Cystine/Glutamate Exchange Regulates Metabotropic Glutamate Receptor Presynaptic Inhibition of Excitatory Transmission and Vulnerability to Cocaine Seeking

Moran, Megan M.; McFarland, Krista; Meléndez, Roberto I.; Kalivas, Peter W.; Seamans, Jeremy K.

doi:10.1523/jneurosci.1007-05.2005

Cited by 373 publications

(383 citation statements)

References 25 publications

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“…Similar to agonists for group II mGluR, the present data demonstrate that administration of the cysteine prodrug N-acetylcysteine blocks PCP-evoked glutamate release in the prefrontal cortex in a manner that requires cystineglutamate exchange and increased group II mGluR signaling. This finding is consistent with several studies demonstrating that cystine-glutamate antiporters regulate endogenous stimulation of these receptors (Baker et al, 2002(Baker et al, , 2003Moran et al, 2005). These studies reinforce the hypothesis that multiple pools of glutamate exist and that extrasynaptic pools provide negative feedback regulating synaptic release.…”

Section: N-acetylcysteine Reversal Of Psychotomimetic Effects Of Pcpsupporting

confidence: 92%

“…Previous work indicates that cystine-glutamate antiporters regulate synaptic glutamate through activation of group II mGluRs (Baker et al, 2002;Moran et al, 2005). As a result, we examined whether the capacity of N-acetylcysteine to restore working memory requires group II mGluR signaling.…”

Section: N-acetylcysteine Attenuates Pcp-evoked Performance Deficitsmentioning

confidence: 98%

“…Noncompetitive NMDA receptor antagonists increase glutamate in the synaptic cleft thereby generating behaviors dependent upon AMPA receptor stimulation (Moghaddam et al, 1997;Takahata and Moghaddam, 2003). Conversely, cystineglutamate exchange releases glutamate into the extrasynaptic compartment thereby stimulating proximal receptors such as group II mGluRs (Baker et al, 2002(Baker et al, , 2003Moran et al, 2005). By stimulating extrasynaptic group II mGluRs without exerting postsynaptic effects (Moran et al, 2005), extrasynaptic glutamate appears to influence negatively the synaptic pools (Baker et al, 2002;Moran et al, 2005).…”

Section: N-acetylcysteine Reversal Of Psychotomimetic Effects Of Pcpmentioning

confidence: 99%

“…Cystine-glutamate antiporters represent a mechanism capable of nonvesicular glutamate release into the extrasynaptic compartment following the exchange of extracellular cystine for intracellular glutamate (Baker et al, 2002;Moran et al, 2005). Studies utilizing microdialysis in the nucleus accumbens or electrophysiological recordings from acute prefrontal cortical or nucleus accumbens tissue slices indicate that nonvesicular glutamate release from cystineglutamate exchange stimulates extrasynaptic group II metabotropic glutamate receptors (mGluR) (Baker et al, 2002;Xi et al, 2002a;Moran et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

“…Studies utilizing microdialysis in the nucleus accumbens or electrophysiological recordings from acute prefrontal cortical or nucleus accumbens tissue slices indicate that nonvesicular glutamate release from cystineglutamate exchange stimulates extrasynaptic group II metabotropic glutamate receptors (mGluR) (Baker et al, 2002;Xi et al, 2002a;Moran et al, 2005). Because group II mGluRs function as autoreceptors (Baskys and Malenka, 1991;Cochilla and Alford, 1998;Hu et al, 1999b;Schoepp, 2001;Valenti et al, 2002;Xi et al, 2002b), extrasynaptic glutamate maintained by cystine-glutamate exchange negatively modulates synaptic release of glutamate (Moran et al, 2005). Since most studies focus on synaptic content, the failure to account for the presence of high, steady-state levels of glutamate in the extrasynaptic space represents a critical gap in attempts to model the contribution of excitatory neurotransmission to brain functioning in both the normal and diseased states.…”

Section: Introductionmentioning

confidence: 99%

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Contribution of Cystine–Glutamate Antiporters to the Psychotomimetic Effects of Phencyclidine

