect the locomotor system resulting in impaired movement and gait. In this study we performed a whole-body high-speed video gait analysis in three different mouse lines of neurodegenerative movement disorders to investigate the motor phenotype. Based on precise computerized motion tracking of all relevant joints and the tail, a custom-developed algorithm generated individual and comprehensive locomotor profiles consisting of 164 spatial and temporal parameters. Gait changes observed in the three models corresponded closely to the classical clinical symptoms described in these disorders: Muscle atrophy due to motor neuron loss in SOD1 G93A transgenic mice led to gait characterized by changes in hind-limb movement and positioning. In contrast, locomotion in huntingtin N171-82Q mice modeling Huntington's disease with basal ganglia damage was defined by hyperkinetic limb movements and rigidity of the trunk. Harlequin mutant mice modeling cerebellar degeneration showed gait instability and extensive changes in limb positioning. Moreover, model specific gait parameters were identified and were shown to be more sensitive than conventional motor tests. Altogether, this technique provides new opportunities to decipher underlying disease mechanisms and test novel therapeutic approaches.

  14. Diurnal changes in the synthesis of the neurosteroid 7alpha-hydroxypregnenolone stimulating locomotor activity in newts.

    PubMed

    Koyama, Teppei; Haraguchi, Shogo; Vaudry, Hubert; Tsutsui, Kazuyoshi

    2009-04-01

    We recently identified 7alpha-hydroxypregnenolone as a novel amphibian neurosteroid stimulating locomotor activity in newts. Because male newts show marked diurnal changes in locomotor activity, we hypothesized that 7alpha-hydroxypregnenolone may be a key factor for the induction of diurnal changes in locomotor activity in male newts. In this study, we found diurnal changes in 7alpha-hydroxypregnenolone synthesis in the brain of male newts, which paralleled locomotor activity. Interestingly, the production of 7alpha-hydroxypregnenolone in the male newt brain increased during the dark phase when locomotor activity of males was high.

  15. Spontaneous alternation and locomotor activity in three species of marine crabs: green crab (Carcinus maenas), blue crab (Callinectes sapidus), and fiddler crab (Uca pugnax).

    PubMed

    Balcı, Fuat; Ramey-Balcı, Patricia A; Ruamps, Perrine

    2014-02-01

    Spontaneous alternation refers to the tendency of organisms to explore places that they have least recently visited. Our previous work showed that alternation performance of Carcinus maenas (invasive European green crab) was significantly higher than Callinectes sapidus (native blue crab), and chance level performance (Ramey, P. A., Teichman, E., Oleksiak, J., & Balcı, F. [2009]. Spontaneous alternation in marine crabs: Invasive versus native species. Behavioural Processes, 82, 51-55.). In the current study, we first tested the robustness of these findings in the absence of visual cues, longer test durations, and wider maze dimensions. These manipulations enabled us to determine whether these two crab species relied on the visual cues provided during the spontaneous alternation task in our prior work, and allowed for better characterization of their exploratory activity in the maze. Our original findings were reproduced in the present study under these new task conditions, suggesting no role for visual cues during alternation, and emphasizing the robustness and generalizability of the corresponding interspecies differences in alternation performance. We also tested whether the lower alternation performance of C. sapidus also applied to another native crab species, Uca pugnax (fiddler crab). Spontaneous alternation performance of U. pugnax was significantly lower than C. maenas but indistinguishable from C. sapidus. Finally, we examined whether the potentially higher inherent risk-sensitivity of C. sapidus could have contributed to their lower alternation performance by testing C. maenas in the presence of a larger natural predator (stressor). Higher risk sensitivity presumably induced by the stressor led to locomotor activity patterns that better resembled those of C. sapidus, however the resultant reduction in alternation performance was not statistically significant.

  16. THP-1 monocytes but not macrophages as a potential alternative for CD34{sup +} dendritic cells to identify chemical skin sensitizers

    SciTech Connect

    Lambrechts, Nathalie Verstraelen, Sandra Lodewyckx, Hanne; Felicio, Ana; Hooyberghs, Jef; Witters, Hilda; Tendeloo, Viggo van; Cauwenberge, Paul van; Nelissen, Inge; Heuvel, Rosette van den; Schoeters, Greet

    2009-04-15

    Early detection of the sensitizing potential of chemicals is an emerging issue for chemical, pharmaceutical and cosmetic industries. In our institute, an in vitro classification model for prediction of chemical-induced skin sensitization based on gene expression signatures in human CD34{sup +} progenitor-derived dendritic cells (DC) has been developed. This primary cell model is able to closely mimic the induction phase of sensitization by Langerhans cells in the skin, but it has drawbacks, such as the availability of cord blood. The aim of this study was to investigate whether human in vitro cultured THP-1 monocytes or macrophages display a similar expression profile for 13 predictive gene markers previously identified in DC and whether they also possess a discriminating capacity towards skin sensitizers and non-sensitizers based on these marker genes. To this end, the cell models were exposed to 5 skin sensitizers (ammonium hexachloroplatinate IV, 1-chloro-2,4-dinitrobenzene, eugenol, para-phenylenediamine, and tetramethylthiuram disulfide) and 5 non-sensitizers (L-glutamic acid, methyl salicylate, sodium dodecyl sulfate, tributyltin chloride, and zinc sulfate) for 6, 10, and 24 h, and mRNA expression of the 13 genes was analyzed using real-time RT-PCR. The transcriptional response of 7 out of 13 genes in THP-1 monocytes was significantly correlated with DC, whereas only 2 out of 13 genes in THP-1 macrophages. After a cross-validation of a discriminant analysis of the gene expression profiles in the THP-1 monocytes, this cell model demonstrated to also have a capacity to distinguish skin sensitizers from non-sensitizers. However, the DC model was superior to the monocyte model for discrimination of (non-)sensitizing chemicals.

  17. Locomotor Stimulant and Rewarding Effects of Inhaling Methamphetamine, MDPV, and Mephedrone via Electronic Cigarette-Type Technology.

