Inhibition Of Motor Activity Research Articles

583 The Role of Adenosine in Esophageal Nociception in Patients with Functional Chest Pain

esophageal motility (IEM), 9 with nutcracker esophagus (NE) and 1 with diffuse esophageal spasm (DES). Abnormal manometry in VS was demonstrated in 31 patients (67.4%, 21 IEM, 9 NE, 1 DES). Abnormal transit in LS and VS was demonstrated in 14 (25.9 %) and 18 (33.3%), respectively. The manometric and transit abnormalities were more common in patients with dysphagia (78.5% vs. 21.4%, p=0.04) and in patients with posture instability gait disturbance assessed by UPDRS (p=0.02). Abnormal esophageal function was not correlated to age or Hoehn & Yahr stage. Repetitive deglutition during single swallow was observed in 143 of 540 (26.5%) swallows (mean 1.4±0.4/LS, 1.4±0.5/VS). Repetitive deglutition was significantly correlated with failed peristalsis and incomplete bolus transit (p<0.0001). Abnormal inhibition of motor activity in the oesophageal body during MRS was observed in 30 out of 49 (61.2%) patients; 26 with incomplete inhibition (repetitive contraction), and 4 with failed peristalsis. Abnormal MRS response correlated with abnormal manometry (p=0.043). Conclusion: Repetitive deglutition with abnormal inhibition of motor activity in the oesophageal body is frequently observed in patients with early PD. MRS provides further evidence of selective involvement of either the brain stem or the esophageal myenteric plexus in the early PD.

584 An Optimal Dysphagia-Sensitive Algorithm for Assessing Deglutitive Intrabolus Pressure Using Esophageal High-Resolution Manometry

esophageal motility (IEM), 9 with nutcracker esophagus (NE) and 1 with diffuse esophageal spasm (DES). Abnormal manometry in VS was demonstrated in 31 patients (67.4%, 21 IEM, 9 NE, 1 DES). Abnormal transit in LS and VS was demonstrated in 14 (25.9 %) and 18 (33.3%), respectively. The manometric and transit abnormalities were more common in patients with dysphagia (78.5% vs. 21.4%, p=0.04) and in patients with posture instability gait disturbance assessed by UPDRS (p=0.02). Abnormal esophageal function was not correlated to age or Hoehn & Yahr stage. Repetitive deglutition during single swallow was observed in 143 of 540 (26.5%) swallows (mean 1.4±0.4/LS, 1.4±0.5/VS). Repetitive deglutition was significantly correlated with failed peristalsis and incomplete bolus transit (p<0.0001). Abnormal inhibition of motor activity in the oesophageal body during MRS was observed in 30 out of 49 (61.2%) patients; 26 with incomplete inhibition (repetitive contraction), and 4 with failed peristalsis. Abnormal MRS response correlated with abnormal manometry (p=0.043). Conclusion: Repetitive deglutition with abnormal inhibition of motor activity in the oesophageal body is frequently observed in patients with early PD. MRS provides further evidence of selective involvement of either the brain stem or the esophageal myenteric plexus in the early PD.

Short-term erythrosine B-induced inhibition of the brain regional serotonergic activity suppresses motor activity (exploratory behavior) of young adult mammals

Previous studies showed that repeated ingestion of erythrosine B (artificial food color) developed behavioral hyperactivity, but nothing is known about its single administration effect as well as the neurochemical (s) involvement. The present study provides evidence that a single higher dosage (10, 100 or 200 mg/kg, p.o.) of erythrosine administration to young adult male rats reduced motor activity (MA) maximally at 2 h and brain regional (medulla-pons, hippocampus and hypothalamus) serotonergic activity (measuring steady-state levels of 5-HT and 5-HIAA, pargyline-induced 5-HT accumulation and 5-HIAA declination rate and 5-HT receptor binding) under similar experimental condition. The degree of erythrosine-induced inhibition of both MA and brain regional serotonergic activity was dosage dependent. Lower dosage (1 mg/kg, p.o.) did not affect either of the above. Erythrosine (100 or 200 mg/kg, p.o.)-induced MA suppression was also observed in the presence of specific MAO-A inhibitor, clorgyline (5 mg/kg, i.p.) or MAO-B inhibitor, deprenyl (5 mg/kg, i.p.); but their co-application (5 mg/kg, i.p., each) effectively prevented the erythrosine-induced motor suppression. Altogether these results suggest that a single higher dosage of erythrosine (10–200 mg/kg, p.o.) may reduce MA by reducing serotonergic activity with modulation of central dopaminergic activity depending on the brain regions.

