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Highlights • SMLM reveals contiguous scatters of GLT-1 molecules near excitatory synapses. • Bassoon and Homer1 molecules are on average 120 nm apart. • GLT-1 molecules occur closer to Homer1 than to bassoon. • Three-colour 3D dSTORM is adaptable to various tissues and targets., Astroglia are vital facilitators of brain development, homeostasis, and metabolic support. In addition, they are also essential to the formation and regulation of synaptic circuits. Due to the extraordinary complex, nanoscopic morphology of astrocytes, the underlying cellular mechanisms have been poorly understood. In particular, fine astrocytic processes that can be found in the vicinity of synapses have been difficult to study using traditional imaging techniques. Here, we describe a 3D three-colour super-resolution microscopy approach to unravel the nanostructure of tripartite synapses. The method is based on the SMLM technique direct stochastic optical reconstruction microscopy (dSTORM) which uses conventional fluorophore-labelled antibodies. This approach enables reconstructing the nanoscale localisation of individual astrocytic glutamate transporter (GLT-1) molecules surrounding presynaptic (bassoon) and postsynaptic (Homer1) protein localisations in fixed mouse brain sections. However, the technique is readily adaptable to other types of targets and tissues.

We assessed early rearing conditions on aging-related changes in mouse behavior. Two isolated-housing groups, running wheel (IHRW) and empty cage (IHEC), were compared against two enriched environments, static (EEST) and dynamic (EEDY), both of which included toys and other mice. For EEDY, the location of toys and sources of food and water changed daily, but remained constant for EEST. All mice, randomly assigned to one of the four groups at ∼4 weeks of age, remained in their respective environments for 25 weeks followed by single housing in empty cages. Beginning at ∼40 weeks of age, all mice were tested at monthly intervals in a plus-shaped maze in which we measured the number of arm entries and the probability of entering a perpendicular arm. Despite making significantly more arm entries than any other group, IHEC mice also were less likely to turn into the left or right arm, a sign of motor inflexibility. Both EEDY and EEST mice showed enhanced turning relative to IHRW and IHEC groups, but only EEDY mice maintained their turning performance for up to ∼100 weeks of age. EEDY and EEST mice also were unique in showing an increase in expression of the major glutamate transporter (GLT1) in striatum, but a decrease in motor cortex, suggesting a need for further assessment of environmental manipulations on long-term changes in forebrain glutamate transmission. Our behavioral results indicate that early exposure to continually changing environments, rather than socialization or exercise alone, results in life-long changes in patterns of motor exploration.

Although the selective excitatory amino acid transporter subtype 1 (EAAT1) inhibitor UCPH-101 has become a standard pharmacological tool compound for in vitro and ex vivo studies in the EAAT research field, its inability to penetrate the blood-brain barrier makes it unsuitable for in vivo studies. In the present study, per os (p.o.) administration (40 mg kg(-1) ) of the closely related analogue UCPH-102 in rats yielded respective plasma and brain concentrations of 10.5 and 6.67 μm after 1 h. Three analogue series were designed and synthesized to improve the bioavailability profile of UCPH-102, but none displayed substantially improved properties in this respect. In vitro profiling of UCPH-102 (10 μm) at 51 central nervous system targets in radioligand binding assays strongly suggests that the compound is completely selective for EAAT1. Finally, in a rodent locomotor model, p.o. administration of UCPH-102 (20 mg kg(-1) ) did not induce acute effects or any visible changes in behavior.

