Blockade of the GLT-1 Transporter in the Central Nucleus of the Amygdala Induces both Anxiety and Depressive-Like Symptoms

Depression has been associated with abnormalities in glutamatergic neurotransmission and decreased astrocyte number in limbic areas. We previously demonstrated that global and prefrontal cortical blockade of the astrocytic glutamate transporter (GLT-1) induces anhedonia and c-Fos expression in areas that regulate anxiety, including the central amygdala (CEA). Given the role of the amygdala in anxiety and the high degree of comorbidity between anxiety and depression, we hypothesized that GLT-1 blockade in the CEA would induce symptoms of anhedonia and anxiety in rats. We microinjected the GLT-1 inhibitor, dihydrokainic acid (DHK), into the CEA and examined effects on intracranial self-stimulation (ICSS) as an index of hedonic state, and on behavior in two anxiety paradigms, elevated plus maze (EPM) and fear conditioning. At lower doses, intra-CEA DHK produced modest increases in ICSS responding (T0). Higher doses resulted in complete cessation of responding for 15 min, suggesting an anhedonic or depressive-like effect. Intra-CEA DHK also increased anxiety-like behavior such that percent time in the open arms and total entries were decreased in the EPM and acquisition of freezing behavior to the tone was increased in a fear-conditioning paradigm. These effects did not appear to be explained by non-specific changes in activity, because effects on fear conditioning were assessed in a drug-free state, and a separate activity test showed no significant effects of intra-CEA DHK on locomotion. Taken together, these studies suggest that blockade of GLT-1 in the CEA is sufficient to induce both anhedonia and anxiety and therefore that a lack of glutamate uptake resulting from glial deficits may contribute to the comorbidity of depression and anxiety.     

Blockade of Astrocytic Glutamate Uptake in Rats Induces Signs of Anhedonia and Impaired Spatial Memory

Mood disorders are associated with regional brain abnormalities, including reductions in glial cell and neuron number, glutamatergic irregularities, and differential patterns of brain activation. Because astrocytes are modulators of neuronal activity and are important in trafficking the excitatory neurotransmitter glutamate, it is possible that these pathologies are interrelated and contribute to some of the behavioral signs that characterize depression and related disorders. We tested this hypothesis by determining whether depressive-like signs were induced by blocking central astrocytic glutamate uptake with the astrocytic glutamate transporter (GLT-1) inhibitor, dihydrokainic acid (DHK), in behavioral tests that quantify aspects of mood, including reward and euthymia/dysthymia: intracranial self-stimulation (ICSS) and place conditioning. We found that DHK elevated ICSS thresholds, a depressive-like effect that could reflect reduced sensitivity to reward (anhedonia) or increased aversion (dysphoria). However, DHK treatment did not establish conditioned place aversions, suggesting that this treatment does not induce dysphoria. To identify the brain regions mediating the behavioral effects of DHK, we examined c-Fos expression in areas implicated in motivation and emotion. DHK increased c-Fos expression in many of these regions. The dentate gyrus of the hippocampus was robustly activated, which led us to explore whether DHK alters hippocampal learning. DHK impaired spatial memory in the MWM. These findings identify disruption of astrocyte glutamate uptake as one component of the complex circuits that mediate anhedonia and cognitive impairment, both of which are common symptoms of depression. These finding may have implications for the etiology of depression and other disorders that share the features of anhedonia and cognitive impairment.     

Blockade of Astrocytic Glutamate Uptake in the Prefrontal Cortex Induces Anhedonia

Major depression is associated with both dysregulated glutamatergic neurotransmission and fewer astrocytes in limbic areas including the prefrontal cortex (PFC). These deficits may be functionally related. Notably, astrocytes regulate glutamate levels by removing glutamate from the synapse via the glutamate transporter (GLT-1). Previously, we demonstrated that central blockade of GLT-1 induces anhedonia and c-Fos expression in the PFC. Given the role of the PFC in regulating mood, we hypothesized that GLT-1 blockade in the PFC alone would be sufficient to induce anhedonia in rats. We microinjected the GLT-1 inhibitor, dihydrokainic acid (DHK), into the PFC and examined the effects on mood using intracranial self-stimulation (ICSS). At lower doses, intra-PFC DHK produced modest increases in ICSS thresholds, reflecting a depressive-like effect. At higher doses, intra-PFC DHK resulted in cessation of responding. We conducted further tests to clarify whether this total cessation of responding was related to an anhedonic state (tested by sucrose intake), a nonspecific result of motor impairment (measured by the tape test), or seizure activity (measured with electroencephalogram (EEG)). The highest dose of DHK increased latency to begin drinking without altering total sucrose intake. Furthermore, neither motor impairment nor evidence of seizure activity was observed in the tape test or EEG recordings. A decrease in reward value followed by complete cessation of ICSS responding suggests an anhedonic-like effect of intra-PFC DHK; a conclusion that was substantiated by an increased latency to begin sucrose drinking. Overall, these results suggest that blockade of astrocytic glutamate uptake in the PFC is sufficient to produce anhedonia, a core symptom of depression.     

