14 replies to this topic

[gamesguru]

One role of NAD+ is as a co-factor to glutamate dehydrogenase^[1].  So supplemental NAC ⇒ lower ratio of glutamate to α-ketoglutarate

 

As for cysteine,

Whether the extracellular glutamate activates mostly autoreceptors or receptors will be determined by the receptor density, synapse structure, and flow/current.

L-cysteine sulfinic acid as an endogenous agonist of a novel metabotropic receptor coupled to stimulation of phospholipase D activity.

Disulfide bonding and cysteine accessibility in the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor subunit GluRD. Implications for redox modulation of glutamate receptors.
dithiothreitol (DTT)-induced increase in agonist affinity of certain ionotropic glutamate receptors (GluRs), presumably due to reduction of a disulfide bridge formed between cysteine residues conserved among all GluRs [by preventing bonds, DTT conserves/increases cysteine, which is a co-factor to/increases glutamate]

 

Effect of amino acid ergot alkaloids on glutamate transport via human glutamate transporter hGluT-1
Effect of amino acid ergot alkaloids on glutamate transport via the human glutamate transporter (hGluT-1) was investigated using hGluT-HeLaS3 cells, which stably expressed high levels of hGluT-1. Ergotamine enhanced the glutamate uptake of hGluT-HeLaS3 cells in a concentration-dependent manner, increasing the initial velocity of glutamate uptake by 1.45 times at 10 microM. Other amino acid alkaloids, bromocriptine and dihydroergotamine, also augmented glutamate uptake, whereas amine alkaloids, ergonovine or lisuride did not influence glutamate uptake. The accelerating effect required a preincubation longer than 5 min. Kinetic studies on hGluT-1 revealed that ergot alkaloids decreased a Michaelis constant (Km) for glutamate with unchanged maximum velocity. The effect of bromocriptine was not mediated by dopamine D1 or D2 receptors, and was independent of its antioxidant action. Amino acid ergot alkaloids may serve as a prototype for agents that regulate glutamate transporters. These results may be useful in exploring new agents for neurological diseases associated with glutamatergic neurotoxicity.

 

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Curcumin inhibits glutamate release in nerve terminals from rat prefrontal cortex: possible relevance to its antidepressant mechanism.
There is abundant evidence suggesting the relevance of glutamate to depression and antidepressant mechanisms. Curcumin, a major active compound of Curcuma longa, has been reported to have the biological function of antidepressant. The aim of the present study was to investigate the effect of curcumin on endogenous glutamate release in nerve terminals of rat prefrontal cortex and the underlying mechanisms. The results showed that curcumin inhibited the release of glutamate that was evoked by exposing synaptosomes to the K(+) channel blocker 4-aminopyridine (4-AP). This phenomenon was blocked by the chelating the extracellular Ca(2+) ions, and by the vesicular transporter inhibitor bafilomycin A1, but was insensitive to the glutamate transporter inhibitor DL-threo-β-benzyl-oxyaspartate (DL-TBOA). Further experiments demonstrated that curcumin decreased depolarization-induced increase in [Ca(2+)]©, whereas it did not alter the resting membrane potential or 4-AP-mediated depolarization. Furthermore, the inhibitory effect of curcumin on evoked glutamate release was prevented by blocking the Ca(v)2.2 (N-type) and Ca(v)2.1 (P/Q-type) channels, but not by blocking intracellular Ca(2+) release or Na(+)/Ca(2+) exchange. These results suggest that curcumin inhibits evoked glutamate release from rat prefrontocortical synaptosomes by the suppression of presynaptic Ca(v)2.2 and Ca(v)2.1 channels. Additionally, we also found that the inhibitory effect of curcumin on 4-AP-evoked glutamate release was completely abolished by the clinically effective antidepressant fluoxetine. This suggests that curcumin and fluoxetine use a common intracellular mechanism to inhibit glutamate release from rat prefrontal cortex nerve terminals.