    PubMed

    Nguyen, Jacques D; Aarde, Shawn M; Cole, Maury; Vandewater, Sophia A; Grant, Yanabel; Taffe, Michael A

    2016-10-01

    Although inhaled exposure to drugs is a prevalent route of administration for human substance abusers, preclinical models that incorporate inhaled exposure to psychomotor stimulants are not commonly available. Using a novel method that incorporates electronic cigarette-type technology to facilitate inhalation, male Wistar rats were exposed to vaporized methamphetamine (MA), 3,4-methylenedioxypyrovalerone (MDPV), and mephedrone (4-methylmethcathinone) in propylene glycol vehicle using concentrations ranging from 12.5 to 200 mg/ml. Rats exhibited increases in spontaneous locomotor activity, measured by implanted radiotelemetry, following exposure to methamphetamine (12.5 and 100 mg/ml), MDPV (25, 50, and 100 mg/ml), and mephedrone (200 mg/ml). Locomotor effects were blocked by pretreatment with the dopamine D1-like receptor antagonist SCH23390 (10 μg/kg, intraperitoneal (i.p.)). MA and MDPV vapor inhalation also altered activity on a running wheel in a biphasic manner. An additional group of rats was trained on a discrete trial intracranial self-stimulation (ICSS) procedure interpreted to assess brain reward status. ICSS-trained rats that received vaporized MA, MDPV, or mephedrone exhibited a significant reduction in threshold of ICSS reward compared with vehicle. The effect of vapor inhalation of the stimulants was found comparable to the locomotor and ICSS threshold-reducing effects of i.p. injection of mephedrone (5.0 mg/kg), MA (0.5-1.0 mg/kg), or MDPV (0.5-1.0 mg/kg). These data provide robust validation of e-cigarette-type technology as a model for inhaled delivery of vaporized psychostimulants. Finally, these studies demonstrate the potential for human use of e-cigarettes to facilitate covert use of a range of psychoactive stimulants. Thus, these devices pose health risks beyond their intended application for the delivery of nicotine.

  18. Electrophysiological characterization of V2a interneurons and their locomotor-related activity in the neonatal mouse spinal cord.

    PubMed

    Zhong, Guisheng; Droho, Steven; Crone, Steven A; Dietz, Shelby; Kwan, Alex C; Webb, Watt W; Sharma, Kamal; Harris-Warrick, Ronald M

    2010-01-06

    The V2a class of Chx10-expressing interneurons has been implicated in frequency-dependent control of left-right phase during locomotion in the mouse. We have used the Chx10::CFP mouse line to further investigate the properties and locomotion-related activity of V2a interneurons in the isolated neonatal spinal cord. V2a interneurons can be divided into three classes, based on their tonic, phasic, or delayed-onset responses to step depolarization. Electrical coupling is found only between neurons of same class and helps to synchronize neuronal activity within the class. Serotonin (5-HT) excites isolated tonic V2a interneurons by depolarizing the neurons and increasing their membrane input resistance, with no significant effects on action potential properties, a mechanism distinct from 5-HT excitation of commissural interneurons. During NMDA-/5-HT-induced locomotor-like activity, patch-clamp recordings and two-photon calcium imaging experiments show that approximately half of V2a interneurons fire rhythmically with ventral root-recorded motor activity; the rhythmic V2a interneurons fired during one half of the cycle, in phase with either the ipsilateral or the contralateral L2 ventral root bursts. The percentage of rhythmically firing V2a interneurons increases during higher-frequency fictive locomotion, and they become significantly more rhythmic in their firing during the locomotor cycle; this may help to explain the frequency-dependent shift in left-right coupling in Chx10::DTA mice, which lack these neurons. Our results together with data from the accompanying paper (Dougherty and Kiehn, 2009) reinforce earlier proposals that the V2a interneurons are components of the hindlimb central pattern generator, helping to organize left-right locomotor coordination in the neonatal mouse spinal cord.

  19. Ontogeny of joint mechanics in squirrel monkeys (Saimiri boliviensis): functional implications for mammalian limb growth and locomotor development

    PubMed Central

    Young, Jesse W.

    2009-01-01

    Summary Juvenile animals must often compete against adults for common resources, keep pace during group travel and evade common predators, despite reduced body size and an immature musculoskeletal system. Previous morphometric studies of a diverse array of mammals, including jack rabbits, cats and capuchin monkeys, have identified growth-related changes in anatomy, such as negative allometry of limb muscle mechanical advantage, which should theoretically permit young mammals to overcome such ontogenetic limits on performance. However, it is important to evaluate the potential impact of such `compensatory' growth trajectories within the context of developmental changes in locomotor behavior. I used standard kinematic and kinetic techniques to investigate the ontogenetic scaling of joint postures, substrate reaction forces, joint load arm lengths and external joint moments in an ontogenetic sample of squirrel monkeys (Saimiri boliviensis). Results indicated that young squirrel monkeys were frequently able to limit forelimb and hind limb joint loading via a combination of changes in limb posture and limb force distribution, potentially compensating for limited muscularity at younger ages. These results complement previous morphometric studies and suggest that immature mammals may utilize a combination of behavioral and anatomical mechanisms to mitigate ontogenetic limits on locomotor performance. However, ontogenetic changes in joint posture, not limb length per se, explained most of the variation in load arm lengths and joint loading in growing squirrel monkeys, indicating the importance of incorporating both anatomical and performance measures when studying the ontogeny of limb joint mechanics. PMID:19411552

  20. Different Contribution of Redox-Sensitive Transient Receptor Potential Channels to Acetaminophen-Induced Death of Human Hepatoma Cell Line

    PubMed Central

    Badr, Heba; Kozai, Daisuke; Sakaguchi, Reiko; Numata, Tomohiro; Mori, Yasuo

    2016-01-01

    Acetaminophen (APAP) is a safe analgesic antipyretic drug at prescribed doses. Its overdose, however, can cause life-threatening liver damage. Though, involvement of oxidative stress is widely acknowledged in APAP-induced hepatocellular death, the mechanism of this increased oxidative stress and the associated alterations in Ca2+ homeostasis are still unclear. Among members of transient receptor potential (TRP) channels activated in response to oxidative stress, we here identify that redox-sensitive TRPV1, TRPC1, TRPM2, and TRPM7 channels underlie Ca2+ entry and downstream cellular damages induced by APAP in human hepatoma (HepG2) cells. Our data indicate that APAP treatment of HepG2 cells resulted in increased reactive oxygen species (ROS) production, glutathione (GSH) depletion, and Ca2+ entry leading to increased apoptotic cell death. These responses were significantly suppressed by pretreatment with the ROS scavengers N-acetyl-L-cysteine (NAC) and 4,5-dihydroxy-1,3-benzene disulfonic acid disodium salt monohydrate (Tiron), and also by preincubation of cells with the glutathione inducer Dimethylfumarate (DMF). TRP subtype-targeted pharmacological blockers and siRNAs strategy revealed that suppression of either TRPV1, TRPC1, TRPM2, or TRPM7 reduced APAP-induced ROS formation, Ca2+ influx, and cell death; the effects of suppression of TRPV1 or TRPC1, known to be activated by oxidative cysteine modifications, were stronger than those of TRPM2 or TRPM7. Interestingly, TRPV1 and TRPC1 were labeled by the cysteine-selective modification reagent, 5,5′-dithiobis (2-nitrobenzoic acid)-2biotin (DTNB-2Bio), and this was attenuated by pretreatment with APAP, suggesting that APAP and/or its oxidized metabolites act directly on the modification target cysteine residues of TRPV1 and TRPC1 proteins. In human liver tissue, TRPV1, TRPC1, TRPM2, and TRPM7 channels transcripts were localized mainly to hepatocytes and Kupffer cells. Our findings strongly suggest that APAP