Baker

Madayag

Kristiansen

et al. 2007

Neuropsychopharmacol

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Altered glutamate signaling contributes to a myriad of neural disorders, including schizophrenia. While synaptic levels are intensely studied, nonvesicular release mechanisms, including cystine-glutamate exchange, maintain high steady-state glutamate levels in the extrasynaptic space. The existence of extrasynaptic receptors, including metabotropic group II glutamate receptors (mGluR), pose nonvesicular release mechanisms as unrecognized targets capable of contributing to pathological glutamate signaling. We tested the hypothesis that activation of cystine-glutamate antiporters using the cysteine prodrug N-acetylcysteine would blunt psychotomimetic effects in the rodent phencyclidine (PCP) model of schizophrenia. First, we demonstrate that PCP elevates extracellular glutamate in the prefrontal cortex, an effect that is blocked by N-acetylcysteine pretreatment. To determine the relevance of the above finding, we assessed social interaction and found that N-acetylcysteine reverses social withdrawal produced by repeated PCP. In a separate paradigm, acute PCP resulted in working memory deficits assessed using a discrete trial t-maze task, and this effect was also reversed by Nacetylcysteine pretreatment. The capacity of N-acetylcysteine to restore working memory was blocked by infusion of the cystineglutamate antiporter inhibitor (S)-4-carboxyphenylglycine into the prefrontal cortex or systemic administration of the group II mGluR antagonist LY341495 indicating that the effects of N-acetylcysteine requires cystine-glutamate exchange and group II mGluR activation. Finally, protein levels from postmortem tissue obtained from schizophrenic patients revealed significant changes in the level of xCT, the active subunit for cystine-glutamate exchange, in the dorsolateral prefrontal cortex. These data advance cystine-glutamate antiporters as novel targets capable of reversing the psychotomimetic effects of PCP.

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Section: N-acetylcysteine Reversal Of Psychotomimetic Effects Of Pcpsupporting

confidence: 92%

Section: N-acetylcysteine Attenuates Pcp-evoked Performance Deficitsmentioning

confidence: 98%

Section: N-acetylcysteine Reversal Of Psychotomimetic Effects Of Pcpmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Contribution of Cystine–Glutamate Antiporters to the Psychotomimetic Effects of Phencyclidine

Baker

Madayag

Kristiansen

et al. 2007

Neuropsychopharmacol

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Metabotropic Glutamate Receptors

Monn

Johnson

Schoepp

2007

Handbook of Contemporary Neuropharmacology

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Since the first suggestion of G‐protein coupled glutamate receptor(s) and the subsequent cloning of eight different subtypes within the past 2 decades, our understanding of the neurophysiologic role and importance of the metabotropic glutamate (mGlu) receptors has greatly advanced, in large part owing to discovery and advancement of potent and selective pharmacological agents. These include orthosteric (i.e. N‐terminal glutamate‐site) agonists and antagonists possessing remarkable selectivity for one of the three mGlu receptor groups: Group I (mGlu1 and mGlu5), Group II (mGlu2 and mGlu3), or Group III (mGlu4, mGlu6, mGlu7 and mGlu8). More recently, subtype selective allosteric modulators that bind to the seven transmembrane (7‐TM) domain (potentiators, non‐competitive antagonists, and/or inverse agonists) for one or more of the eight mGlu receptor subtypes have been described. This chapter will focus on a brief description and summary of key findings for a number of these neuropharmacologic agents.

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Recent advances in the neurobiology of anxiety disorders: Implications for novel therapeutics

Mathew

Price

Charney

2008

American J of Med Genetics Pt C

149

121

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Anxiety disorders are a highly prevalent and disabling class of psychiatric disorders. This review focuses on new directions in neurobiological research and implications for the development of novel psychopharmacological treatments. Neuroanatomical and neuroimaging research in anxiety disorders has centered on the role of the amygdala, reciprocal connections between the amygdala and the prefrontal cortex, and, most recently, alterations in interoceptive processing by the anterior insula. Anxiety disorders are characterized by alterations in a diverse range of neurochemical systems, suggesting ample novel targets for drug therapies. Corticotropin-releasing factor (CRF) concentrations are elevated in a subset of anxiety disorders, which suggests the potential utility of CRF receptor antagonists. Pharmacological blockade of the memory-enhancing effects of stress hormones such as glucocorticoids and noradrenaline holds promise as a preventative approach for trauma-related anxiety. The glutamatergic system has been largely overlooked as a potential pharmacological target, although convergent preclinical, neuroimaging, and early clinical findings suggest that glutamate receptor antagonists may have potent anxiolytic effects. Glutamatergic receptor agonists (e.g., D-cycloserine) also have an emerging role in the treatment of anxiety as facilitators of fear extinction during concurrent behavioral interventions. The neuropeptides substance P, neuropeptide Y, oxytocin, orexin, and galanin are each implicated in anxiety pathways, and neuropeptide analogs or antagonists show early promise as anxiolytics in preclinical and/or clinical research. Each of these active areas of research holds promise for expanding and improving evidence-based treatment options for individuals suffering with clinical anxiety.

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Cystine/Glutamate Exchange Regulates Metabotropic Glutamate Receptor Presynaptic Inhibition of Excitatory Transmission and Vulnerability to Cocaine Seeking

Cited by 373 publications

References 25 publications

Contribution of Cystine–Glutamate Antiporters to the Psychotomimetic Effects of Phencyclidine

Contribution of Cystine–Glutamate Antiporters to the Psychotomimetic Effects of Phencyclidine

Metabotropic Glutamate Receptors

Recent advances in the neurobiology of anxiety disorders: Implications for novel therapeutics

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