Effects of yokukansan, a traditional Japanese medicine, on aggressiveness induced by intracerebroventricular injection of amyloid β protein into mice

The effects of yokukansan, a traditional Japanese medicine, on aggressiveness and motor activities were examined in mice after injection of amyloid beta protein (Abeta) into the lateral ventricle of the brain. The results were compared with those of conventional (haloperidol) and atypical (risperidone) antipsychotic medicines. A significant increase in aggressiveness was observed on day 7 after injection of Abeta, and it lasted until day 28. A single oral administration of yokukansan (1.0 g/kg) did not ameliorate the aggressiveness observed on day 7. However, a tendency toward amelioration of the aggressiveness was observed after the administration of yokukansan (0.5 and 1.0 g/kg) for 1 week (days 7-14). The 3 week administration (days 7-28) of yokukansan significantly ameliorated the aggressiveness in a dose-dependent manner without inhibition of motor activity. In contrast, a single administration of intraperitoneal haloperidol (0.03-0.1 mg/kg) or oral risperidone (0.1-0.3 mg/kg) on day 28 significantly reduced aggressiveness in a dose-dependent manner. However, motor activities were significantly suppressed. These results suggest yokukansan reduces aggressiveness without suppressing physical activity.

Mushroom Bodies Enhance Initial Motor Activity in drosophila

: The central body (or central complex, CCX) and the mushroom bodies (MBs) are brain structures in most insect phyla that have been shown to influence aspects of locomotion. The CCX regulates motor coordination and enhances activity while MBs have, thus far, been shown to suppress motor activity levels measured over time intervals ranging from hours to weeks. In this report, we investigate MB involvement in motor behavior during the initial stages (15 minutes) of walking in Buridan's paradigm. We measured aspects of walking in flies that had MB lesions induced by mutations in six different genes and by chemical ablation. All tested flies were later examined histologically to assess MB neuroanatomy. Mutant strains with MB structural defects were generally less active in walking than wild-type flies. Most mutants in which MBs were also ablated with hydroxyurea (HU) showed additional activity decrements. Variation in measures of velocity and orientation to landmarks among wild-type and mutant flies was attributed to pleiotropy, rather than to MB lesions. We conclude that MBs upregulate activity during the initial stages of walking, but suppress activity thereafter. An MB influence on decision making has been shown in a wide range of complex behaviors. We suggest that MBs provide appropriate contextual information to motor output systems in the brain, indirectly fine tuning walking by modifying the quantity (i.e., activity) of behavior.

Obestatin inhibits motor activity in the antrum and duodenum in the fed state of conscious rats

Obestatin is a novel peptide encoded by the ghrelin precursor gene; however, its effects on gastrointestinal motility remain controversial. Here we have examined the effects of obestatin on fed and fasted motor activities in the stomach and duodenum of freely moving conscious rats. We examined the effects of intravenous (IV) injection of obestatin on the percentage motor index (%MI) and phase III-like contractions in the antrum and duodenum. The brain mechanism mediating the action of obestatin on gastroduodenal motility and the involvement of vagal afferent pathway were also examined. Between 30 and 90 min after IV injection, obestatin decreased the %MI in the antrum and prolonged the time taken to return to fasted motility in the duodenum in fed rats given 3 g of chow after 18 h of fasting. Immunohistochemical analysis demonstrated that corticotropin-releasing factor- and urocortin-2-containing neurons in the paraventricular nucleus in the hypothalamus were activated by IV injection of obestatin. Intracerebroventricular injection of CRF type 1 and type 2 receptor antagonists prevented the effects of obestatin on gastroduodenal motility. Capsaicin treatment blocked the effects of obestatin on duodenal motility but not on antral motility. Obestatin failed to antagonize ghrelin-induced stimulation of gastroduodenal motility. These results suggest that, in the fed state, obestatin inhibits motor activity in the antrum and duodenum and that CRF type 1 and type 2 receptors in the brain might be involved in these effects of obestatin on gastroduodenal motility.