  1. The Potential Of Geomatics In The Realization Of A Map Of Desertification Sensitivity Southern Massif Belezma - Batna - (Algeria)

    NASA Astrophysics Data System (ADS)

    Benmessaoud, H.; Chergui, F.; Sahnouni, R.; Chafai, C.

    2015-04-01

    Desertification is the gradual and sustained reduction in the quantity and quality of the biological productivity of arid and semi-arid land. The study area is located in the North Eastern part of Algeria, it has a rich heritage in its biodiversity, however weather conditions and adverse human reality, induce a degradation of the physical environment in the form of a regression of vegetation cover. To assess desertification in our study area map of desertification sensitivity is a tool for decision support. For the realization of this Map we used the ArcGis software applied a methodology which is inspired by the concept MEDALUS (Mediterranean Desertification and Land Use, 1999) by crossing four thematic layers that may have an impact on the process of desertification. The results of Cartography and statistical analysis permit the classification of our region in terms of sensitivity to desertification in four very important classes. (Not affected, Insensitive, Sensitive and highly sensitive). More than 69.92% of the surface area were classified sensitive to very sensitive, For against 30.07% is classified in unallocated insensitive. Planning restoration work and the fight against desertification are expected to limit the risk of desertification in the study area perspectives.

  2. A dual-potential electrochemiluminescence ratiometric approach based on graphene quantum dots and luminol for highly sensitive detection of protein kinase activity.

    PubMed

    Zhao, Hui-Fang; Liang, Ru-Ping; Wang, Jing-Wu; Qiu, Jian-Ding

    2015-08-14

    A novel Au NP mediated dual-potential ECL ratiometric approach for highly sensitive protein kinase activity and inhibition assay has been developed based on the simultaneous decrease of cathodic ECL from GQDs and enhancement of anodic ECL from luminol in the same bioanalysis.

  3. Watershed Modeling to Assess the Sensitivity of Streamflow, Nutrient, and Sediment Loads to Potential Climate Change and Urban Development in 20 U.S. Watersheds (Final Report)

    EPA Science Inventory

    In September 2013, EPA announced the release of the final report, Watershed Modeling to Assess the Sensitivity of Streamflow, Nutrient, and Sediment Loads to Potential Climate Change and Urban Development in 20 U.S. Watersheds.

    Watershed modeling was conducted in ...

  4. Watershed Modeling to Assess the Sensitivity of Streamflow, Nutrient, and Sediment Loads to Potential Climate Change and Urban Development in 20 U.S. Watersheds (External Review Draft)

    EPA Science Inventory

    EPA has released for independent external peer review and public comment a draft report titled, Watershed Modeling to Assess the Sensitivity of Streamflow, Nutrient, and Sediment Loads to Potential Climate Change and Urban Development in 20 U.S. Watersheds. This is a draft...

  5. Sensitization of locomotion following repeated ventral tegmental injections of cytisine.

    PubMed

    Museo, E; Wise, R A

    1994-06-01

    Systemic injections of nicotine increase locomotion, and repeating these injections brings about a sensitization of the locomotor response. Ventral tegmental injections of the nicotinic agonist cytisine also increase locomotion. In the present study cytisine was administered repeatedly into the ventral tegmentum to determine whether sensitization of its locomotor-activating effects would develop. Four groups of animals were tested; each group received a total of six injections at a rate of one injection every 48 h. Two of these groups received injections of cytisine (10 nmol/side): one group received injections into the ventral tegmentum, and, to insure the anatomical specificity of the locomotor effect, a second group received injections dorsal to the ventral tegmentum. The remaining two groups received vehicle injections: one group received injections into the ventral tegmentum, and the other received injections into more dorsal sites. The group of animals that received injections of cytisine into the ventral tegmentum locomoted more than any other group. In addition, only with this group was a progressive increase in the locomotor response evident across test days. These findings raise the possibility that a neural substrate in the ventral tegmentum mediates the locomotor-activating and sensitizing effects associated with the systemic administration of nicotine.

  6. Hepatic mTORC1 controls locomotor activity, body temperature, and lipid metabolism through FGF21.

    PubMed

    Cornu, Marion; Oppliger, Wolfgang; Albert, Verena; Robitaille, Aaron M; Trapani, Francesca; Quagliata, Luca; Fuhrer, Tobias; Sauer, Uwe; Terracciano, Luigi; Hall, Michael N

    2014-08-12

    The liver is a key metabolic organ that controls whole-body physiology in response to nutrient availability. Mammalian target of rapamycin (mTOR) is a nutrient-activated kinase and central controller of growth and metabolism that is negatively regulated by the tumor suppressor tuberous sclerosis complex 1 (TSC1). To investigate the role of hepatic mTOR complex 1 (mTORC1) in whole-body physiology, we generated liver-specific Tsc1 (L-Tsc1 KO) knockout mice. L-Tsc1 KO mice displayed reduced locomotor activity, body temperature, and hepatic triglyceride content in a rapamycin-sensitive manner. Ectopic activation of mTORC1 also caused depletion of hepatic and plasma glutamine, leading to peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α)-dependent fibroblast growth factor 21 (FGF21) expression in the liver. Injection of glutamine or knockdown of PGC-1α or FGF21 in the liver suppressed the behavioral and metabolic defects due to mTORC1 activation. Thus, mTORC1 in the liver controls whole-body physiology through PGC-1α and FGF21. Finally, mTORC1 signaling correlated with FGF21 expression in human liver tumors, suggesting that treatment of glutamine-addicted cancers with mTOR inhibitors might have beneficial effects at both the tumor and whole-body level.