目的：研究玻璃体腔注射外源性胶质细胞源神经营养因子(Glial cell derived neurotrophic factor, GDNF)对视神经轴突切断(optic nerve axotomy, ONA)大鼠视网膜兴奋性氨基酸转运蛋白-1(Excitatory Amino Acid Transporter-1, EAAT-1)和谷氨酰胺合酶(Glutamine synthetase, GS)表达影响。方法：建立Sprague-Dawley (SD)大鼠单眼视神经轴突切断模型56只，并随机分为4组，各组16只SD大鼠。伤后即刻、7 d玻璃体腔内分别注射GDNF(Glial cell derived neurotrophic factor) 1 µg (实验组1)、2 µg (实验组2)、3 µg (实验组3)和0.1 M磷酸缓冲液(阴性对照组)，阴性对照组大鼠的对侧眼作为正常对照组。各组于术后7 d随机选择2只大鼠上丘脑逆行标记荧光金视神经轴突切断状况。术后14 d、21 d随机选择6只实验大鼠，免疫组织化学分析视网膜EAAT-1和GS的表达。结果：视网膜神经节细胞逆行标记显示视神经夹伤后视神经轴突被完全切断。ONA后14 d、21 d，正常对照组、实验组2的EAAT-1、GS表达均高于阴性对照组；ONA后14 d，实验组3的GS表达高于阴性对照组。ONA后21 d，实验组1的EAAT-1、GS表达低于正常对照组。结论：玻璃体腔注射适当剂量的外源性GDNF能促进视神经损伤后大鼠视网膜EAAT-1、GS的表达。 Objective: To investigate the effect of exogenous Glial cell derived neurotrophic factor (GDNF) on the expression of retinal excitatory amino acid transporter-1 (EAAT-1) and glutamine synthetase (GS) of rats after optic nerve axotomy. Methods: Right unilateral optic nerve crush (ONA) model of Sprague-Dawley rats (56) was established, and divided into 4 groups randomly. Right eyes of each group were injected intravitreously 1 µg (test 1 group), 2 µg (test 2 group ), 3 µg ( test 3 group) GDNF, and 0.1 M phosphate buffered saline (negative control group) after ONA immediately. Injec-tions were repeated 7 days after ONA. The left eyes of negative control group were intact, and served as normal control group. FluoroGold was injected into the superior colliculi of 2 rats out of each group to retrogradely label retinal ganglion cells in order to examine the optic nerve axotomy. The expression of GS, EAAT-1 of each group was tested with immnohistochemisty 14 and 21 days after ONA. Results: Retinal ganglion cells axotomy were confirmed by FluoroGold retrogradely labeling. The expression of EAAT-1, GS of normal control group and test 2 group was high significantly than that of negative control group at 14, 21 days after ONA. The expression of GS of test 3 group was also high significantly than that of negative control group at 14 days after ONA. The expression of EAAT-1, GS of test 1 group was lower than that of normal control group at 21 days after ONA. Conclusion: Exogenous GDNF injected intravitreously with adequate dose can enhance the expression of EAAT-1, GS after optic nerve axotomy.

Excitatory amino acid transporters (EAATs) are membrane proteins that control excitatory synaptic transmission in the brain ([Bergles et al., 1999][1]; [Danbolt, 2001][2]; [Robinson and Jackson, 2016][3]). As classical secondary active transporters, which use the energy stored within ion gradients

Background Antipsychotic drugs are the first line intervention to treat psychosis in schizophrenia and D2 receptor blockade is thought to be their primary mechanism of action. However, multiple lines of evidence from human and animal studies show that D2 receptor blockade is not always correlated with markers of antipsychotic efficacy. We previously demonstrated that reduced antipsychotic efficacy occurs after chronic antipsychotic administration in rodents despite stable D2 blockade, examined using PET imaging. Instead, we found that changes in expression of the dopamine transporter (DAT) were associated with decreases in endogenous dopamine and dopamine-mediated autoinhibition. These studies have led us to examine the DAT as a critical player in generation of an antipsychotic response. Methods Using antisense morpholino oligonucleotides, administered for 3 consecutive days using Long Evans rats, we selectively blocked translation of DAT or GLT-1 mRNA in the core of the nucleus accumbens, a brain region critical for motor outputs in response to salient stimuli. Baseline locomotion was monitored prior to and after an acute i.p. injection of haloperidol. Next, locomotion was monitored in response to a tail pinch or acute i.p. administration of cocaine. Transporter expression was quantified during acute or chronic haloperidol treatment using confocal microscopy. Results We found that DAT knockdown enhanced tail pinch-induced locomotion after acute haloperidol administration. Additionally, knockdown of the glutamate transporter GLT-1 strongly enhanced locomotion induced by tail pinch or cocaine injection after antipsychotic treatment. Confocal analysis of GLT-1 expression after acute or chronic haloperidol revealed significant GLT-1 up-regulation during a time period associated with antipsychotic efficacy. Discussion Our findings demonstrate a cause/effect relationship between reduced DAT and the behavioral response to an acute injection of antipsychotics in rodents. In all, our data point to the importance of both dopamine and glutamate uptake in the efficacy of antipsychotic drugs and argue against a D2-centric hypothesis of antipsychotic action.