Luteolin inhibits the release of glutamate in rat cerebrocortical nerve terminals.
The present study investigated the effect and possible mechanism of luteolin, a food-derived flavonoid, on endogenous glutamate release in nerve terminals of rat cerebral cortex (synaptosomes). Luteolin inhibited the release of glutamate evoked by the K(+) channel blocker 4-aminopyridine (4-AP), and this phenomenon was concentration-dependent. The effect of luteolin on the evoked glutamate release was prevented by the chelation of the extracellular Ca(2+) ions and by the vesicular transporter inhibitor, but was insensitive to the glutamate transporter inhibitor. Luteolin decreased the 4-AP-induced increase in [Ca(2+)]©, whereas it did not alter 4-AP-mediated depolarization. Furthermore, the effect of luteolin on evoked glutamate release was abolished by blocking the Ca(v)2.2 (N-type) and Ca(v)2.1 (P/Q-type) channels, but not by blocking the ryanodine receptors or the mitochondrial Na(+)/Ca(2+) exchange. In addition, the inhibitory effect of luteolin on evoked glutamate release was prevented by the mitogen-activated/extracellular signal-regulated kinase (MEK) inhibitors. Western blot analyses showed that luteolin decreased the 4-AP-induced phosphorylation of extracellular signal-regulated kinase 1 and 2 (ERK1/2) and synapsin I, the main presynaptic target of ERK. Thus, it was concluded that luteolin inhibits glutamate release from rat cortical synaptosomes through the suppression of presynaptic voltage-dependent Ca(2+) entry and MEK/ERK signaling cascade.
 

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(-)-Epigallocatechin gallate, the most active polyphenolic catechin in green tea, presynaptically facilitates Ca2+-dependent glutamate release via activation of protein kinase C in rat cerebral cortex.
(-)-Epigallocatechin gallate (EGCG), the main polyphenolic constituent of green tea, has been reported to improve cognitive decline. Considering the central glutamatergic activity is crucial to cognitive function, the objective of this study was to investigate the effect of EGCG on the release of endogenous glutamate using nerve terminals purified from rat cerebral cortex. Results showed that the release of glutamate evoked by 4-aminopyridine (4AP) was facilitated by EGCG in a concentration-dependent manner, and this effect resulted from an enhancement of vesicular exocytosis and not from an increase in Ca2+-independent efflux via glutamate transporter. Examination of the effect of EGCG on cytoplasmic free Ca2+ concentration ([Ca2+]c) revealed that the facilitation of glutamate release could be attributed to an increase in Ca2+ influx through N- and P/Q-type voltage-dependent Ca2+ channels. Consistent with this, the EGCG-mediated facilitation of 4AP-evoked glutamate release was significantly prevented in synaptosomes pretreated with a combination of the N- and P/Q-type Ca2+ channel blockers. Additionally, inhibition of protein kinase C (PKC) by treatment with Ro318220 significantly reduced the facilitatory effect of EGCG on 4AP-evoked glutamate release and phosphorylation of PKC or its presynaptic target myristoylated alanine-rich C kinase substrate (MARCKS). These results suggest that EGCG effects a facilitation of glutamate release from glutamatergic terminals by positively modulating N- and P/Q-type Ca2+ channel activation through a signaling cascade involving PKC. In this EGCG/PKC signaling cascade facilitating glutamate release, the regulation of cytoskeleton dynamics was also indicated to be involved by disruption of cytoskeleton organization with cytochalasin D occluded the EGCG-mediated facilitation of 4AP-evoked glutamate release.

 

It appears to be regulatory in the case of (sorry) hypoglutaminergic states, suggesting if you respond adversely to it, you are in a (sorry) hyperglutaminergic state.

In any case, I don't think NAC is super effective at regulating hypoglutamate dysfunction.