  7. Hepatic mTORC1 controls locomotor activity, body temperature, and lipid metabolism through FGF21

    PubMed Central

    Cornu, Marion; Oppliger, Wolfgang; Albert, Verena; Robitaille, Aaron M.; Trapani, Francesca; Quagliata, Luca; Fuhrer, Tobias; Sauer, Uwe; Terracciano, Luigi; Hall, Michael N.

    2014-01-01

    The liver is a key metabolic organ that controls whole-body physiology in response to nutrient availability. Mammalian target of rapamycin (mTOR) is a nutrient-activated kinase and central controller of growth and metabolism that is negatively regulated by the tumor suppressor tuberous sclerosis complex 1 (TSC1). To investigate the role of hepatic mTOR complex 1 (mTORC1) in whole-body physiology, we generated liver-specific Tsc1 (L-Tsc1 KO) knockout mice. L-Tsc1 KO mice displayed reduced locomotor activity, body temperature, and hepatic triglyceride content in a rapamycin-sensitive manner. Ectopic activation of mTORC1 also caused depletion of hepatic and plasma glutamine, leading to peroxisome proliferator–activated receptor γ coactivator-1α (PGC-1α)–dependent fibroblast growth factor 21 (FGF21) expression in the liver. Injection of glutamine or knockdown of PGC-1α or FGF21 in the liver suppressed the behavioral and metabolic defects due to mTORC1 activation. Thus, mTORC1 in the liver controls whole-body physiology through PGC-1α and FGF21. Finally, mTORC1 signaling correlated with FGF21 expression in human liver tumors, suggesting that treatment of glutamine-addicted cancers with mTOR inhibitors might have beneficial effects at both the tumor and whole-body level. PMID:25082895

  8. Dopamine neurotransmission is involved in the attenuating effects of 5-HT3 receptor antagonist MDL 72222 on acute methamphetamine-induced locomotor hyperactivity in mice.

    PubMed

    Yoo, Ji-Hoon; Nam, Yun-Sun; Lee, Seok-Yong; Jang, Choon-Gon

    2008-01-01

    We have previously shown that 5-HT3 receptors are involved in the development and expression of methamphetamine (MAP)-induced locomotor sensitization in mice. In the present study, we further examined whether the dopaminergic system is involved in the attenuating effects of MDL 72222, a 5-HT3 receptor antagonist, on acute MAP-induced locomotor hyperactivity. For this, we examined alterations of dopamine (DA) in the form of D1 receptor, D2 receptor, and dopamine transporter (DAT) binding labeled with [3H]SCH23390 for D1, [3H]raclopride for D2, and [3H]mazindol for DAT binding in the mouse brains with acute MAP exposure or pretreatment of MDL 72222 with MAP. No significant differences were detected in the D1 receptor, D2 receptor, or DAT binding between any of the groups studied. Interestingly, we found increased DA levels in the striatum following acute MAP exposure; these increased levels were reversed by pretreatment with MDL 72222, but did not affect 5-HT levels in the dorsal raphe. Overall, our results suggest that dopamine neurotransmission plays an important role in the attenuating effects of 5-HT3 receptor antagonist MDL 72222 on acute MAP-induced locomotor hyperactivity in mice.

  9. Novel technology for modulating locomotor activity as an operant response in the mouse: implications for neuroscience studies involving "exercise" in rodents.

    PubMed

    Fantegrossi, William E; Xiao, Wendy R; Zimmerman, Sarah M

    2013-01-30

    We have developed a novel, low-cost device designed to monitor and modulate locomotor activity in murine subjects. This technology has immediate application to the study of effects of physical exercise on various neurobiological endpoints, and will also likely be useful in the study of psychomotor sensitization and drug addiction. Here we demonstrate the capacity of these devices to establish locomotor activity as an operant response reinforced by food pellet presentations, and show that schedules of reinforcement can reliably control this behavior. Importantly, these data show that varying degrees of increased locomotor activity (in other words, "exercise") can be elicited and maintained in mice by manipulating the schedule of reinforcement. Our findings argue that the present technology might reduce the imposition of stress and motivational bias inherent in more traditional procedures for establishing exercise in laboratory rodents, while allowing for true random assignment to experimental groups. As interest in physical exercise as a modulating factor in numerous clinical conditions continues to grow, technologies like the one proposed here are likely to become critical in conducting future experiments along these lines.

  10. Evaluation of the sensitizing potential of antibiotics in vitro using the human cell lines THP-1 and MUTZ-LC and primary monocyte‐derived dendritic cells

    SciTech Connect

    Sebastian, Katrin; Ott, Hagen; Zwadlo-Klarwasser, Gabriele; Skazik-Voogt, Claudia; Marquardt, Yvonne; Czaja, Katharina; Merk, Hans F.; Baron, Jens Malte

    2012-08-01

    Since the 7th amendment to the EU cosmetics directive foresees a complete ban on animal testing, alternative in vitro methods have been established to evaluate the sensitizing potential of small molecular weight compounds. To find out whether these novel in vitro assays are also capable to predict the sensitizing potential of small molecular weight drugs, model compounds such as beta-lactams and sulfonamides – which are the most frequent cause of adverse drug reactions – were co-incubated with THP-1, MUTZ-LC, or primary monocyte‐derived dendritic cells for 48 h and subsequent expression of selected marker genes (IL-8, IL-1β, CES1, NQO1, GCLM, PIR and TRIM16) was studied by real time PCR. Benzylpenicillin and phenoxymethylpenicillin were recognized as sensitizing compounds because they are capable to induce the mRNA expression of these genes in moDCs and, except for IL-8, in THP-1 cells but not in MUTZ-LC. Ampicillin stimulated the expression of some marker genes in moDCs and THP-1 cells. SMX did not affect the expression of these genes in THP-1, however, in moDCs, at least PIR was enhanced and there was an increase of the release of IL-8. These data reveal that novel in vitro DC based assays might play a role in the evaluation of the allergenic potential of novel drug compounds, but these systems seem to lack the ability to detect the sensitizing potential of prohaptens that require metabolic activation prior to sensitization and moDCs seem to be superior with regard to the sensitivity compared with THP-1 and MUTZ-3 cell lines. -- Highlights: ► We tested the sensitizing potential of small molecular weight drugs in vitro. ► In vitro assays were performed with moDCs and THP-1 cells. ► Beta-lactam antibiotics can be recognized as sensitizing compounds. ► They affect the expression of metabolic enzymes, cytokines and transcription factors. ► Sulfamethoxazole has no measurable effect on THP-1 cells and moDCs.