AM404, an inhibitor of anandamide reuptake decreases Fos-immunoreactivity in the spinal cord of neuropathic rats after non-noxious stimulation

Cannabinoids like anandamide are involved in pain transmission. In this study we evaluated the effects of administrating N-(4-hydroxyphenyl)-5Z,8Z,11Z,14Z-eicosatetraenamide (AM404), an inhibitor of anandamide reuptake and monitoring the expression of c-fos, a marker of activated neurons in an experimental model of neuropathic pain (sciatic nerve tying). Fos expression was monitored 14 days after tying of sciatic nerve and 2 h after non-noxious stimulation. We showed that non-noxious stimulation increased Fos-positivity in the dorsal superficial laminae of the lumbar spinal cord of tied animals but not in the control animals. AM404 significantly reduced Fos induction in tied animals. Co-administration of cannabinoid CB1 receptor, cannabinoid CB2 receptor and transient receptor potential vanilloid type 1 (TRPV-1) antagonists reduced the effect of AM404 and this reduction was higher using cannabinoid CB1 receptor antagonist. These results suggest that AM404 could be a useful drug to reduce neuropathic pain and that cannabinoid CB1 receptor, cannabinoid CB2 receptor and vanilloid TRPV-1 receptor are involved.     

脊髓谷氨酸转运体1对大鼠坐骨神经慢性压迫损伤及吗啡耐受的影响

为了探讨脊髓谷氨酸转运体1 (GLT-1) 的表达量和活性状态与吗啡耐受和神经源性痛的关系,利用大鼠坐骨神经慢性压迫损伤 (CCI) 模型,以机械性缩足痛阈值 (MWT) 为评估指标,谷氨酸转运体激动剂β内酰胺类抗生素头孢曲松钠为工具药,观察对大鼠机械痛敏和吗啡耐受的影响;以实时定量PCR及Western blotting考察脊髓GLT-1表达水平的变化。结果表明,CCI大鼠在术后1周与对照组相比MWT值下降约80%;CCI大鼠单独使用吗啡产生快速耐受,给药第3天与CCI模型对照组大鼠比较MWT值已无明显差异,脊髓GLT-1表达也明显下调;单独使用头孢曲松钠对痛敏有改善作用,脊髓GLT-1表达明显上调;吗啡伴随头孢曲松钠给药组耐受速度明显减慢,给药6天后MWT值仍保持在较高水平,与CCI吗啡耐受组比较有显著性差异,GLT-1表达明显上调。因此,脊髓GLT-1活性变化与神经源性痛及吗啡耐受的形成密切相关,促进GLT-1功能可显著延缓吗啡耐受与痛敏形成。     

NMDA受体介导皮下注射福尔马林诱发的大鼠脊髓Fos蛋白的表达

AIM: To examine the effects of N-methyl-D-aspartate (NMDA) and non-NMDA receptors on noxious stimulation-induced Fos expression in the rat spinal cord. METHODS: Formalin (2%) was injected s.c. into one hindpaw of the rat. Fos expression was exhibited by immunocytochemical technique. RESULTS: Two hours after s.c. formalin, Fos-like immunoreactive (FLI) neurons were distributed mainly in medial part of the lamina I and the outer lamina II of the ipsilateral dorsal horn. dl-2-Amino-5-phosphonovalerate (APV) administered intrathecally (10 microL, 0.01, 0.1, or 1 g.L-1) before injection of formalin into a hindpaw reduced the number of FLI neurons dose-dependently in the dorsal horn (P < 0.01), while 6,7-dinitroquinoxaline-2, 3(1H,4H)-dione (DNQX) (1 g.L-1) was ineffective. CONCLUSION: NMDA receptor mediated noxious stimulation-induced Fos expression in the rat spinal cord.     