Mechanisms of action of N-acetylcysteine (NAC). Top to bottom: increased activity of cystine–glutamate antiporter results in increased activation of metabotropic glutamate receptors on inhibitory neurons and facilitates vesicular dopamine release; NAC is associated with reduced levels of inflammatory cytokines and acts as a substrate for glutathione synthesis. These actions are believed to converge upon mechanisms promoting cell survival and growth factor synthesis, leading to increased neurite sprouting. BDNF = brain-derived neurotrophic factor; IL = interleukin; NADP = nicotinamide adenine dinucleotide phosphate; NADPH = reduced form of NADP; TNF = tumour necrosis factor.

Edited by gamesguru, 17 September 2015 - 09:05 PM.

[Blackkzeus]

I know Memantine is an NMDA antagonist but does it increase or inhibit glutamine release? 

[gamesguru]

Memantine depresses glutamate release through inhibition of voltage-dependent Ca2+ entry and protein kinase C in rat cerebral cortex nerve terminals: an NMDA receptor-independent mechanism.
Memantine has been used to treat several neurological diseases, including those associated with excessive glutamate release. It has been believed that the neuroprotective effect of memantine results from its inhibitory effect on glutamate-induced neurotoxicity via postsynaptic N-methyl-d-aspartate receptor (NMDAR) antagonism. However, the presynaptic effect of memantine on glutamate release has never been examined. Therefore, the aim of this study was to investigate the effect of memantine on the release of glutamate from rat cerebral cortex nerve terminals (synaptosomes). Results showed that memantine inhibited the release of glutamate evoked by 4-aminopyridine (4-AP) in a concentration-dependent manner. The effect of memantine on the evoked glutamate release was insensitive to the NMDAR antagonist D-AP5, but prevented by the chelating intrasynaptosomal Ca2+ ions, and by the vesicular transporter inhibitor bafilomycin A1. In addition, memantine reduced depolarization-induced increase in cytosolic Ca2+ without any effect on synaptosomal excitability, and the reduction of glutamate release could be prevented by blocking the N and P/Q type Ca2+ channels. Furthermore, the memantine-mediated inhibition on 4-AP-evoked glutamate release could be diminished by the protein kinase C (PKC) inhibitors, and memantine significantly reduced the depolarization-induced phosphorylation of PKC, and PKCalpha. Thus, the effect of memantine on evoked glutamate release is linked to a decrease in [Ca2+]i contributed by Ca2+ entry through presynaptic voltage-dependent Ca2+ channels and to the subsequent suppression of the PKC signaling cascade.

[Area-1255]

I know Memantine is an NMDA antagonist but does it increase or inhibit glutamine release? 

A little of both; NMDAR's can be pre-synaptic and given their role in calcium channel activation - combined with knowledge of co-localization with other receptors; like D1-dopamine and A1-adrenergic - blocking them could force a flood of calcium to other metabatropic receptors thus leading to inhibition of GABA and then rerunning the glutamate release back etc

 

Additionally, Memantine also has nicotinic antagonist properties; of which could decrease or increase glutamate; depending on net acetylcholine threshold and degree of muscarinic activation.

 

It also however, has serotonin 5-HT3 antagonist effects; which can lead to an enhancement of Glutamate activity.

 

http://onlinelibrary...3.tb00254.x/pdf

 

http://www.researchg...substance_abuse

 

http://www.medscape....rticle/748581_3

 

http://www.ncbi.nlm....les/PMC3481041/

 

http://www.ncbi.nlm....pubmed/19420298

[nootist]

To what's already been said, I'd add that NAC causes release of glutamate into extracellular space, and activates mGluR group II (2,3).  The result is inhibitory rather than excitative.  This lets it do things which look a little paradoxical, like increasing the amount of glutamate available to a speedfreak's brain, while putting a damper on their buzz.  