The synergy between synaptic Glu release and astrocytic Glu-Na+ symport is essential to the signalling function of the tripartite synapse. Here we used kinetic data of astrocytic Glu transporters (EAAT) and the Na+/Ca2+ exchanger (NCX) to simulate Glu release, Glu uptake and subsequent Na+ and Ca2+ dynamics in the astrocytic leaflet microdomain following single release event. Model simulations show that Glu-Na+ symport differently affect intracellular [Na+] in synapses with different extent of astrocytic coverage. Surprisingly, NCX activity alone has been shown to generate markedly stable, spontaneous Ca2+ oscillation in the astrocytic leaflet. These on-going oscillations appear when NCX operates either in the forward or reverse direction. We conjecture that intrinsic NCX activity may play a prominent role in the generation of astrocytic Ca2+ oscillations.

Summary A new study in fruit flies identifies a molecule, Eaat2, that regulates both sleep and metabolic rate. Surprisingly, Eaat2 acts in a specific glial subtype to modulate both processes, suggesting a cellular link in the brain between sleep and metabolism.

Amyotrophic lateral sclerosis (ALS) is a chronic neurodegenerative disorder characterized by the selective loss of motor neurons. The precise mechanisms that cause the selective death of motor neurons remain unclear, but a growing body of evidence suggests that glutamate-mediated excitotoxicity has been considered to play an important role in the mechanisms of motor neuron degeneration in ALS. Reductions in glutamate transporter GLT1 have been reported in animal models of ALS and the motor cortex and spinal cord of ALS patients. However, it remains unknown whether the reduction in GLT1 has a primary role in the induction of motor neuron degeneration in ALS. Here, we generated conditional knockout mice that lacked GLT1 specifically in the spinal cord by crossing floxed-GLT1 mice and Hoxb8-Cre mice. Hoxb8-Cre/GLT1flox/flox mice showed motor deficits and motor neuron loss. Thus, loss of the glial glutamate transporter GLT1 is sufficient to cause motor neuron death in mice.

BACKGROUND: Accumulating evidence suggests the involvement of abnormal glutamateric neurotransmission and N-methyl-D-aspartate receptor (NMDAR) hypofunction in the pathophysiology of psychotic disorders. The purpose of this study was to quantify in vivo glutamate (Glu) and glycine (Gly) levels in patients with first-episode psychosis as well as age-matched healthy controls with MR spectroscopy. METHODS: The subjects were 46 patients with first-episode psychosis (20 schizophrenia-spectrum disorders (SZ), 26 bipolar disorder (BD)) and 50 age-matched healthy controls (HC). Glu and Gly levels were measured in vivo in the anterior cingulate cortex (ACC) and posterior cingulate cortex (PCC) of the subjects by using the echo-time (TE)-averaged proton MR spectroscopy technique ((1)H-MRS) at 4 T (i.e., modified PRESS sequence: 24 TE steps with 20 ms increments). Metabolite levels were quantified using LCModel with simulated basis sets. RESULTS: Significantly higher Glu and Gly levels were found in both the ACC and PCC of patients with first-episode psychosis as compared to healthy controls. Glu and Gly levels were positively correlated in patients. SZ and BD patients showed similar abnormalities. CONCLUSIONS: Our findings demonstrate abnormally elevated brain Glu and Gly levels in patients with first-episode psychosis by means of TE-averaged (1)H-MRS at 4 T. The findings implicate dysfunction of NMDAR and glutamatergic neurotransmission in the pathophysiology of the acute early phase of psychotic illnesses.