CNQX对伤害性刺激隐神经诱发大鼠脊髓Fos蛋白表达的影响

目的 探讨伤害性刺激隐神经（SN）能否诱发脊髓神经元Fos蛋白表达及发生机制.方法 应用免疫组化方法观察伤害性刺激SN和尾静脉注射谷氨酸非NMDA受体拮抗剂（CNQX）后诱发脊髓神经元Fos蛋白表达的变化.结果 伤害性刺激SN后,诱导脊髓神经元Fos蛋白表达显著增强,CNQX拮抗了Fos蛋白表达的显著增强.结论 以伤害性刺激SN模拟躯体痛后,CNQX拮抗了伤害性刺激SN引起的脊髓神经元Fos蛋白表达的显著增加,表明非NMDA受体在躯体痛的调控中起到了重要的作用.     

Measurement of glutamate uptake and reversed transport by rat synaptosome transporters

To establish an assay system for evaluation of the uptake and reversed transport of glutamate, we examined the effects of Na(+)-concentration and pharmacological agents on the extracellular glutamate concentration ([Glu](o)) in rat cortical synaptosomes in vitro. There was a decrease and increase of the [Glu](o) at high and low Na(+) concentrations, respectively, in a Ca(2+)-free medium. The changes in [Glu](o) in both directions were temperature-sensitive, and reversed at around 30 mM of Na(+). Dihydrokainate (DHK), a non-transportable inhibitor selective for glial glutamate transporter GLT-1, suppressed the decrease in [Glu](o), and the reversal of [Glu](o) change was shifted to about 60 mM Na(+). There was no change in the maximum [Glu](o) at total Na(+) substitution. Further pharmacological analysis revealed that D-aspartate and DL-threo-beta-hydroxy-aspartate (THA), transportable substrates of glutamate transporters, increased the [Glu](o) in standard media. In contrast, beta-phenylglutamic acid, a structural analogue of glutamate, suppressed both the decrease in [Glu](o) in standard medium and the increase in [Glu](o) in low Na(+) medium. It is, thus, concluded that both the direction and the amount of [Glu](o) changes are determined by a balance of the uptake and reversed transport of glutamate, and that this assay system is suitable for evaluation of the effect of this on glutamate transporters.     

The neuroprotective agent MS-153 stimulates glutamate uptake

We investigated the effect of (R)-(-)-5-methyl-1-nicotinoyl-2-pyrazoline (MS-153), a novel neuroprotective agent, on L-[3H]glutamate uptake through GLT-1, a Na(+)/K(+)-dependent glial glutamate transporter, expressed in COS-7 cells. MS-153 (1-100 microM) accelerated the L-[3H]glutamate uptake through GLT-1 in a concentration-dependent and time-dependent manner. Eadie-Hofstee analysis revealed that MS-153 significantly decreased the K(m) of the glutamate uptake by COS-7 cells expressing GLT-1. In contrast, [3H]gamma-aminobutyric acid (GABA) uptake through a glial GABA transporter was not affected. In addition, MS-153 increased Na(+) currents through GLT-1 expressed in Xenopus oocytes. We also investigated the effect of MS-153 on amino acid efflux from rat hippocampal slices. The increase in glutamate efflux induced by 50 mM KCl was significantly attenuated by the treatment with MS-153 at 10 microM, while MS-153 had no significant effect on the K(+)-evoked efflux of GABA. Furthermore, the increase in glutamate efflux by ischemia (hypoxia/aglycemia) was partially, but significantly inhibited by MS-153. These results suggest that the cerebroprotective effect of MS-153 in this ischemic model in vivo is due to the specific reduction of the glutamate concentration in the extracellular space, which can probably be attributed to the acceleration of glutamate uptake by the indirect modulation of the glutamate transporter activity.     

Activation of ERK／CREB pathway in spinal cord contributes to chronic constrictive injury-induced neuropathic pain in rats

