DRG2 Deficient Mice Exhibit Impaired Motor Behaviors with Reduced Striatal Dopamine Release.

Developmentally regulated GTP-binding protein 2 (DRG2) was first identified in the central nervous system of mice. However, the physiological function of DRG2 in the brain remains largely unknown. Here, we demonstrated that knocking out DRG2 impairs the function of dopamine neurons in mice. DRG2 was strongly expressed in the neurons of the dopaminergic system such as those in the striatum (Str), ventral tegmental area (VTA), and substantia nigra (SN), and on neuronal cell bodies in high-density regions such as the hippocampus (HIP), cerebellum, and cerebral cortex in the mouse brain. DRG2 knockout (KO) mice displayed defects in motor function in motor coordination and rotarod tests and increased anxiety. However, unexpectedly, DRG2 depletion did not affect the dopamine (DA) neuron population in the SN, Str, or VTA region or dopamine synthesis in the Str region. We further demonstrated that dopamine release was significantly diminished in the Str region of DRG2 KO mice and that treatment of DRG2 KO mice with l-3,4-dihydroxyphenylalanine (L-DOPA), a dopamine precursor, rescued the behavioral motor deficiency in DRG2 KO mice as observed with the rotarod test. This is the first report to identify DRG2 as a key regulator of dopamine release from dopamine neurons in the mouse brain.

Pharmacokinetic drug interaction and safety after coadministration of clarithromycin, amoxicillin, and ilaprazole: a randomised, open-label, one-way crossover, two parallel sequences study.

PURPOSE: Ilaprazole, the latest proton pump inhibitor, can be used with clarithromycin and amoxicillin as a triple therapy regimen for eradicating Helicobacter pylori. The aim of this study was to evaluate pharmacokinetic drug interactions and safety profiles after coadministration of clarithromycin, amoxicillin, and ilaprazole. METHODS: A randomised, open-label, one-way crossover, two parallel sequences study was conducted in 32 healthy subjects. In part 1, the subjects received a single dose of ilaprazole 10 mg in period 1 and clarithromycin 500 mg and amoxicillin 1000 mg twice daily for 6 days in period 2. In part 2, the subjects received clarithromycin 500 mg and amoxicillin 1000 mg once in period 1 and ilaprazole 10 mg twice daily for 6 days in period 2. In both sequences, the three drugs were coadministrated once on day 5 in period 2. Pharmacokinetic evaluations of ilaprazole (part 1), and clarithromycin and amoxicillin (part 2) were conducted. RESULTS: Twenty-eight subjects completed the study. For ilaprazole, the peak concentration (Cmax) slightly decreased from 479 (ilaprazole alone) to 446 ng/mL (triple therapy) [Geometric least square mean ratio (90% confidence interval), 0.93 (0.70-1.22)]. The area under the concentration-time curve from 0 h to the last measurable concentration (AUClast) slightly increased from 3301 to 3538 µg·h/mL [1.07 (0.85-1.35)]. For clarithromycin, the Cmax slightly decreased from 1.87 to 1.72 µg/mL [0.90 (0.70-1.15)], and AUClast slightly increased from 14.6 to 16.5 µg·h/mL [1.09 (0.87-1.37)]. For amoxicillin, the Cmax slightly decreased from 9.37 to 8.14 µg/mL [0.86 (0.74-1.01)], and AUClast slightly decreased from 27.9 to 26.7 µg·h/mL [0.98 (0.83-1.16)]. These changes in the PK parameters of each drug were not statistically significant. CONCLUSIONS: The coadministration of ilaprazole, clarithromycin, and amoxicillin was tolerable and did not cause a significant PK drug interaction. Thus, a triple therapy regimen comprising ilaprazole, clarithromycin, and amoxicillin may be an option for the eradication of H. pylori. Clinicaltrials.gov number: NCT02998437.

Acupuncture reduces relapse to cocaine-seeking behavior via activation of GABA neurons in the ventral tegmental area.

There is growing public interest in alternative approaches to addiction treatment and scientific interest in elucidating the neurobiological underpinnings of acupuncture. Our previous studies showed that acupuncture at a specific Shenmen (HT7) points reduced dopamine (DA) release in the nucleus accumbens (NAc) induced by drugs of abuse. The present study was carried out to evaluate the effects of HT7 acupuncture on γ-aminobutyric acid (GABA) neuronal activity in the ventral tegmental area (VTA) and the reinstatement of cocaine-seeking behavior. Using microdialysis and in vivo single-unit electrophysiology, we evaluated the effects of HT7 acupuncture on VTA GABA and NAc DA release and VTA GABA neuronal activity in rats. Using a within-session reinstatement paradigm in rats self-administering cocaine, we evaluated the effects of HT7 stimulation on cocaine-primed reinstatement. Acupuncture at HT7 significantly reduced cocaine suppression of GABA release and GABA neuron firing rates in the VTA. HT7 acupuncture attenuated cocaine-primed reinstatement, which was blocked by VTA infusions of the selective GABAB receptor antagonist 2-hydroxysaclofen. HT7 stimulation significantly decreased acute cocaine-induced DA release in the NAc, which was also blocked by 2-hydroxysaclofen. HT7 acupuncture also attenuated cocaine-induced sensitization of extracellular DA levels in the NAc. Moreover, HT7 acupuncture reduced both locomotor activity and neuronal activation in the NAc induced by acute cocaine in a needle-penetration depth-dependent fashion. These results suggest that acupuncture may suppress cocaine-induced DA release in the NAc and cocaine-seeking behavior through activation of VTA GABA neurons. Acupuncture may be an effective therapy to reduce cocaine relapse by enhancing GABAergic inhibition in the VTA.