  11. Locomotor activity and tissue levels following acute administration of lambda- and gamma-cyhalothrin in rats

    EPA Science Inventory

    Pyrethroids produce neurotoxicity that depends, in part, on the chemical structure. Common behavioral effects include locomotor activity changes and specific toxic syndromes (types I and II). In general these neurobehavioral effects correlate well with peak internal dose metric...

  12. Muscle spindle feedback directs locomotor recovery and circuit reorganization after spinal cord injury.

    PubMed

    Takeoka, Aya; Vollenweider, Isabel; Courtine, Grégoire; Arber, Silvia

    2014-12-18

    Spinal cord injuries alter motor function by disconnecting neural circuits above and below the lesion, rendering sensory inputs a primary source of direct external drive to neuronal networks caudal to the injury. Here, we studied mice lacking functional muscle spindle feedback to determine the role of this sensory channel in gait control and locomotor recovery after spinal cord injury. High-resolution kinematic analysis of intact mutant mice revealed proficient execution in basic locomotor tasks but poor performance in a precision task. After injury, wild-type mice spontaneously recovered basic locomotor function, whereas mice with deficient muscle spindle feedback failed to regain control over the hindlimb on the lesioned side. Virus-mediated tracing demonstrated that mutant mice exhibit defective rearrangements of descending circuits projecting to deprived spinal segments during recovery. Our findings reveal an essential role for muscle spindle feedback in directing basic locomotor recovery and facilitating circuit reorganization after spinal cord injury.

  13. Prenatal Iron Deficiency in Guinea Pigs Increases Locomotor Activity but Does Not Influence Learning and Memory.

    PubMed

    Fiset, Catherine; Rioux, France M; Surette, Marc E; Fiset, Sylvain

    2015-01-01

    The objective of the current study was to determine whether prenatal iron deficiency induced during gestation in guinea pigs affected locomotor activity and learning and memory processes in the progeny. Dams were fed either iron-deficient anemic or iron-sufficient diets throughout gestation and lactation. After weaning, all pups were fed an iron-sufficient diet. On postnatal day 24 and 40, the pups' locomotor activity was observed within an open-field test, and from postnatal day 25 to 40, their learning and memory processes were assessed within a Morris Water Maze. The behavioural and cognitive tests revealed that the iron deficient pup group had increased locomotor activity, but solely on postnatal day 40, and that there were no group differences in the Morris Water Maze. In the general discussion, we propose that prenatal iron deficiency induces an increase in nervousness due to anxiety in the progeny, which, in the current study, resulted in an increase of locomotor activity.

  14. Medial hypothalamic 5-hydroxytryptamine (5-HT)1A receptors regulate neuroendocrine responses to stress and exploratory locomotor activity: application of recombinant adenovirus containing 5-HT1A sequences.

    PubMed

    Li, Qian; Holmes, Andrew; Ma, Li; Van de Kar, Louis D; Garcia, Francisca; Murphy, Dennis L

    2004-12-01

    Our previous studies found that serotonin transporter (SERT) knock-out mice showed increased sensitivity to minor stress and increased anxiety-like behavior but reduced locomotor activity. These mice also showed decreased density of 5-hydroxytryptamine (5-HT1A) receptors in the hypothalamus, amygdala, and dorsal raphe. To evaluate the contribution of hypothalamic 5-HT1A receptors to these phenotypes of SERT knock-out mice, two studies were conducted. Recombinant adenoviruses containing 5-HT1A sense and antisense sequences (Ad-1AP-sense and Ad-1AP-antisense) were used to manipulate 5-HT1A receptors in the hypothalamus. The expression of the 5-HT1A genes is controlled by the 5-HT1A promoter, so that they are only expressed in 5-HT1A receptor-containing cells. (1) Injection of Ad-1AP-sense into the hypothalamus of SERT knock-out mice restored 5-HT1A receptors in the medial hypothalamus; this effect was accompanied by elimination of the exaggerated adrenocorticotropin responses to a saline injection (minor stress) and reduced locomotor activity but not by a change in increased exploratory anxiety-like behavior. (2) To further confirm the observation in SERT-/- mice, Ad-1AP-antisense was injected into the hypothalamus of normal mice. The density and the function of 5-HT1A receptors in the medial hypothalamus were significantly reduced in Ad-1AP-antisense-treated mice. Compared with the control group (injected with Ad-track), Ad-1A-antisense-treated mice showed a significant reduction in locomotor activity, but again no changes in exploratory anxiety-like behaviors, tested by elevated plus-maze and open-field tests. Thus, the present results demonstrate that medial hypothalamic 5-HT1A receptors regulate stress responses and locomotor activity but may not regulate exploratory anxiety-like behaviors.

  15. A strong and stretchable self-healing film with self-activated pressure sensitivity for potential artificial skin applications

    PubMed Central

    Hou, Chengyi; Huang, Tao; Wang, Hongzhi; Yu, Hao; Zhang, Qinghong; Li, Yaogang

    2013-01-01

    Artificial skin, which mimics the functions of natural skin, will be very important in the future for robots used by humans in daily life. However, combining skin's pressure sensitivity and mechanical self-healing properties in a man-made material remains a challenging task. Here, we show that graphene and polymers can be integrated into a thin film which mimics both the mechanical self-healing and pressure sensitivity behavior of natural skin without any external power supply. Its ultimate strain and tensile strength are even two and ten times larger than the corresponding values of human skin, respectively. It also demonstrates highly stable sensitivity to a very light touch (0.02 kPa), even in bending or stretching states. PMID:24190511

  16. Inbreeding affects locomotor activity in Drosophila melanogaster at different ages.

    PubMed

    Manenti, Tommaso; Pertoldi, Cino; Moghadam, Neda Nasiri; Nasiri, Neda; Schou, Mads Fristrup; Kjærsgaard, Anders; Cavicchi, Sandro; Loeschcke, Volker

    2015-01-01

    The ability to move is essential for many behavioural traits closely related to fitness. Here we studied the effect of inbreeding on locomotor activity (LA) of Drosophila melanogaster at different ages under both dark and light regimes. We expected to find a decreased LA in inbred lines compared to control lines. We also predicted an increased differentiation between lines due to inbreeding. LA was higher in the dark compared to the light regime for both inbred and outbred control lines. As expected, inbreeding increased phenotypic variance in LA, with some inbred lines showing higher and some lower LA than control lines. Moreover, age per se did not affect LA neither in control nor in inbred lines, while we found a strong line by age interaction between inbred lines. Interestingly, inbreeding changed the daily activity pattern of the flies: these patterns were consistent across all control lines but were lost in some inbred lines. The departure in the daily pattern of LA in inbred lines may contribute to the inbreeding depression observed in inbred natural populations.