[nootist]

I'm not sure that I'm disagreeing with what Gamesguru said, since it could be true in some cases which haven't occurred to me.  Right now I'm testing some things on three people who could be said to be in a sorry hyperglutamatergic state; two of them are autistic and the third has OCD and a history of vasovagal syncope with grand mal seizures.  All have responded well to NAC, and for the last four days I've added in faso and coluracetam, which boost mGluR2,3,4,7 and mGluR2,3 respectively.  The excitatory mGluRs are group I (1,5), which activate phospholipase C, while II (2.3), and III (4,6,7,8) are generally deemed inhibitory.  (They do a lot of other things too, which I'm skipping for now.)  mGluR7 has been characterized as a possible "emergency brake" for the glutamate system, and when de novo mutations have knocked out either 6 or 7 in humans, they had seizures, symptoms of autism, and hyperglutamatergy.

 

I wouldn't want to pile up my oversimplifications and act like that's all there is to NAC, because mGluRs are just the tip of the iceberg.   Glutathione, obviously, and then there are the various other sorts of receptors, and interactions between the lot of them, whether direct or indirect.  For the next bit of the thread I'm doing on autism, I'll be getting pretty deep into mGluRs, so I don't want to load up your thread with stuff I'm preparing to document elsewhere, but I have to say that they really tie into everything in the body.  Example:

 

mGluR3 interacts with GRIP1, which interacts with GRIA2, 3, and 4, and GRIK 2 and 3.

mGluR3 also interacts with PICK1, which interacts with mGluR7, GRIA2, 3, and 4, GRIK 1, 2 and 3, ACCN2, HER2, BNC1, and the dopamine transport system.

 

I could go on, but you get the idea.  Changing even one thing, cascades into incredibly complicated sequences of events.  I'd imagine that someone could respond badly (or well) to NAC for quite a number of reasons, but will leave it to Gamesguru to clarify what he had in mind when he said that.  I'm a pathetic mindreader.  :-P

 

 

 

To what's already been said, I'd add that NAC causes release of glutamate into extracellular space, and activates mGluR group II (2,3).  The result is inhibitory rather than excitative.  This lets it do things which look a little paradoxical, like increasing the amount of glutamate available to a speedfreak's brain, while putting a damper on their buzz.  

 

Do you disagree, then, with gamesguru's statement that NAC "appears to be regulatory in the case of (sorry) hypoglutaminergic states, suggesting if you respond adversely to it, you are in a (sorry) hyperglutaminergic state." I feel farther away from the truth the more evidence I look into. Are mGLu group II (2,3) receptors like brakes which inhibit glutamate release in other areas? Gamesguru seems so sure of himself, yet, if you search on google, many people say the opposite; that their glutamate is overfiring and that NAC dampens this action. They often cite that NAC causes more glutamate to be used up for glutathione synthesis.

 

 

Edited by nootist, 30 September 2015 - 05:58 AM.

[gamesguru]

i sure forgot some stuff...

whether anxious or relaxed, the state will be determined by the brain areas affected.  eg) activating areas with mGluR1/5 tends to be anxiogenic, activating areas with mGluR2 is anxiolytic

when effects compete, the dominant one determines the net effect. talking in terms of a global or system glutamate boost (which NAC should achieve), i think though there are 6 inhibitory types and only 2 excitatory, mGluR5 activation is particularly dominant in terms of producing anxiety. iirc

 

part of the confusion and difficulty stems from this:

Receptors in groups II and III reduce the activity of postsynaptic potentials, both excitatory and inhibitory, in the cortex.[5]

meaning that they can reduce inhibition!!!

https://en.wikipedia...tamate_receptor

 

Btw, just one more piece of evidence in favor of my idea (not claiming indubitable verification obviously, not based on a flimsy "case report"):

Hypothesis: is infantile autism a hypoglutamatergic disorder? Relevance of glutamate - serotonin interactions for pharmacotherapy.
N-acetylcysteine for treatment of autism, a case report

[nootist]

I like one of those articles much better than the other.

 

The first, which hypothesised that autism was hypoglutamatergic, seemed like a fine idea 17 years ago.  People started testing it, and the results leaned more in the opposite direction, so eight years ago the opposite hypothesis was floated.  You can't find even an abstract of the following article without going through a paywall, but I'll post the opening paragraph as fair use.