Phosphorylation Relieves Autoinhibition of the Kinetochore Motor Cenp-E

During mitosis, chromosome alignment depends on the regulated dynamics of microtubules and on motor protein activities. At the kinetochore, the interplay between microtubule-binding proteins, motors, and kinases is poorly understood. Cenp-E is a kinetochore-associated kinesin involved in chromosome congression, but the mechanism by which this is achieved is unclear. Here, we present a study of the regulation of Cenp-E motility by using purified full-length (FL) Xenopus Cenp-E protein, which demonstrates that FL Cenp-E is a genuine plus-end-directed motor. Furthermore, we find that the Cenp-E tail completely blocks the motility of Cenp-E in vitro. This is achieved through direct interaction between its motor and tail domains. Finally, we show that Cenp-E autoinhibition is reversed by MPS1- or CDK1-cyclin B-mediated phosphorylation of the Cenp-E tail. This suggests a model of dynamic control of Cenp-E motility, and hence chromosome congression, dependent upon phosphorylation at the kinetochore.

Differential Regulation of Dynein and Kinesin Motor Proteins by Tau

Dynein and kinesin motor proteins transport cellular cargoes toward opposite ends of microtubule tracks. In neurons, microtubules are abundantly decorated with microtubule-associated proteins (MAPs) such as tau. Motor proteins thus encounter MAPs frequently along their path. To determine the effects of tau on dynein and kinesin motility, we conducted single-molecule studies of motor proteins moving along tau-decorated microtubules. Dynein tended to reverse direction, whereas kinesin tended to detach at patches of bound tau. Kinesin was inhibited at about a tenth of the tau concentration that inhibited dynein, and the microtubule-binding domain of tau was sufficient to inhibit motor activity. The differential modulation of dynein and kinesin motility suggests that MAPs can spatially regulate the balance of microtubule-dependent axonal transport.

Motor and cognitive functions of the neostriatum during bilateral blockade of its dopamine receptors

Studies on 60 Sprague-Dawley rats were performed to compare systemic and intrastriate administration of the selective D1 dopamine receptor blocker SCH23390 on the acquisition of a discriminant conditioned active avoidance reflex (CAAR) in a T maze and on behavior in an open field test. Systemic treatment at a dose of 0.025 mg/kg produced several-fold reductions in the proportion of correct performances of the discriminant CAAR and motor activity in the open field test. At the same time, bilateral microinjection of SCH23390 into the rat neostriatum at doses of 0.004-1.0 microg did not induce any deterioration in learning of the discriminant CAAR as compared with intact controls, though there was a sharp inhibition of motor activity in the open field test. Bilateral microinjections of the D2 dopamine receptor blocker raclopride into the rat neostriatum at a dose of 0.004 microg produced a marked and long-lasting degradation of learning of the discriminant CAAR. These data lead to the following conclusions: 1) the differences in the effects of systemic and intrastriate administration of SCH23390 appear to be associated with the fact that the behavioral changes seen after systemic administration may be mediated mainly by structures differing from neostriatal D1 receptors, and 2) the D1-mediated effects of the nigrostriatal dopaminergic system on the neostriatum are complex, with activation of motor activity (projection spiny neurons of the direct pathway) and weak modulation of the learning process (large aspiny cholinergic interneurons). Modulation of the learning process evidently occurs via neostriatal D2 dopaminergic receptors.

The Preclinical Properties of a Novel Group II Metabotropic Glutamate Receptor Agonist LY379268

Activation of group II metabotropic glutamate (mGlu2/3) receptors reduces excessive glutamate release that is often associated with neurodegenerative and psychiatric disorders. This finding encouraged the search for potent and selective agonists as potential therapeutic agents. The search led to the discovery of LY379268 {(-)-2-oxa-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylic acid}, which is a highly potent and systemically available mGlu2/3 receptor agonist. LY379268 was effective in several animal models of stroke, epilepsy, drug abuse, schizophrenia, and pain. Suppression of motor activity is the major side effect of LY379268. Upon repeated administration tolerance develops to this side effect, while the therapeutic effects of LY379268 remain. To date, no clinical data with LY379268 are available. This review article summarizes the preclinical pharmacology of LY379268.