  17. Remote Control of Respiratory Neural Network by Spinal Locomotor Generators

    PubMed Central

    Le Gal, Jean-Patrick; Juvin, Laurent; Cardoit, Laura; Thoby-Brisson, Muriel; Morin, Didier

    2014-01-01

    During exercise and locomotion, breathing rate rapidly increases to meet the suddenly enhanced oxygen demand. The extent to which direct central interactions between the spinal networks controlling locomotion and the brainstem networks controlling breathing are involved in this rhythm modulation remains unknown. Here, we show that in isolated neonatal rat brainstem-spinal cord preparations, the increase in respiratory rate observed during fictive locomotion is associated with an increase in the excitability of pre-inspiratory neurons of the parafacial respiratory group (pFRG/Pre-I). In addition, this locomotion-induced respiratory rhythm modulation is prevented both by bilateral lesion of the pFRG region and by blockade of neurokinin 1 receptors in the brainstem. Thus, our results assign pFRG/Pre-I neurons a new role as elements of a previously undescribed pathway involved in the functional interaction between respiratory and locomotor networks, an interaction that also involves a substance P-dependent modulating mechanism requiring the activation of neurokinin 1 receptors. This neurogenic mechanism may take an active part in the increased respiratory rhythmicity produced at the onset and during episodes of locomotion in mammals. PMID:24586951

  18. Evolving Hox Activity Profiles Govern Diversity in Locomotor Systems

    PubMed Central

    Jung, Heekyung; Mazzoni, Esteban O.; Soshnikova, Natalia; Hanley, Olivia; Venkatesh, Byrappa; Duboule, Denis; Dasen, Jeremy S.

    2014-01-01

    Summary The emergence of limb-driven locomotor behaviors was a key event in the evolution of vertebrates and fostered the transition from aquatic to terrestrial life. We show that the generation of limb-projecting lateral motor column (LMC) neurons in mice relies on a transcriptional autoregulatory module initiated via transient activity of multiple genes within the HoxA and HoxC clusters. Repression of this module at thoracic levels restricts expression of LMC determinants, thus dictating LMC position relative to the limbs. This suppression is mediated by a key regulatory domain that is specifically found in the Hoxc9 proteins of appendage-bearing vertebrates. The profile of Hoxc9 expression inversely correlates with LMC position in land vertebrates, and likely accounts for the absence of LMC neurons in limbless species such as snakes. Thus, modulation of both Hoxc9 protein function and Hoxc9 gene expression likely contributed to evolutionary transitions between undulatory and ambulatory motor circuit connectivity programs. PMID:24746670

  19. Sex differences in Siberian hamster ultradian locomotor rhythms

    PubMed Central

    Prendergast, Brian J.; Stevenson, Tyler J.; Zucker, Irving

    2014-01-01

    Sex differences in ultradian activity rhythms (URs) and circadian rhythms (CRs) were assessed in Siberian hamsters kept in long day (LD) or short day (SD) photoperiods for 40 weeks. For both sexes URs of locomotor activity were more prevalent, greater in amplitude and more robust in SDs. The UR period was longer in females than males in both day lengths. The reproductive system underwent regression and body mass declined during the initial 10 weeks of SD treatment, and in both sexes these traits spontaneously reverted to the LD phenotype at or before 40 weeks in SD, reflecting the development of neuroendocrine refractoriness to SD patterns of melatonin secretion. Hamsters of both sexes, however, continued to display SD-like URs at the 40 weeks time point. CRs were less prevalent and the waveform less robust and lower in amplitude in SDs than LDs; the SD circadian waveform also did not revert to the long-day phenotype after 40 weeks of SD treatment. Short day lengths enhanced ultradian and diminished circadian rhythms in both sexes. Day length controls several UR characteristics via gonadal steroid and melatonin-independent mechanisms. Sex differences in ultradian timing may contribute to sex diphenisms in rhythms of sleep, food intake and exercise. PMID:23333554

  20. Locomotor behavior of fish hatched from embryos exposed to flight conditions

    NASA Technical Reports Server (NTRS)

    Kleerekoper, H.

    1978-01-01

    Embryos of Fundulus heteroclitus in various stages of development were exposed to space flight conditions aboard Apollo spacecraft and Cosmos satellites. The objective of the study was to ascertain whether fish hatched from these embryos displayed locomotor behavior different from that of control fish of the same age. An electronic monitoring technique was used to record behavior. Results indicate no change in locomotor behavior in fish on Apollo Spacecraft, but inexplicable significant changes were noted in fish aboard Cosmos Satellites.

  1. Effect of locomotor training in completely spinalized cats previously submitted to a spinal hemisection.

    PubMed

    Martinez, Marina; Delivet-Mongrain, Hugo; Leblond, Hugues; Rossignol, Serge

    2012-08-08

    After a spinal hemisection in cats, locomotor plasticity occurring at the spinal level can be revealed by performing, several weeks later, a complete spinalization below the first hemisection. Using this paradigm, we recently demonstrated that the hemisection induces durable changes in the symmetry of locomotor kinematics that persist after spinalization. Can this asymmetry be changed again in the spinal state by interventions such as treadmill locomotor training started within a few days after the spinalization? We performed, in 9 adult cats, a spinal hemisection at thoracic level 10 and then a complete spinalization at T13, 3 weeks later. Cats were not treadmill trained during the hemispinal period. After spinalization, 5 of 9 cats were not trained and served as control while 4 of 9 cats were trained on the treadmill for 20 min, 5 d a week for 3 weeks. Using detailed kinematic analyses, we showed that, without training, the asymmetrical state of locomotion induced by the hemisection was retained durably after the subsequent spinalization. By contrast, training cats after spinalization induced a reversal of the left/right asymmetries, suggesting that new plastic changes occurred within the spinal cord through locomotor training. Moreover, training was shown to improve the kinematic parameters and the performance of the hindlimb on the previously hemisected side. These results indicate that spinal locomotor circuits, previously modified by past experience such as required for adaptation to the hemisection, can remarkably respond to subsequent locomotor training and improve bilateral locomotor kinematics, clearly showing the benefits of locomotor training in the spinal state.