The role of reactive oxygen species in methamphetamine self-administration and dopamine release in the nucleus accumbens.

Methamphetamine (METH) markedly increases dopamine (DA) release in the mesolimbic DA system, which plays an important role in mediating the reinforcing effects of METH. METH-induced DA release results in the formation of reactive oxygen species (ROS), leading to oxidative damage. We have recently reported that ROS are implicated in behavior changes and DA release in the nucleus accumbens (NAc) following cocaine administration. The aim of this study was to evaluate the involvement of ROS in METH-induced locomotor activity, self-administration and enhancement of DA release in the NAc. Systemic administration of a non-specific ROS scavenger, N-tert-butyl-α-phenylnitrone (PBN; 0, 50 and 75 mg/kg, IP) or a superoxide-selective scavenger, 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPOL; 0, 50 and 100 mg/kg, IP), attenuated METH-induced locomotor activity without affecting generalized behavior in METH-naïve rats. PBN and TEMPOL significantly attenuated METH self-administration without affecting food intake. Increased oxidative stress was found in neurons, but not astrocytes, microglia or oligodendrocytes, in the NAc of METH self-administering rats. In addition, TEMPOL significantly decreased METH enhancement of DA release in the NAc. Taken together, these results suggest that enhancement of ROS in the NAc contributes to the reinforcing effect of METH.

Botulinum Toxin Injection for the Treatment of Compression of Lateral Plantar Nerve by Flexor Digitorum Accessorius Longus.

ABSTRACT: The flexor digitorum accessorius longus is an anomalous muscle with a reported prevalence of 1.6%-12.2% in cadaveric studies. Flexor digitorum accessorius longus courses through the tarsal tunnel and has been reported as an etiology of tarsal tunnel syndrome in previous case reports. The flexor digitorum accessorius longus is intimately related to the neurovascular bundle and may impinge on the lateral plantar nerves. However, very few cases of lateral plantar nerve compression by the flexor digitorum accessorius longus have been reported. Herein, we report a case of lateral plantar nerve compression caused by the flexor digitorum accessorius longus muscle in a 51-year-old man who complained of insidious pain at the lateral sole and hypoesthesia at the left third-fifth toe and lateral sole, and the pain improved after treatment of botulinum toxin injection into the flexor digitorum accessorius longus muscle.

A Study on the Characteristics of 304 Stainless Steel According to the Water Temperature Changes in Underwater Laser Beam Machining.

In underwater laser beam machining (ULBM), water provides a cooling effect by reducing the influence of the laser heat source, which makes ULBM more suitable for marking, cutting, and postprocessing than laser beam machining (LBM). Because the laser heat source not only affects the substrate temperature, but also heats the water, this study analyzes how the cooling effect occurs when water is heated. In this study, the heat-transformed zones in ULBM and heated underwater laser beam machining (HULBM) were improved by approximately 33% and 24%, respectively, compared to LBM at 400 W. In addition, the heat-affected zones in ULBM and HULBM improved by approximately 15% and 9%, respectively, compared to LBM. The hardness of ULBM and HULBM was higher than that of LBM. Based on these results, it was confirmed that water can reduce the effect of the laser heat source and improve the mechanical properties. Experiments will be conducted on the underwater laser beam machining of various substrates, such as Inconel718 and Ti-6Al-4V, in a future study. In addition, experiments will be conducted on the underwater laser beam machining of various substrates using a cooling system that can lower the temperature of water.

Acupuncture attenuates alcohol dependence through activation of endorphinergic input to the nucleus accumbens from the arcuate nucleus.

A withdrawal-associated impairment in ß-endorphin neurotransmission in the arcuate nucleus (ARC) of the hypothalamus is associated with alcohol dependence characterized by a chronic relapsing disorder. Although acupuncture activates ß-endorphin neurons in the ARC projecting to the nucleus accumbens (NAc), a role for ARC ß-endorphin neurons in alcohol dependence and acupuncture effects has not been examined. Here, we show that acupuncture at Shenmen (HT7) points attenuates behavioral manifestation of alcohol dependence by activating endorphinergic input to the NAc from the ARC. Acupuncture attenuated ethanol withdrawal tremor, anxiety-like behaviors, and ethanol self-administration in ethanol-dependent rats, which are mimicked by local injection of ß-endorphin into the NAc. Acupuncture also reversed the decreased ß-endorphin levels in the NAc and a reduction of neuronal activity in the ARC during ethanol withdrawal. These results suggest that acupuncture may provide a novel, potential treatment strategy for alcohol use disorder by direct activation of the brain pathway.