Astrocytes carry two glutamate transporters—GLAST and GLT-1—the latter of which is responsible for >90% of glutamate uptake activity in the brain; however, under culture conditions, the GLT-1 expression in astrocytes is exceedingly low, as is the glutamate uptake activity mediated by GLT-1. This study aimed to elucidate the effects of yokukansan (YKS) in relation to the GLT-1-mediated regulation of extracellular glutamate concentrations. Thus, we treated cultured astrocytes with tumor necrosis factor-α (TNF-α) and dibutyryl-cAMP (dBcAMP) (hereinafter, referred to as “TA”) to increase GLT-1 expression and then functionally examined how YKS would affect glutamate uptake ability derived from GLT-1. Contrary to expectations, although the TA treatments did not affect the uptake activity, YKS significantly augmented it. Conversely, GLAST-derived glutamate uptake was significantly reduced by TA treatments but was unaffected by YKS. Subsequently, we analyzed the GLT-1 protein and mRNA levels and found that TA treatments had significantly increased them, which were then further augmented by YKS. These findings suggest that YKS enhances GLT-1-derived glutamate transport functions in TA-treated cultured astrocytes and that this process entails increased GLT-1 protein and mRNA levels. This type of mechanism may contribute to the YKS-mediated regulation of extracellular glutamate concentrations.

Author(s): Kieson, Emily | Abstract: Practitioners of Equine Assisted Activities and Therapies (EAAT) use it to help individuals suffering from a wide range of physical and psychological disorders as an alternative practice in physical and psychotherapy. Although there is plenty of research to support the benefits of these therapies, there is little research in equine behavior in this context, specifically how equine behaviors can best be utilized to improve the health of the human component. Although much of EAAT uses horses in physical therapy, newer practices in EAAT focus on assisting individuals in building and improving interpersonal skills through practicing those skills with horses. To fully understand and develop this area of EAAT, researchers need to look at the behavioral patterns of horses, how they learn and adapt to changes in human emotions and behaviors, and how these behaviors correspond to bonding with regards to friendships and relationships within the context of equine-human interactions. To do this, scientists need to rely upon the principles of learning theory and behavioral sciences associated with comparative psychology. The scientific methods used in comparative psychology are critical for researching these areas of EAAT.

Objective To observe the effect of subarachnoid nerve block anesthesia on glutamate transporter glutamate-aspartate transporter (GLAST) and GLT-1 expressions in rabbits, and to investigate the effect of peripheral nerve anesthesia on the morphology and function of the spinal cord. Methods Twenty healthy New Zealand white rabbits were randomly divided into two groups: the experimental group and control group; with 10 rabbits in each group. For spinal nerve anesthesia, 5 g/L of bupivacaine was used in the experimental group, and sterile saline was used in the control group. After 30 min of cardiac perfusion, GLAST and GLT-1 protein expression in spinal neurons were detected by immunohistochemistry and immunofluorescence staining. Results GLAST and GLT-1 protein-positive cells increased in neurons in the experimental group, compared with the control group ( P Conclusions After subarachnoid nerve block anesthesia, rabbit glutamate transporter GLAST and GLT-1 expression is increased; and spinal cord nerve cell function is inhibited.