  2. Anatomical and electrophysiological plasticity of locomotor networks following spinal transection in the salamander.

    PubMed

    Cabelguen, Jean-Marie; Chevallier, Stéphanie; Amontieva-Potapova, Ianina; Philippe, Céline

    2013-08-01

    Recovery of locomotor behavior following spinal cord injury can occur spontaneously in some vertebrates, such as fish, urodele amphibians, and certain reptiles. This review provides an overview of the current status of our knowledge on the anatomical and electrophysiological changes occurring within the spinal cord that lead to, or are associated with the re-expression of locomotion in spinally-transected salamanders. A better understanding of these processes will help to devise strategies for restoring locomotor function in mammals, including humans.

  3. Action-potential duration and the modulation of transmitter release from the sensory neurons of Aplysia in presynaptic facilitation and behavioral sensitization.

    PubMed

    Hochner, B; Klein, M; Schacher, S; Kandel, E R

    1986-11-01

    Presynaptic facilitation of transmitter release from Aplysia sensory neurons is an important contributor to behavioral sensitization of the gill and siphon withdrawal reflex. The enhanced release is accompanied by reduction of the serotonin-sensitive S current in the sensory neurons and a consequent increase in duration of the presynaptic action potential (ranging from 10% to 30%). We find that changes of similar magnitude in the duration of depolarizing voltage-clamp steps in sensory neurons in intact abdominal ganglia yield increases in synaptic potentials of 45-120%. In dissociated cell culture, these changes lead to increases of 25-60% in the synaptic potential. Prolongation of presynaptic depolarization using voltage clamp or prolongation of the duration of the action potential by K(+)-channel blockers leads to prolongation of the time-to-peak of the synaptic potentials; similar changes in time-to-peak occur during presynaptic facilitation. The time-to-peak is not changed by homosynaptic depression or by changing the Ca(2+) concentration, procedures that alter release without changing the duration of the action potential. Preventing the spike from broadening by voltage clamping the presynaptic neuron substantially reduces or blocks the facilitation. These results suggest that broadening of the action potential during facilitation is a causal factor in the enhancement of transmitter release.

  4. Sprint sensitivity and locomotor trade-offs in green anole (Anolis carolinensis) lizards.

    PubMed

    Sathe, Erik A; Husak, Jerry F

    2015-07-01

    How well an organism completes an ecologically relevant task - its performance - is often considered a key factor in determining individual fitness. Historically, ecomorphological studies have examined how morphological traits determine individual performance in a static manner, assuming that differential fitness in a population is due indirectly to differences in morphological traits that determine a simple measure of performance. This assumption, however, ignores many ecological factors that can constrain performance in nature, such as substrate variation and individual behavior. We examined some of these complexities in the morphology-performance-fitness paradigm, primarily the impact that substrate variation has on performance. We measured maximal sprint speed of green anole lizards on four substrates that varied in size and complexity and are used by or available to individuals in nature. Performance decreased significantly from a broad substrate to a narrow substrate, and lizards were three times slower on a complex substrate than the broadest substrate. We also detected trade-offs in running on substrates with different diameters and in cluttered versus uncluttered environments. Furthermore, morphological predictors of performance varied among substrates. This indicates that natural selection may act on different morphological traits, depending on which substrates are used by individuals, as well as an individual's ability to cope with changes in substrate rather than maximal capacities.

  5. Progress on the development of human in vitro dendritic cell based assays for assessment of the sensitizing potential of a compound

    SciTech Connect

    Galvao dos Santos, G.; Reinders, J.; Ouwehand, K.; Rustemeyer, T.; Scheper, R.J.; Gibbs, S.

    2009-05-01

    Allergic contact dermatitis is the result of an adaptive immune response of the skin to direct exposure to an allergen. Since many chemicals are also allergens, European regulations require strict screening of all ingredients in consumer products. Until recently, identifying a potential allergen has completely relied on animal testing (e.g.: Local Lymph Node Assay). In addition to the ethical problems, both the 7th Amendment to the Cosmetics Directive and REACH have stimulated the development of alternative tests for the assessment of potential sensitizers. This review is aimed at summarising the progress on cell based assays, in particular dendritic cell based assays, being developed as animal alternatives. Primary cells (CD34{sup +} derived dendritic cells, monocyte derived dendritic cells) as well as dendritic cell-like cell lines (THP-1, U-937, MUTZ-3, KG-1, HL-60, and K562) are extensively described along with biomarkers such as cell surface markers, cytokines, chemokines and kinases. From this review, it can be concluded that no single cell based assay nor single marker is yet able to distinguish all sensitizers from non-sensitizers in a test panel of chemicals, nor is it possible to rank the sensitizing potential of the test chemicals. This suggests that sensitivity and specificity may be increased by a tiered assay approach. Only a limited number of genomic and proteomic studies have been completed until now. Such studies have the potential to identify novel biomarkers for inclusion in future assay development. Although progress is promising, this review suggests that it may be difficult to meet the up and coming European regulatory deadlines.

  6. Relating ranging ecology, limb length, and locomotor economy in terrestrial animals.

    PubMed

    Pontzer, Herman

    2012-03-07

    Ecomorphological analyses have identified a number of important evolutionary trends in vertebrate limb design, but the relationships between daily travel distance, locomotor ecology, and limb length in terrestrial animals remain poorly understood. In this paper I model the net rate of energy intake as a function of foraging efficiency, and thus of locomotor economy; improved economy leads to greater net energy intake. However, the relationship between locomotor economy and net intake is highly dependent on foraging efficiency; only species with low foraging efficiencies experience strong selection pressure for improved locomotor economy and increased limb length. Examining 237 terrestrial species, I find that nearly all taxa obtain sufficiently high foraging efficiencies that selection for further increases in economy is weak. Thus selection pressures for increased economy and limb length among living terrestrial animals may be relatively weak and similar in magnitude across ecologically diverse species. The Economy Selection Pressure model for locomotor economy may be useful in investigating the evolution of limb design in early terrestrial taxa and the coevolution of foraging ecology and locomotor anatomy in lineages with low foraging efficiencies.

  7. Neurochemical factors underlying individual differences in locomotor activity and anxiety-like behavioral responses in zebrafish.

