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

Abstract

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.

Activation of metabotropic glutamate 2/3 receptors attenuates methamphetamine-induced hyperlocomotion and increase in prefrontal serotonergic neurotransmission

“…This suggests the involvement of other transmitter systems in the locomotor-stimulant effect of methamphetamine. In this respect, we found that methamphetamine and MGS0028 did not affect the extracellular glutamate levels in the prefrontal cortex and nucleus accumbens, although the previous microdialysis studies showed that phencyclidine increased the extracellular glutamate levels (Baker et al 2008;Moghaddam and Adams 1998). Taken together, it is likely that the mechanism for the antipsychotic effect of mGlu2/3 receptor agonists differs between the phencyclidine-and psychostimulant-induced hyperlocomotion models.…”

Glutamatergic Model Psychoses: Prediction Error, Learning, and Inference

“…We will briefly discuss some of those aspects with relevance to psychosis and the model under consideration. There are high steady-state glutamate levels in the extrasynaptic space, controlled by extrasynaptic metabotropic group II glutamate receptors (mglur2), which interact with an active exchange mechanism that shuttles cystine into and glutamate out of the glial cells that surround synapses (Baker et al, 2008). As mglur2s function as presynaptic autoreceptors (Baskys and Malenka, 1991), extrasynaptic glutamate negatively modulates the synaptic release of glutamate (Moran et al, 2005).…”

The Cystine/Glutamate Antiporter System xc−in Health and Disease: From Molecular Mechanisms to Novel Therapeutic Opportunities

“…In a rodent model of schizophrenia, where the NMDA antagonist phencyclidine (PCP) is administered, deficits in working memory, as evaluated using a t-maze, are linked to increased synaptic glutamate release in prefrontal cortex. Baker et al showed that these deficits can be restored by increasing the activity of system x c -and, as such, inducing a negative feedback loop via group II metabotropic glutamate receptor activation, which subsequently leads to reduced presynaptic glutamate release (7).…”