 

The hyperglutamatergic hypothesis of autism

S.H. Fatemi

doi:10.1016/j.pnpbp.2007.11.004

Shinohe et al. (2006) measured serum levels of glutamate in 18 male adult patients with autism and 19 age-matched healthy controls. Serum levels of glutamate were significantly higher in subjects with autism vs. controls. In their explanations for this phenomenon, the authors mention association of high glutamate levels in autism with a higher seizure risk and with inflammatory events in autism.

→ source (external link)

 

Fatemi then goes on to suggest that reduced levels of glutamic acid decarboxylase found in autistics may be responsible, as may the relative abundance of astroglial cells, since they can convert glutamine to glutamate via glutaminase.  Like with the earlier paper, these seemed reasonable at the time, and while he didn't exactly nail the whole subject, his ideas have aged much better than Carlsson's.  For example, the genes GAD65 and 67, which Fatemi implicated, have since been tested in parents of autistics, and there was indeed trouble there.  There have been at least 20 or 30 papers written in the last five years which flat out call autism a hyperglutamatergic condition, and while that's an oversimplification, and not true throughout the brain, it's considered the better oversimplification these days.

 

Other causes (then Fatemi guessed) have been found as well, like when someone noticed that MTHFR issues were common on the spectrum, and reflected in the homocysteine levels in blood tests of their parents.  That's why methylcobalamin and folinic acid are used a lot in treating autism now, they're key to glutathione redox, so can help with the skewed ratio of glutathione to oxidized glutathione in people on the spectrum.  It also raises their cysteine levels.  See, for example, http://www.ncbi.nlm....les/PMC2647708/

 

The second paper I like a lot better, and could add some more like it.  It points out that NAC is generally helpful, although the mechanism isn't clear.  NAC hits receptors in possibly useful ways, and the antioxidant/anti-inflammatory side can't be overlooked either.  OCD is often found along with autism, and also responds to NAC, for presumably the same reasons.  http://www.ncbi.nlm....ubmed/25712432 

 

An article from April proposes the following:

It has been postulated that cysteine may cross the BBB via a sodium-dependent transport system where it is converted into cystine, the di-sulfide derivative of cysteine. High levels of cystine stimulate the exchange of intracellular glutamate for cystine through the cystine-glutamate antiporter, thereby elevating non-synaptic glutamate. This process activates the metabotropic glutamate receptors (mGluR2/3) on presynaptic neurons, responsible for inhibiting the synaptic release of glutamate and thereby restoring extracellular glutamate levels in the nucleus accumbens. Regulating this exchange system has been shown to improve impulse control and reduce addictive behaviour both pre-clinically and clinically. Intracellular cystine can then be reduced back to cysteine and used for GSH production, the potent and most abundant endogenous antioxidant in the body.

→ source (external link)

 

As tidy as the above makes things sound, there's still plenty which is clear as mud.  For example, the anterior cingulate is still sometimes hypoglutamatergic in people with OCD, and seems to correlate with severity of some symptoms.  Maybe we can go with the notion of, extracellular glutamate good, synaptic glutamate bad?

 

 

 

Btw, just one more piece of evidence in favor of my idea (not claiming indubitable verification obviously, not based on a flimsy "case report"):

Hypothesis: is infantile autism a hypoglutamatergic disorder? Relevance of glutamate - serotonin interactions for pharmacotherapy.
N-acetylcysteine for treatment of autism, a case report

 

 

[gamesguru]

i think by non-synaptic they mean intracellular, cause the synapse space is part of the extracellular space, unless they mean it's dissipating and dispersing far away

 

also plasma ≠ cerebral,as if things weren't complicated enough

There was no correlation between plasma Glu and either medial prefrontal cortical Glu or Glx (R_1,15 = 0.019, p = 0.944 and R_1,15 = 0.081, p = 0.757, respectively). Similarly, there was no correlation between plasma Gln and either mPFC Glu or Glx (R_1,15 = 0.029, p = 0.911 and R_1,15 = 0.025, p = 0.925, respectively).