Multiple rapid swallowing in idiopathic achalasia: evidence for patients’ heterogeneity*

In order to evaluate the function of inhibitory neural pathways in achalasia, we compared the response of the oesophageal body and lower oesophageal sphincter (LOS) to single swallows (SS) and multiple rapid swallowing (MRS) in 20 consecutive patients with untreated idiopathic achalasia (10 men, aged 23-81 years) and in 20 control patients without dysphagia (nine men, aged 31-73 years), using sleeve manometry; 277 SS and 85 MRS were analysed. In the control group, MRS inhibited motor activity in the oesophageal body and induced a slightly lower (P < 0.05) nadir LOS pressure compared with SS. In the achalasia patients, MRS induced a variable response: eight patients had simultaneous motor activity during all MRS although onset was delayed compared with SS [median (interquartile range), 3.5 s (1.7-6.1) vs 1.4 s (0.8-3.9); P < 0.05], whereas eight patients showed motor inhibition which occurred during all MRS in four of them, and the remaining four had no motor activity both after SS and during MRS. Overall MRS did not decrease nadir LOS pressure compared with SS [12 mmHg (5-20) vs 16 mmHg (7-22); P > 0.1]; however, it induced complete LOS relaxation in three of the patients. MRS gives further evidence of functional heterogeneity among achalasia patients.

Performance of Cocaine Dependent Individuals and Controls on a Response Inhibition Task with Varying Levels of Difficulty

An assay in which groups perform at both similar and significantly different levels within the same test session may have experimental advantages both in understanding underlying behavioral-cognitive processes and in helping to resolve neuroimaging issues regarding functional significance vs. performance confounds. Here we report behavioral data from a response inhibition (Go/No-Go) task with two levels of No-Go difficulty (easy, hard). The sample included individuals with current cocaine dependence (N = 18) and controls (N = 15). Using signal detection methodology (d′ and Beta), significant main effects were observed for group and trial type on d′. Post-hoc analyses revealed the cocaine-dependent individuals performed significantly worse than controls on difficult, but not easy, trials. Differences on d′ but not Beta, and slower reaction times in cocaine subjects, suggest that response inhibition deficits were related to disruption in visual information processing rather than inhibition of motor activity.

Despite strong behavioral disruption, Δ 9-tetrahydrocannabinol does not affect cell proliferation in the adult mouse dentate gyrus

Marijuana is a widely abused illicit drug known to cause significant cognitive impairments. Marijuana has been hypothesized to target neurons in the hippocampus because of the abundance of cannabinoid receptors present in this structure. While there is no clear evidence of neuropathology in vivo, suppression of brain mitogenesis, and ultimately neurogenesis, may provide a sensitive index of marijuana's more subtle effects on neural mechanisms subserving cognitive functions. We examined the effects of different doses and treatment regimens of Δ 9-tetrahydrocannabinol (THC), the main active ingredient in marijuana, on cell proliferation in the dentate gyrus of adult male mice. Following drug treatment, the thymidine analog 5-bromo-2′-deoxyuridine (BrdU; 200 mg/kg, i.p.) was administered two hours prior to sacrifice to assess cell proliferation, the first step in neurogenesis. Administration of THC produced dose-dependent catalepsy and suppression of motor activity. The number of BrdU-labeled cells was not significantly changed from vehicle control levels following either acute (1, 3, 10, 30 mg/kg, i.p.), sequential (two injections of 10 or 30 mg/kg, i.p., separated by 5 h), or chronic escalating (20 to 80 mg/kg, p.o.; for 3 weeks) drug administration. Furthermore, acute administration of the potent synthetic cannabinoid receptor agonist R-(+)-WIN 55,212-2 (WIN; 5 mg/kg, i.p.) also had no significant effect on cell proliferation. These findings provide no evidence for an effect of THC on hippocampal cell proliferation, even at doses producing gross behavioral intoxication. Whether marijuana or THC affects neurogenesis remains to be explored.