Aim: To investigate whether activation and translocation of extracellular signalregulated kinase (ERK) is involved in the induction and maintenance of neuropathic pain, and effects of activation and translocation of ERK on expression of pCREB and Fos in the chronic neuropathic pain. Methods: Lumbar intrathecal catheters were chronically implanted in male Sprague-Dawley rats. The left sciatic nerve was loosely ligated proximal to the sciatica‘s trifurcation at approximately 1.0 mm intervals with 4-0 silk sutures. The mitogen-activated protein kinase kinase (MEK) inhibitor U0126 or phosphorothioate-modified antisense oligonucleotides (ODN) were intrathecally administered every 12 h, 1 d pre-chronic constriction injury (CCI) and 3 d post-CCI. Thermal and mechanical nociceptive thresholds were assessed with the paw withdrawal latency (PWL) to radiant heat and von Frey filaments. The expression of pERK, pCREB, and Fos were assessed by both Western blotting and immunohistochemical analysis. Results: Intrathecal injection of U0126 or ERK antisense ODN significantly attenuated CCI-induced mechanical allodynia and thermal hyperalgesia. CCI significantly increased the expression of p-ERK-IR neurons in the ipsilateral spinal dorsal horn to injury, not in the contralateral spinal dorsal horn. The time courses of pERK expression showed that the levels of both cytosol and nuclear pERK, but not total ERK, were increased at all points after CCI and reached a peak level on postoperative d 5. CCI also significantly increased the expression of pCREB and Fos. Phospho-CREB-positive neurons were distributed in all laminae of the bilateral spinal cord and Fos was expressed in laminae I and II of the ipsilateral spinal dorsal horn. Intrathecal injection of U0126 or ERK antisense ODN markedly suppressed the increase of CCI-induced pERK, pCREB and c-Fos expression in the spinal cord. Conclusion:The activation of ERK pathways contributes to neuropathic pain in CCI rats, and the function of pERK may partly be accomplished via the cAMP response element binding protein (CREB)-dependent gene expression.     

Aroclor 1254 selectively inhibits expression of glial GLT-1 glutamate transporter in the forebrain of chronically exposed adult rat

Aroclor 1254, a commercially produced mixture of polychlorinated biphenyls, is known to cause many adverse conditions, including neurotoxicity. It has been recently postulated that upregulation of N-methyl-d-aspartate receptors (NMDARs) and enhanced glutamate signalling which leads to excitotoxicity, is the mechanism of Aroclor-induced neurotoxicity. To obtain insights into the mechanisms underlying glutamatergic overstimulation, we investigated the function and expression of sodium-dependent glutamate transporters which are known to regulate extracellular glutamate concentrations in the brain. Exposure to Aroclor 1254 was found to significantly lower the uptake of radioactive glutamate into gliosomal fractions obtained from adult rat brains. It also markedly decreased the expression of both protein and mRNA of GLT-1, the main glial glutamate transporter. This indicates that downregulation of GLT-1 may potentially lead to disturbances in glutamate clearance. The expression of GLAST, another astroglial glutamate transporter, was unchanged under conditions of Aroclor toxicity. Conversely, we observed enhanced glutamate uptake into nerve-endings fractions paralleled by increased EAAC1 protein expression. This may reflect the induction of protective mechanisms.     

Role of glutamate transporters in the modulation of stress-induced lactate metabolism in the rat brain

Rationale Lactate, like glucose, has recently been found to be an energy substrate for neural activity. It is indicated that lactate is produced by astrocytes under the regulation of glutamatergic tone. Objectives Using in vivo microdialysis technique, we measured extracellular lactate concentrations in the medial prefrontal cortex (mPFC) and basolateral amygdala (BLA) of rats. To investigate the role of the glutamate transporter in the modulation of footshock stress-induced energy demands in both brain regions, we attempted to determine whether the footshock stress-induced changes of extracellular lactate concentrations are attenuated by local perfusion of the glutamate uptake inhibitor dihydrokainate (DHK). Results Perfusion of 1.0 mM DHK produced an increase in basal extracellular lactate levels in the mPFC and BLA, whereas 0.1 mM DHK did not affect lactate concentrations in either region. DHK also attenuated stress-induced increment of extracellular lactate concentrations in the mPFC, and completely prevented it in the BLA. Conclusions These results suggest that glutamate transporters regulate lactate availability in astrocytes and indicate that the rapid energy demand induced by glutamate contributes to local lactate production.     