Edited by gamesguru, 02 October 2015 - 04:16 AM.

[gamesguru]

I really feel NAC boosts glutamate

 

 

"We will discuss how alternative antipsychotic strategies may emerge by using drugs that reduce excessive glutamatergic response without altering the balance of synaptic and extrasynaptic normal glutamatergic neurotransmission."

[Hypoglutamatergic hypothesis of schizophrenia: evidence from genetic studies].

conflicting study:   Is NMDA Receptor Hypofunction in Schizophrenia Associated With a Primary Hyperglutamatergic State?
N-acetylcysteine in psychiatry: current therapeutic evidence and potential mechanisms of action
N-Acetyl Cysteine as a Glutathione Precursor for Schizophrenia—A Double-Blind, Randomized, Placebo-Controlled Trial
NAC amino acid offers a potential therapeutic alternative in psychiatric disorders

[gamesguru]

It appears to modulate glutamate in both directions, perhaps not without some regional dependence.

 

From Revolution to Evolution: The Glutamate Hypothesis of Schizophrenia and its Implication for Treatment
On the presynaptic level, the most obvious potential cause of NMDAR dysfunction would be a reduction in overall glutamatergic tone in the brain, leading to a global deficit in glutamatergic neurotransmission. However, while some findings of reduced CSF glutamate levels were reported (Kim et al, 1980), ultimately these were not confirmed (Javitt and Zukin, 1991), suggesting that more complex disturbances in glutamatergic function might be involved. In fact, over the last 20 years, it has been increasingly demonstrated that hyper, rather than hypo, glutamatergic function, potentially mediated through activation of AMPA receptors may be critical in schizophrenia, and that ideal treatment approaches may reduce rather than increase presynaptic glutamate levels (Moghaddam, 2003).

One key finding leading to the glutamate hyperactivity theory was that, in awake animals (but not in brain slice preparations or anesthetized animals), systemic injection of NMDAR antagonists at doses that impaired cognitive functions and produced motor stereotypy increase glutamate efflux in the prefrontal cortex (Liu and Moghaddam, 1995; Moghaddam et al, 1997; Moghaddam and Adams, 1998; Lorrain et al, 2003). This increase in the extracellular levels of glutamate had functional significance because blockade of AMPA receptors reduced the motoric and cognitive detriments of NMDAR blockade (Moghaddam et al, 1997). Thus, NMDAR antagonists appeared to increase the release of glutamate at some synapses, which then abnormally increased glutamate neurotransmission at non-NMDAR, in particular AMPA receptors (Figure 1). This finding, therefore, suggested that behavioral consequences of NMDAR deficiency is not due to a generalized ‘glutamate hypofunction' but dysregulation of glutamate neurotransmission that may potentially involve NMDAR hypofunction but excessive activity of non-NMDA receptors.

Interactive effects of N-acetylcysteine and antidepressants

Highlighting the role of glutamate in depressive states and the mode of action of various classes of ADs, it has been shown that NMDA antagonists not only possess antidepressant activity but also potentiate the effects of standard ADs (Maj et al., 1992, Petrie et al., 2000 and Trullas and Skolnick, 1990). In comparison with known NMDA antagonists that show antidepressant effects, but also a range of unwanted effects that hinder its clinical use, given its safety and tolerability profile (Whyte et al., 2007) NAC may be an ideal candidate to translate to clinical setting the concept of potentiating ADs effects with glutamate antagonists. The availability of glutamate to its various receptors is primarily determined by the astrocytic sodium-dependent glutamate transport (Diamond, 2001, Dunlop, 2006, Huang and Bergles, 2004 and Huang et al., 2004). Glutamate availability can be additionally tuned by the astrocytic cystine–glutamate exchanger, a mechanism of non-vesicular glutamate release into the extrasynaptic compartment (Baker et al., 2002). By controlling extrasynaptic glutamate levels, the cystine–glutamate exchanger modulates group II metabotropic glutamate autoreceptors, ultimately leading to reduced glutamate synaptic release (Moran et al., 2005). It is through the astrocytic cystine–glutamate exchanger that NAC is thought to modulate glutamate pathways in a clinically relevant manner (Baker et al., 2002 and Dean et al., 2011). This subtle but effective regulation of glutamate release would be beneficial to CNS diseases accompanied by hyperglutamatergic states, such as addiction (Schmaal et al., 2012), schizophrenia (Jordan et al., 2006), and depression (Sanacora et al., 2012).