Benzo(a)pyrene‐induced acute neurotoxicity in the F‐344 rat: role of oxidative stress

Given the link between neurotoxicity and exposure to pollutants, the potential behavioral neurotoxicity of benzo(a)pyrene [B(a)P] was investigated. Studies have established that B(a)P requires metabolic activation to highly reactive species to elicit many of its adverse effects. This study investigated the perturbation of nervous system function by correlating behavioral changes with the metabolism of B(a)P, antioxidant enzyme levels and lipid peroxidation in selected brain regions. The neurobehavioral effects of single oral doses of B(a)P (25-200 mg kg(-1) body weight) on motor activity were examined in male F-344 rats at 2, 4, 6, 12, 24, 48, 72 and 96 h post treatment. Parent B(a)P and metabolites were measured at the above mentioned time points by reverse phase HPLC. The activity of several antioxidant enzymes (superoxide dismutase, catalase and glutathione peroxidase) and levels of malondialdehyde were determined at 6 and 96 h in both the striatum and hippocampus of B(a)P exposed rats. Suppression of motor activity (up to 70%) reached a maximum at 6 h, but was reversible at 96 h in all dose groups. The kinetics of disposition data show a strong link between B(a)P metabolism and the onset and duration of behavioral effects. Benzo(a)pyrene caused a 15-70% inhibition in the activity of superoxide dismutase and glutathione peroxidase and an enhancement in catalase and lipid peroxidation (up to 68%) in the striatum and hippocampus at 6 and 96 h post treatment, respectively. These findings suggest that B(a)P-induced acute neurobehavioral toxicity may occur through oxidative stress due to inhibition of the brain antioxidant scavenging system.

Basolateral amygdala noradrenergic activity mediates corticosterone-induced enhancement of auditory fear conditioning

The present experiment examined whether posttraining noradrenergic activity within the basolateral complex of the amygdala (BLA) is required for mediating the facilitating effects of acutely administered glucocorticoids on memory for auditory-cue classical fear conditioning. Male Sprague–Dawley rats received five pairings of a single-frequency auditory stimulus and footshock, followed immediately by bilateral infusions of the β 1-adrenoceptor antagonist atenolol (0.5 μg in 0.2 μl) or saline into the BLA together with a subcutaneous injection of either corticosterone (3.0 mg/kg) or vehicle. Retention was tested 24 h later in a novel test chamber and suppression of ongoing motor behavior served as the measure of conditioned fear. Corticosterone facilitated memory as assessed by suppression of motor activity during the 10-s presentation of the auditory stimulus and intra-BLA administration of atenolol selectively blocked this corticosterone-induced memory enhancement. These findings provide evidence that, as found with other emotionally arousing tasks, the enhancing effects of corticosterone on memory consolidation of auditory-cue fear conditioning require posttraining noradrenergic activity within the BLA.

Absence of quasi-morphine withdrawal syndrome in adenosine A2A receptor knockout mice

Caffeine and other methylxanthines induce behavioral activation and anxiety responses in mice via antagonist action at A2A adenosine receptors. When combined with the opioid antagonist naloxone, methylxanthines produce a characteristic quasi-morphine withdrawal syndrome (QMWS) in opiate-naive animals. The aim of this study was to establish the role of A2A receptors in the quasi-morphine withdrawal syndrome induced by co-administration of caffeine and naloxone and in the behavioral effects of caffeine. We have used A2A receptor knockout (A(2A)R(-/-)) mice in comparison with their wild-type and heterozygous littermates to measure locomotor activity in the open field and withdrawal symptoms induced by caffeine and naloxone. Naïve wild-type and knockout mice were also examined for enkephalin and dynorphin mRNA expression by in situ hybridization and for mu-opiate receptor by ligand binding autoradiography to check for possible opiate receptor changes induced by A2A receptor inactivation. Caffeine increases locomotion and anxiety in wild-type animals, but it has no psychomotor effects in A(2A)R(-/-) mice. Co-administration of caffeine (20 mg/kg) and naloxone (2 mg/kg) resulted in a severe quasi-morphine withdrawal syndrome in wild-type mice that was almost completely abolished in A(2A)R(-/-) mice. Heterozygous animals exhibited a 40% reduction in withdrawal symptoms, suggesting that there is no genetic/developmental compensation for the inactivation of one of the A(2A)R alleles. A(2A)R(-/-) and wild-type mice have similar levels of striatal mu-opioid receptors, thus the effect is not due to altered opioid receptor expression. Our results demonstrate that A2A receptors are required for the induction of quasi-morphine withdrawal syndrome by co-administration of caffeine and naloxone and implicate striatal A2A receptors and mu-opiate receptors in tonic inhibition of motor activity in the striatum.