Spinal pathways involved in somatosensory inhibition of the psychomotor actions of cocaine.

Previous studies have demonstrated that somatosensory stimuli influence dopamine transmission in the mesolimbic reward system and can reduce drug-induced motor behaviors, craving and dependence. Until now, the central links between somatosensory and brain reward systems are not known. Here, we show that the dorsal column (DC) somatosensory pathway contains projections that convey an inhibitory input from the periphery to mesolimbic reward circuits. Stimulation of the ulnar nerve under HT7 acupoint suppressed psychomotor response to cocaine, which was abolished by disruption of the DC pathway, but not the spinothalamic tract (STT). Low-threshold or wide-dynamic range neurons in the cuneate nucleus (CN) were excited by peripheral stimulation. Lesions of dorsal column or lateral habenula (LHb) prevented the inhibitory effects of peripheral stimulation on cocaine-induced neuronal activation in the nucleus accumbens (NAc). LHb neurons projecting to the ventral tegmental area (VTA)/rostromedial tegmental nucleus (RMTg) regions were activated by peripheral stimulation and LHb lesions reversed the inhibitory effects on cocaine locomotion produced by peripheral stimulation. These findings suggest that there exists a pathway in spinal cord that ascends from periphery to mesolimbic reward circuits (spino-mesolimbic pathway) and the activation of somatosensory input transmitted via the DC pathway can inhibit the psychomotor response to cocaine.

Comparison of Mechanical Allodynia and Recovery of Locomotion and Bladder Function by Different Parameters of Low Thoracic Spinal Contusion Injury in Rats.

BACKGROUND: The present study was designed to examine the functional recovery following spinal cord injury (SCI) by adjusting the parameters of impact force and dwell-time using the Infinite Horizon (IH) impactor device. METHODS: Sprague-Dawley rats (225-240 g) were divided into eight injury groups based on force of injury (Kdyn) and dwell time (seconds), indicated as Force-Dwell time: 150-4, 150-3, 150-2, 150-1, 150-0, 200-0, 90-2 and sham controls, respectively. RESULTS: After T10 SCI, higher injury force produced greater spinal cord displacement (P < 0.05) and showed a significant correlation (r = 0.813) between the displacement and the force (P < 0.05). In neuropathic pain-like behavior, the percent of paw withdrawals scores in the hindpaw for the 150-4, 150-3, 150-2, 150-1 and the 200-0 injury groups were significantly lowered compared with sham controls (P < 0.05). The recovery of locomotion had a significant within-subjects effect of time (P < 0.05) and the 150-0 group had increased recovery compared to other groups (P < 0.05). In addition, the 200-0 and the 90-2 recovered significantly better than all the 150 kdyn impact groups that included a dwell-time (P < 0.05). In recovery of spontaneous bladder function, the 150-4 injury group took significantly longer recovery time whereas the 150-0 and the 90-2 groups had the shortest recovery times. CONCLUSIONS: The present study demonstrates SCI parameters optimize development of mechanical allodynia and other pathological outcomes.

A histopathologic study of the nervous system after inhalation exposure of 1-bromopropane in rat.

1-Bromopropane (1-BP) has recently become known as an alternative cleaning material with less damage to the ozone layer. However, its toxicity is not fully evaluated. This study was designed to investigate the repeated inhalation toxicity of 1-BP on the nervous systems in Sprague-Dawley rats. The experiment was done by repeated exposure of the rats to 0, 200, 500, and 1250 ppm for 6 h per day, 5 days a week, for 13 weeks, respectively. Morphologic studies were done for the central nervous system, sacral and peroneal nerves. The serial sections of the brain and spinal cord of 1-BP inhalation groups revealed no pathological features either in the gray or white matter. The nerve fiber teasing, light and electron microscopic studies of the sacral and peroneal nerve fibers showed no significant difference between 1-BP inhalation groups and the control group. From these results, it is concluded that the nervous system is histologically resistant to the repeated inhalation of 1-BP up to 1250 ppm for 13 weeks. Experiments with higher concentrations of 1-BP and the functional studies are necessary to clarify the 1-BP toxicity.

Dependence potential of propofol: behavioral pharmacology in rodents.

Propofol is an anesthetic commonly used to provide sedation or to induce and maintain an anesthetic stated. However, there are reports which indicate propofol may cause psychological dependence or be abused. In the present study, we used various behavioral tests including climbing test, jumping test, conditioned place preference, and self-administration test to assess the dependence potential and abuse liability of propofol compared to a positive control (methamphetamine) or a negative control (saline or intralipid). Among the tests, the conditioned place preference test was conducted with a biased method, and the selfadministration test was performed under a fixed ratio (FR) 1 schedule, 1 h per session. No difference was found in the climbing test and jumping test, but propofol (30 mg/kg, i.p.) increased the rewarding effect in the conditioned place preference test, and it showed a positive reinforcing effect compared to the vehicle. These results indicate that propofol tends to show psychological dependence rather than physical dependence, and it seems not to be related with dopaminergic system.