 

Repeated N-Acetylcysteine Administration Alters Plasticity-Dependent Effects of Cocaine
Cocaine produces a persistent reduction in cystine–glutamate exchange via system xc− in the nucleus accumbens that may contribute to pathological glutamate signaling linked to addiction. System xc− influences glutamate neurotransmission by maintaining basal, extracellular glutamate in the nucleus accumbens, which, in turn, shapes synaptic activity by stimulating group II metabotropic glutamate autoreceptors. In the present study, we tested the hypothesis that a long-term reduction in system xc− activity is part of the plasticity produced by repeated cocaine that results in the establishment of compulsive drug seeking. To test this, the cysteine prodrug N-acetylcysteine was administered before daily cocaine to determine the impact of increased cystine–glutamate exchange on the development of plasticity-dependent cocaine seeking. Although N-acetylcysteine administered before cocaine did not alter the acute effects of cocaine on self-administration or locomotor activity, it prevented behaviors produced by repeated cocaine including escalation of drug intake, behavioral sensitization, and cocaine-primed reinstatement. Because sensitization or reinstatement was not evident even 2–3 weeks after the last injection of N-acetylcysteine, we examined whether N-acetylcysteine administered before daily cocaine also prevented the persistent reduction in system xc− activity produced by repeated cocaine. Interestingly, N-acetylcysteine pretreatment prevented cocaine-induced changes in [35S]cystine transport via system xc−, basal glutamate, and cocaine-evoked glutamate in the nucleus accumbens when assessed at least 3 weeks after the last N-acetylcysteine pretreatment. These findings indicate that N-acetylcysteine selectively alters plasticity-dependent behaviors and that normal system xc− activity prevents pathological changes in extracellular glutamate that may be necessary for compulsive drug seeking.

Thinking Outside the Cleft to Understand Synaptic Activity: Contribution of the Cystine-Glutamate Antiporter (System xc−) to Normal and Pathological Glutamatergic Signaling
System xc− represents an intriguing target in attempts to understand the pathological states of the central nervous system. Also called a cystine-glutamate antiporter, system xc− typically functions by exchanging one molecule of extracellular cystine for one molecule of intracellular glutamate. Nonvesicular glutamate released during cystine-glutamate exchange activates extrasynaptic glutamate receptors in a manner that shapes synaptic activity and plasticity. These findings contribute to the intriguing possibility that extracellular glutamate is regulated by a complex network of release and reuptake mechanisms, many of which are unique to glutamate and rarely depicted in models of excitatory signaling. Because system xc− is often expressed on non-neuronal cells, the study of cystine-glutamate exchange may advance the emerging viewpoint that glia are active contributors to information processing in the brain. It is noteworthy that system xc− is at the interface between excitatory signaling and oxidative stress, because the uptake of cystine that results from cystine-glutamate exchange is critical in maintaining the levels of glutathione, a critical antioxidant. As a result of these dual functions, system xc− has been implicated in a wide array of central nervous system diseases ranging from addiction to neurodegenerative disorders to schizophrenia. In the current review, we briefly discuss the major cellular components that regulate glutamate homeostasis, including glutamate release by system xc−. This is followed by an in-depth discussion of system xc− as it relates to glutamate release, cystine transport, and glutathione synthesis. Finally, the role of system xc− is surveyed across a number of psychiatric and neurodegenerative disorders

 

https://www.google.c...e=lnms&tbm=isch