Effects of the Alkaloid Complex of Nuphar lutea (L.) Smith on the Survival of Carp Underyearlings

A preparation that contained 42% of alkaloids was obtained from rhizomes of yellow water lily (spatterdock, Nuphar lutea (L.) Smith). This alkaloid complex exerted toxic influence on the fish at any modes of its administration, causing inhibition of motor activity, slowing down of respiratory movements of gills, and increased oxygen consumption. The doses 0.3—1.0 g/kg are fatal to fish. When the dose is 0.05 g/kg, the signs of poisoning are observed only during the first hours of experiment.

MAO-inhibitors and SSRIs inhibit running wheel activity without inhibiting motor activity

MAO-inhibitors and SSRIs inhibit running wheel activity without inhibiting motor activity

Effects of urocortin 2 and 3 on motor activity and food intake in rats

Urocortin 2 (Ucn 2) and Ucn 3 are new members of the corticotropin-releasing factor (CRF) family and bind selectively to the CRF type 2 receptor (CRF 2). The effects of these peptides on behavioral changes induced by CRF were examined in rats. In a familiar environment, intracerebroventricular injection of Ucn 2 attenuated the stimulatory effect of CRF on motor activity, although it alone produced no effect. Ucn 3 suppressed motor activity and attenuated the stimulatory effect of CRF. In an open field, CRF decreased locomotion and rearing but increased grooming behavior. Ucn 2 attenuated the inhibition of locomotor activity induced by CRF without affecting other activities, such as rearing or grooming behavior. Ucn 3 had no effect on the behavioral changes induced by CRF, although it alone decreased locomotion and rearing in a manner similar to CRF. Ucn 2 was thus found to have an antagonistic effect on bi-directional motor activation induced by CRF, while Ucn 3 had a suppressive effect on motor activity. Both Ucn 2 and Ucn 3 suppressed food intake in freely-fed rats, but not immediately after injection. These results suggest that the CRF 2 receptor is involved in motor suppressive effects as well as anxiolytic and anorectic effects of Ucn 2 and Ucn 3.

Combined antagonism of aminergic excitatory and amino acid inhibitory receptors in the XII nucleus abolishes REM sleep-like depression of hypoglossal motoneuronal activity.

It is hypothesized that the suppression of motor activity (atonia) that occurs during REM sleep is caused by the combined inhibition of motoneurons by glycine or GABA and withdrawal of excitation mediated by serotonin and norepinephrine. However, it is not known whether these mechanisms can fully account for the atonia. In urethane-anesthetized, paralyzed and artificially ventilated rats, REM sleep-like episodes can be repeatedly elicited by microinjections of a cholinergic agonist, carbachol, into the dorsomedial pons. We used this model to determine whether microinjections of a combination of antagonists of serotonergic, adrenergic, GABA(A) and glycinergic receptors (methysergide, prazosin, bicuculline and strychnine) into the XII nucleus can abolish the carbachol-induced depression of XII motoneuronal activity. REM sleep-like episodes were elicited prior to, and at different times after, antagonist microinjections. In all six rats studied, the depression of XII motoneuronal activity did not occur when tested 30-60 min after the antagonists, whereas other characteristic features of the response (latency, duration, the appearance of hippocampal theta rhythm, activation of the cortical EEG, slowing of the respiratory rate) remained intact. The carbachol-induced depression partially recovered after 2-3 hours. We conclude that the REM sleep-like depression of XII motoneuronal activity can be fully accounted for by all or some of the following mechanisms: a withdrawal of motoneuronal excitation mediated by norepinephrine and serotonin and increased inhibition mediated by GABA and glycine.