Background/Aims: Kinases involved in the regulation of epithelial transport include SPAK (SPS1-related proline/alanine-rich kinase) and OSR1 (oxidative stress-responsive kinase 1). SPAK and OSR1 are both regulated by WNK (with-no-K(Lys)) kinases. The present study explored whether SPAK and/or OSR1 influence the excitatory amino acid transporter EAAT3, which accomplishes glutamate and aspartate transport in kidney, intestine and brain. Methods: cRNA encoding EAAT3 was injected into Xenopus laevis oocytes with or without additional injection of cRNA encoding wild-type SPAK, constitutively active T233ESPAK, WNK insensitive T233ASPAK, catalytically inactive D212ASPAK, wild-type OSR1, constitutively active T185EOSR1, WNK insensitive T185AOSR1 and catalytically inactive D164AOSR1. Glutamate-induced current was taken as measure of electrogenic glutamate transport and was quantified utilizing dual electrode voltage clamp. Furthermore, Ussing chamber was employed to determine glutamate transport in the intestine from gene-targeted mice carrying WNK insensitive SPAK (spaktg/tg) and from corresponding wild-type mice (spak+/+). Results: EAAT3 activity was significantly decreased by wild-type SPAK and T233ESPAK, but not by T233ASPAK and D212ASPAK. SPAK decreased maximal transport rate without affecting significantly affinity of the carrier. Similarly, EAAT3 activity was significantly downregulated by wild-type OSR1 and T185EOSR1, but not by T185AOSR1 and D164AOSR1. Again OSR1 decreased maximal transport rate without affecting significantly affinity of the carrier. Intestinal electrogenic glutamate transport was significantly lower in spak+/+ than in spaktg/tg mice. Conclusion: Both, SPAK and OSR1 are negative regulators of EAAT3 activity.

Parvalbumin (PV)-positive interneurons form dendritic gap junctions with one another, but the connectivity among gap junction-coupled dendrites remains uninvestigated in most neocortical areas. We visualized gap junctions in layer 4 of the mouse barrel cortex and examined their structural details. PV neurons were divided into 4 types based on the location of soma and dendrites within or outside barrels. Type 1 neurons that had soma and all dendrites inside a barrel, considered most specific to single vibrissa-derived signals, unexpectedly formed gap junctions only with other types but never with each other. Type 2 neurons inside a barrel elongated dendrites outward, forming gap junctions within a column that contained the home barrel. Type 3 neurons located outside barrels established connections with all types including Type 4 neurons that were confined inside the inter-barrel septa. The majority (33/38, 86.8%) of dendritic gap junctions were within 75 μm from at least 1 of 2 paired somata. All types received vesicular glutamate transporter 2-positive axon terminals preferentially on somata and proximal dendrites, indicating the involvement of all types in thalamocortical feedforward regulation in which proximal gap junctions may also participate. These structural organizations provide a new morphological basis for regulatory mechanisms in barrel cortex.

Arkhipova et al. caution that the limitations of structural models be taken into account when interpreting crystallographic data., Crystal structures provide visual models of biological macromolecules, which are widely used to interpret data from functional studies and generate new mechanistic hypotheses. Because the quality of the collected x-ray diffraction data directly affects the reliability of the structural model, it is essential that the limitations of the models are carefully taken into account when making interpretations. Here we use the available crystal structures of members of the glutamate transporter family to illustrate the importance of inspecting the data that underlie the structural models. Crystal structures of glutamate transporters in multiple different conformations have been solved, but most structures were determined at relatively low resolution, with deposited models based on crystallographic data of moderate quality. We use these examples to demonstrate the extent to which mechanistic interpretations can be made safely.