Glia mechanisms in mood regulation: a novel model of mood disorders

Introduction Recent evidence in clinical and preclinical studies has implicated glutamate neurotransmissions in pathophysiology of mood disorders. The regulation of amino acid neurotransmission, i.e., glutamate and gamma-aminobutyric acid (GABA) involves coordinated mechanisms of uptake and transport within a tripartite synaptic system that includes neurons and glia. Newly appreciated role of the glia, more specifically astrocytes on neuronal functions combined with reported postmortem abnormalities of glia in patients with mood disorders further supports the role of glia in mood disorders. Materials and methods This report presents some of our preliminary results utilizing glia-selective toxins and other pharmacological tools to suppress glial function within the limbic system to study the resulting behavioral abnormalities, and thus, elucidate glial involvement in the development of mood disorders. Results and discussion We demonstrate that chronic blockade of glutamate uptake by a glial/neuronal transporter antagonist l-trans-pyrrolidine-2,4-dicarboxylic acid (PDC) within the amygdala, a key area implicated in mood regulation, results in dose-dependent reduction in social exploratory behavior and disrupts circadian activity patterns consistent with symptoms of mood disorders. Similarly, the selective astrocytic glutamate transporter type 1 (GLT-1) blocker dihydrokainic acid (DHK) injected into the amygdala also results in reduced social interaction that is blocked by selective glutamate N-methyl-d-aspartate (NMDA) type receptor antagonist AP5. The results are discussed in the context of glial and glutamate mechanisms in mood disorders and potential therapeutic avenues to address these mechanisms.     

Different roles of two nitric oxide activated pathways in spinal long-term potentiation of C-fiber-evoked field potentials

There is accumulating evidence implicating the involvement of nitric oxide (NO) in spinal central sensitization. The long-term potentiation (LTP) of spinal C-fiber-evoked field potentials is considered as a fundamental mechanism of sensitization of nociceptive neurons in the spinal cord. The present study examined the roles of soluble guanylate cyclase (sGC) or ADP-ribosyltransferase (ADPRT), two potential NO targets, in spinal LTP. The results showed that (1) administration of sGC inhibitors, methyl blue (MB, 4mM, 20 microl) or 1H-[1,2,4]oxadiazolo[4,3-a]-quiloxalin-1-one (ODQ, 10 microM, 20 microl) before tetanic stimulation, significantly inhibited the induction of spinal LTP, and this was reversed by 8-Br-cGMP, a membrane-permeable cGMP analog. However, the maintenance of spinal LTP was not changed when application of ODQ 2h after tetanic stimulation. (2) Although our previous experiments have identified a key role for NO in the induction of spinal LTP, NO synthase (NOS) inhibitor, L-NAME (1mM, 20 microl) or hemoglobin (2mg/ml, 20 microl), a scavenger of NO, had no effect on established spinal LTP when applied 2h after the induction of spinal LTP. (3) The mono-ADPRT inhibitor, nicotinamide (10mM, 20 microl), had no effect on the induction and maintenance of spinal LTP. However, the poly-ADPRT inhibitor, benzamide (100 microM, 20 microl), inhibited its maintenance, but not its induction. The results suggest that NO-stimulated guanylyl cyclase activity plays a critical role in the induction of LTP of C-fiber-evoked field potentials in the spinal cord, whereas NO-related poly-ADPRT activity contributes to the maintenance of spinal LTP.     

The role of astroglia in Pb-exposed adult rat brain with respect to glutamate toxicity

Astrocytes maintain neuronal homeostasis in brain and controlling of the released glutamate is one of the most important functions. Since it is suggested that glutamatergic component underlies lead-induced neurotoxic effects and simultaneously, astrocytes serve as a cellular lead (Pb) deposition site, it was of interest to investigate the functioning of astroglia in adult rat brain after short-term exposure to Pb. We examined the expression of main astrocytic glutamate/aspartate transporters--GLAST and GLT-1, which regulate extracellular glutamate concentration. Molecular evidence is provided which indicates overexpression of GLAST mRNA and protein. Simultaneously, decreased expression of GLT-1 mRNA and protein was observed, indicating that of the two glial transporters, GLT-1 is more susceptible to the toxic Pb effect. Protein expression of glutamine synthetase (GS), which converts toxic glutamate to non-toxic glutamine, was doubly enhanced. Moreover, Na+-dependent transport of radioactive glutamine to astroglia-derived fraction was affected in Pb-exposed rats. Both the rate of accumulation and the efflux of amino acid were diminished. Additionally, we observed enhanced expression of glutathione-protein complexes after Pb treatment what suggests activation of S-glutathionylation processes. The results of current studies indicate that lead toxicity in adult rat brain activates astrocytic processes connected with the controlling of glutamate homeostasis. The response of astroglia is rather of neuroprotective character however, downexpression of GLT-1 glutamate transporter and activation of S-glutathionylation processes lead to the question about their significance in Pb-induced neurotoxicity.     