    PubMed

    Tran, Steven; Nowicki, Magda; Muraleetharan, Arrujyan; Chatterjee, Diptendu; Gerlai, Robert

    2016-02-04

    Variation among individuals may arise for several reasons, and may have diverse underlying mechanisms. Individual differences have been studied in a variety of species, but recently a new model organism has emerged in this field that offers both sophistication in phenotypical characterization and powerful mechanistic analysis. Recently, zebrafish, one of the favorites of geneticists, have been shown to exhibit consistent individual differences in baseline locomotor activity. In the current study, we further explore this finding and examine whether individual differences in locomotor activity correlate with anxiety-like behavioral measures and with levels of dopamine, serotonin and the metabolites of these neurotransmitters. In addition, we examine whether individual differences in locomotor activity are also associated with reactivity to the locomotor stimulant effects of and neurochemical responses to acute ethanol exposure (30min long, 1% v/v ethanol bath application). Principal component analyses revealed a strong association among anxiety-like responses, locomotor activity, serotonin and dopamine levels. Furthermore, ethanol exposure was found to abolish the locomotion-dependent anxiety-like behavioral and serotonergic responses suggesting that this drug also engages a common underlying pathway. Overall, our results provide support for an important role of the serotonergic system in mediating individual differences in anxiety-like responses and locomotor activity in zebrafish and for a minor modulatory role of the dopaminergic system.

  8. Reduced Anticipatory Locomotor Responses to Scheduled Meals in Ghrelin Receptor Deficient Mice

    PubMed Central

    Blum, Ian D.; Patterson, Zack; Khazall, Rim; Lamont, Elaine Waddington; Sleeman, Mark W.; Horvath, Tamas L.; Abizaid, Alfonso

    2009-01-01

    Ghrelin, an orexigenic hormone produced by the stomach, is secreted in anticipation of scheduled meals and in correlation with anticipatory locomotor activity. We hypothesized that ghrelin is directly implicated in stimulating locomotor activity in anticipation of scheduled meals. To test this hypothesis, we observed 24 hr patterns of locomotor activity in mice with targeted mutations of the ghrelin receptor gene (GHSR KO) and wild-type littermates, all given access to food for four hours daily for 14 days. While WT and GHSR KO mice produced increases in anticipatory locomotor activity, anticipatory locomotor activity in GHSR KO mice was attenuated (p.< 0.05). These behavioral measures correlated with attenuated levels of Fos immunoreactivity in a number of hypothalamic nuclei from GHSR KO placed on the same restricted feeding schedule for seven days and sacrificed at ZT4. Interestingly, seven daily intraperitoeneal ghrelin injections mimicked hypothalamic Fos expression patterns to those seen in mice under restricted feeding schedules. These data suggest that ghrelin acts in the hypothalamus to augment locomotor activity in anticipation of scheduled meals. PMID:19666088

  9. Treadmill exercise facilitates recovery of locomotor function through axonal regeneration following spinal cord injury in rats

    PubMed Central

    Jung, Sun-Young; Seo, Tae-Beom; Kim, Dae-Young

    2016-01-01

    Spinal cord injury (SCI) disrupts both axonal pathways and segmental spinal cord circuity, resulting in permanent neurological deficits. Physical exercise is known to increase the expression of neurotrophins for improving the injured spinal cord. In the present study, we investigated the effects of treadmill exercise on locomotor function in relation with brain-derived neurotrophic factor (BDNF) expression after SCI. The rats were divided into five groups: control group, sham operation group, sham operation and exercise group, SCI group, and SCI and exercise group. The laminectomy was performed at the T9–T10 level. The exposed dorsal surface of the spinal cord received contusion injury (10 g × 25 mm) using the impactor. Treadmill exercise was performed 6 days per a week for 6 weeks. In order to evaluate the locomotor function of animals, Basso-Beattie-Bresnahan (BBB) locomotor scale was conducted once a week for 6 weeks. We examined BDNF expression and axonal sprouting in the injury site of the spinal cord using Western blot analysis and immunofluorescence staining. SCI induced loss of locomotor function with decreased BDNF expression in the injury site. Treadmill exercise increased the score of BBB locomotor scale and reduced cavity formation in the injury site. BDNF expression and axonal sprouting within the trabecula were further facilitated by treadmill exercise in SCI-exposed rats. The present study provides the evidence that treadmill exercise may facilitate recovery of locomotor function through axonal regeneration via BDNF expression following SCI. PMID:27656624

  10. Effects of sex pheromones and sexual maturation on locomotor activity in female sea lamprey (Petromyzon marinus)

    USGS Publications Warehouse

    Walaszczyk, Erin J.; Johnson, Nicholas S.; Steibel, Juan Pedro; Li, Weiming

    2013-01-01

    Synchronization of male and female locomotor rhythmicity can play a vital role in ensuring reproductive success. Several physiological and environmental factors alter these locomotor rhythms. As sea lamprey, Petromyzon marinus, progress through their life cycle, their locomotor activity rhythm changes multiple times. The goal of this study was to elucidate the activity patterns of adult female sea lamprey during the sexual maturation process and discern the interactions of these patterns with exposure to male pheromones. During these stages, preovulated and ovulated adult females are exposed to sex pheromone compounds, which are released by spermiated males and attract ovulated females to the nest for spawning. The locomotor behavior of adult females was monitored in a natural stream with a passive integrated tag responder system as they matured, and they were exposed to a sex pheromone treatment (spermiated male washings) or a control (prespermiated male washings). Results showed that, dependent on the hour of day, male sex pheromone compounds reduce total activity (p < 0.05) and cause increases in activity during several daytime hours in preovulated and ovulated females. These results are one of the first examples of how sex pheromones modulate a locomotor rhythm in a vertebrate, and they suggest that the interaction between maturity stage and sex pheromone exposure contributes to the differential locomotor rhythms found in adult female sea lamprey. This phenomenon may contribute to the reproductive synchrony of mature adults, thus increasing reproductive success in this species.

  11. Development and Utilization of an Ex Vivo Bromodeoxyuridine Local Lymph Node Assay (LLNA) Protocol for Assessing Potential Chemical Sensitizers

    EPA Science Inventory

    The murine local lymph node assay (LLNA) is widely used to identify chemicals that may cause allergic contact dermatitis. Exposure to a dermal sensitizer results in proliferation of local lymph node T cells, which has traditionally been measured by in vivo incorporation of [3H]m...