Depression after traumatic brain injury (TBI) is common but the mechanisms by which TBI causes depression are unknown. TBI decreases glutamate transporters GLT-1 and GLAST and allows extravasation of thrombin. We examined the effects of thrombin on transporter expression in primary hippocampal astrocytes. Application of a PAR-1 agonist caused down-regulation of GLT-1, which was prevented by inhibition of Rho kinase (ROCK). To confirm these mechanisms in vivo, we subjected mice to closed-skull TBI. Thrombin activity in the hippocampus increased one day following TBI. Seven days following TBI, expression of GLT-1 and GLAST was reduced in the hippocampus, and this was prevented by administration of the PAR-1 antagonist SCH79797. Inhibition of ROCK attenuated the decrease in GLT-1, but not GLAST, after TBI. We measured changes in glutamate levels in the hippocampus seven days after TBI using an implanted biosensor. Stress-induced glutamate levels were significantly increased following TBI and this was attenuated by treatment with the ROCK inhibitor fasudil. We quantified depressive behavior following TBI and found that inhibition of PAR-1 or ROCK decreased these behaviors. These results identify a novel mechanism by which TBI results in down-regulation of astrocyte glutamate transporters and implicate astrocyte and glutamate transporter dysfunction in depression following TBI.

Parkinson's disease (PD), characterized with bradykinesia, static tremor, rigidity and disturbances in balance, is the second most common neurodegenerative disorder. Along with the largely aging population in the world, the incidence is increasing year by year, which imposes the negative impacts on patients, their families and the whole society. Traditional Chinese medicine (TCM) has a positive prospect for the prevention and cure of PD due to its advantages of less side effects and multi-target effects. At present, the pathogenesis of PD is not yet fully discovered. This paper elaborates the mechanisms of TCM underlying the prevention and treatment of PD with regards to the inhibition of oxidative stress, the regulation of mitochondrial dysfunction, the reduction of toxic excitatory amino acids (EAA), the inhibition of neuroinflammation, the inhibition of neuronal apoptosis, and the inhibition of abnormal protein aggregation.

Alzheimer's disease (AD) is a devastating neurological illness with a heavy economic impact. Further comorbidities in combination with the social impact of this disorder increase the urgency of a clearer comprehension of its etiopathogenesis, allowing the execution of novel therapeutic strategies. Despite astrocytes have been widely described as active participant in the regulation of cerebral circuits, available data are still poor. Even less information is available about their precise role in the pathogenesis of illness. Moreover, the scant knowledge about the astrocyte-neuron interplay in health and disease still impedes pioneering discoveries. The focus of this review is to look for new and innovative pharmacological approaches against AD. In order to perform this, we used the following keywords in PubMed search engine: astrocytes, therapy, Alzheimer's disease, and glia in different combinations. With this review, we collected data available in literature describing how also astrocytes besides neurons might be new potential targets for drug discovery. Different approaches currently being studied include modulation of glutamate transporters expression, astroglial genetic manipulation, free radicals inhibition, up-regulation of neurotrophins, and regulation of astrogliosis and neuroinflammation. Since several studies already demonstrated that astrocytes are definitely involved in AD pathogenesis, these cells can represent a promising new therapeutic target.

Contributions of glial cells to neuroenergetics have been the focus of extensive debate. Here we provide positron emission tomography evidence that activation of astrocytic glutamate transport via the excitatory amino acid transporter GLT-1 triggers widespread but graded glucose uptake in the rodent brain. Our results highlight the need for a reevaluation of the interpretation of [(18)F]FDG positron emission tomography data, whereby astrocytes would be recognized as contributing to the [(18)F]FDG signal.

This chapter reviews models of generalized seizures induced by systemic administration of chemical agents in adult rodents. Models of acute seizures induced by chemoconvulsants still represent a valuable research tool used for screening of putative antiseizure drugs, in the toxicology research investigating convulsant properties of naturally occurring and man-made toxins, as well as for studies on mechanisms of action of these convulsant drugs. Models using drugs affecting GABA-A receptor and GABA synthesis, excitatory amino acids, cholinergic agents including organophosphorus compounds, and other drugs, such as strychnine and aminophylline are presented and their major features are described. Information regarding solubility, dosing, and appropriate routes of administration are discussed and examples of seizure outcome are presented including EEG samples recorded in mice and rats.