Effects of milnacipran, a 5-HT and noradrenaline reuptake inhibitor, on C-fibre-evoked field potentials in spinal long-term potentiation and neuropathic pain

BACKGROUND AND PURPOSE

The analgesic action of 5-HT and noradrenaline reuptake inhibitors (SNRIs) on nociceptive synaptic transmission in the spinal cord is poorly understood. We investigated the effects of milnacipran, an SNRI, on C-fibre-evoked field potentials (FPs) in spinal long-term potentiation (LTP), a proposed synaptic mechanism of hypersensitivity, and on the FPs in a neuropathic pain model.

EXPERIMENTAL APPROACH

C-fibre-evoked FPs by electrical stimulation of the sciatic nerve fibres were recorded in the spinal dorsal horn of anaesthetized adult rats, and LTP was induced by high-frequency stimulation of the sciatic nerve fibres. A rat model of neuropathic pain was produced by L5 spinal nerve ligation and transection.

KEY RESULTS

Milnacipran produced prolonged inhibition of C-fibre-evoked FPs when applied spinally after the establishment of LTP of C-fibre-evoked FPs in naïve animals. In the neuropathic pain model, spinal administration of milnacipran clearly reduced the basal C-fibre-evoked FPs. These inhibitory effects of milnacipran were blocked by spinal administration of methysergide, a 5-HT_1/2 receptor antagonist, and yohimbine or idazoxan, α₂-adrenoceptor antagonists. However, spinal administration of milnacipran in naïve animals did not affect the basal C-fibre-evoked FPs and the induction of spinal LTP.

CONCLUSION AND IMPLICATIONS

Milnacipran inhibited C-fibre-mediated nociceptive synaptic transmission in the spinal dorsal horn after the establishment of spinal LTP and in the neuropathic pain model, by activating both spinal 5-hydroxytryptaminergic and noradrenergic systems. The condition-dependent inhibition of the C-fibre-mediated transmission by milnacipran could provide novel evidence regarding the analgesic mechanisms of SNRIs in chronic pain.     

Impaired long-term potentiation and hippocampus-dependent memory formation in AQP4 knockout mice is rescued by GLT-1 activation

OBJECTIVE Although the role of newly identified aquaporin 4(AQP4) in water transport has been extensively investigated,little is known about its contribution to hippocampal synaptic plasticity and memory.Since it has been detected widely co-localized with glutamate transporter 1(GLT-1) in astrocytes,we thus investigated whether AQP4 was implicated in long-term potentiation(LTP) and memory formation via GLT-1.METHODS Using tissue immunofluorescence double staining to measure coexpression of AQP4 and GLT-1.WB was employed to detect the expression of GLT-1.In vivo electrophysiological recording method was established to record the PS,and TBS was developed for the induction of LTP.Contextual fear conditioning test was used to evaluate hippocampus-dependent memory.Golgi impregnation indicated the density of dendritic spines.Results: Our present study demonstrated that AQP4 deficiency impaired hippocampal LTP and hippocampus-dependent memory formation and this impairment was mediated by the down-regulation of GLT-1 expression/function in hippocampus in AQP4 knockout(KO) mice,since it could be rescued by ceftriaxone(Cef),a stimulator of GLT-1.CONCLUSION These results suggest that AQP4 functions as the modulator of synaptic plasticity and actively regulates learning and memory.     

谷氨酸转运体亚型谷氨酸转运体1与其调控药物的研究进展

胞外谷氨酸浓度的动态平衡是由谷氨酸转运体精确调控的,谷氨酸转运体功能或表达失调时导致胞外谷氨酸水平异常,引起一系列神经系统疾病。其中谷氨酸转运体1(GLT-1)起着"谷氨酸泵"作用,近年来还发现了仅在肽链C末端发生改变的GLT-1剪切变异体;其中GLT-1a、GLT-1b和GLT-1v发现与某些疾病具有相关性。药物调控谷氨酸转运体的表达或功能,维持胞外谷氨酸正常浓度,能有效改善病理状况。目前已有多种药物被报道对谷氨酸转运体具有激动或抑制作用,如能够上调GLT-1活性的药物有头孢曲松、苯环己哌啶、胞二磷胆碱、利鲁唑、凝血酶、蛋白激酶B等;下调GLT-1活性的药物有依托咪酯、氯氮平、天冬酰胺类衍生物、内皮素等。该文将调控谷氨酸转运体的药物做一总结,为药物开发和临床治疗提供新的思路。