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Oxidative stress has been implicated in a variety of conditions, including cancer, heart failure, diabetes, neurodegeneration and other diseases. A potential biomarker for oxidative stress is the cystine/glutamate transporter, system xC−. l -Aminosuberic acid ( l -ASu) has been identified as a system xC− substrate. Here we report a facile method for [11C]N-Me labeling of l -ASu, automation of the radiochemical process, and preliminary PET imaging with EL4 tumor bearing mice. The results demonstrate uptake in the tumor above background, warranting further studies on the use of radiolabeled analogs of l -ASu as a PET imaging agent for system xC−.

Throughout the centuries, the horse and human relationship has evolved from one of sustenance to one of partnership. Historically, the idea of horses being partnered with humans in a therapeutic capacity is evident from writings of the ancient Greeks to documentation by European physicians and therapists from the 1500s through the 1800s. The impetus for the development of modern day equine-assisted activities and therapies (EAAT) is credited to a Danish dressage rider named Lis Hartel, who...

Date Presented 04/05/19 This presentation will review findings from a phenomenological study conducted by graduate MOT students to explore the lived experiences of veterans with PTSD participating in equine-assisted activities and therapies (EAAT). Veterans found that this nontraditional treatment provided safety, healing, and meaning to their lives, along with establishing new routines and skills, without the stigma associated with mainstream treatment. Study limitations and future research recommendations will be discussed. Primary Author and Speaker: Elise Bloch Additional Authors and Speakers: Zoey Kramer Contributing Authors: Ashni Franklin, Gianina Padua

Background The glutamate type 1 transporter (GLT1) plays a major role in glutamate homeostasis in the brain. Although alterations of GLT1 activity have been linked to persistent pain, the significance of these changes is poorly understood. Focusing on the rostral ventromedial medulla, a key site in pain modulation, we examined the expression and function of GLT1 and related transcription factor kappa B-motif binding phosphoprotein (KBBP) in rats after adjuvant-induced hind paw inflammation. Results After inflammation, GLT1 and KBBP showed an early upregulation and gradual transition to downregulation that lasted throughout the eight-week observation period. Nitration of GLT1 was reduced at 30 min and increased at eight weeks after inflammation, suggesting an initial increase and later decrease in transporter activity. Mechanical hyperalgesia and paw edema exhibited an initial developing phase with peak hyperalgesia at 4 to 24 h, a subsequent attenuating phase, followed by a late persistent phase that lasted for months. The downregulation of GLT1 occurred at a time when hyperalgesia transitioned into the persistent phase. In the rostral ventromedial medulla, pharmacological block with dihydrokainic acid and RNAi of GLT1 and KBBP increased nociception and overexpression of GLT1 reversed persistent hyperalgesia. Further, the initial upregulation of GLT1 and KBBP was blocked by local anesthetic block, and pretreatment with dihydrokainic acid facilitated the development of hyperalgesia. Conclusions These results suggest that the initial increased GLT1 activity depends on injury input and serves to dampen the development of hyperalgesia. However, later downregulation of GLT1 fosters the net descending facilitation as injury persists, leading to the emergence of persistent pain.

ddosuny@hanmail.net This is an Open-Access article distributed under the terms of t he Creative Commons Attribution Non-Commercial License (http:// creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Copyright © 2013 Korean Academy of Physical Therapy Rehabilitation Science

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

Amyotrophic lateral sclerosis (ALS) is the most common form of motor neuron disease worldwide, leading to progressive muscle atrophy and paralysis. The limited success of conventional treatment for ALS has prompted investigations into complementary and alternative therapies. Herbal remedies provide good prospects of ALS prevention and treatment, with advantages such as multiple targets, multiple links, and few side effects. Studies in vitro and in vivo have shown that herbs have a great potential for treatment of ALS, with therapeutic effects against oxidative stress, excitatory amino acid toxicity, neuroinflammation, and calcium cytotoxicity. Active monomers or ingredients extracted from herbs are considered promising candidates for ALS. Therefore, we review recent experimental research on monomers and compounds isolated from herbal remedies for preventing and treating ALS.