Antipsychotic agents antagonize non-competitiveN-methyl-d-aspartate antagonist-induced behaviors

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.

Section: N-acetylcysteine Reversal Of Psychotomimetic Effects Of Pcpsupporting

confidence: 71%

Section: N-acetylcysteine Attenuates Pcp-evoked Social Withdrawalmentioning

confidence: 99%

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

Baker

Madayag

Kristiansen

et al. 2007

“…The ability of clozapine to attenuate MK-801-evoked change in cortical 5-HT may be related to its superior effects in negative/cognitive symptoms. Actually, clozapine but not haloperidol effectively blocks the hyperactivity, metabolic activation, neurotoxic cell damage, as well as the deficits in prepulse inhibition and social interaction induced by NMDA receptor antagonists (Corbett et al, 1995;Gleason and Shannon, 1997;Abi-Saab et al, 1998;Duncan et al, 1998;Olney et al, 1999;Geyer et al, 2001;Farber et al, 2006). Further research is needed to ascertain the transmitter receptors responsible for such differences between clozapine and haloperidol.…”

Section: Discussionmentioning

confidence: 99%

Clozapine and Haloperidol Differently Suppress the MK-801-Increased Glutamatergic and Serotonergic Transmission in the Medial Prefrontal Cortex of the Rat

López-Gil

Babot

Amargós-Bosch

et al. 2007

170

162

The administration of noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists such as phencyclidine and ketamine has been shown to increase the extracellular concentration of glutamate and serotonin (5-HT) in the medial prefrontal cortex (mPFC). In the present work, we used in vivo microdialysis to examine the effects of the more potent noncompetitive NMDA receptor antagonist, MK-801, on the efflux of glutamate and 5-HT in the mPFC, and whether the MK-801-induced changes in the cortical efflux of both transmitters could be blocked by clozapine and haloperidol given systemically or intra-mPFC. The systemic, but not the local administration of MK-801, induced an increased efflux of 5-HT and glutamate, which suggests that the NMDA receptors responsible for these effects are located outside the mPFC, possibly in GABAergic neurons that tonically inhibit glutamatergic inputs to the mPFC. The MK-801-induced increases of extracellular glutamate and 5-HT were dependent on nerve impulse and the activation of mPFC AMPA/ kainate receptors as they were blocked by tetrodotoxin and NBQX, respectively. Clozapine and haloperidol blocked the MK-801-induced increase in glutamate, whereas only clozapine was able to block the increased efflux of 5-HT. The local effects of clozapine and haloperidol paralleled those observed after systemic administration, which emphasizes the relevance of the mPFC as a site of action of these antipsychotic drugs in offsetting the neurochemical effects of MK-801. The ability of clozapine to block excessive cortical 5-HT efflux elicited by MK-801 might be related to the superior efficacy of this drug in treating negative/cognitive symptoms of schizophrenia.

“…Raclopride, a potent and selective dopamine D 2 receptor antagonist (Lahti et al, 1993;Kohler et al, 1985), was used to probe the classic mechanism of action of first-generation antipsychotics relying on D 2 dopamine blockade. The contribution of dopamine to the psychotogenic action of PCP is still the subject of debate, with the literature showing inconsistent effects of dopamine D 2 blockers in rodents (Idris et al, 2005;Linn et al, 2003;Duncan et al, 1998a;Corbett et al, 1995) and humans (Krystal et al, 1999), despite evidence of altered dopamine release following NMDAR antagonist administration . The effect of raclopride was compared with that of clozapine, a prototypical new-generation antipsychotic that, in addition to blocking dopamine D 2 receptors, possesses multiple antagonistic actions at several other receptors (Meltzer, 1996).…”

Section: Introductionmentioning

confidence: 99%

Differential Effects of Antipsychotic and Glutamatergic Agents on the phMRI Response to Phencyclidine

Gozzi

Large

Schwarz

et al. 2007

107

118

Acute administration of NMDA receptor (NMDAR) antagonists such as phencyclidine (PCP) or ketamine induces symptoms that closely resemble those of schizophrenia in humans, a finding that has led to the hypothesis that a decreased NMDAR function may be a predisposing or even causative factor in schizophrenia. However, the precise neuropharmacological mechanisms underlying these effects remain to be fully elucidated. Here, we applied pharmacological MRI (phMRI) to examine the brain circuitry underlying the psychotomimetic action of PCP in the anesthetized rat, and investigated how these functional changes are modulated by drugs that possess distinct pharmacological mechanisms. Acute administration of PCP (0.5 mg/kg i.v.) produced robust and sustained positive relative cerebral blood volume (rCBV) changes in discrete cortico-limbo-thalamic regions. Pretreatment with the selective D 2 dopamine antagonist raclopride (0.3 mg/kg i.p.) did not significantly affect the rCBV response to PCP, while the atypical antipsychotic clozapine (5 mg/kg i.p.) produced region-dependent effects, with complete suppression of the rCBV response in the thalamus, and weaker attenuation of the response in cortical and hippocampal structures. The response to PCP was strongly suppressed in all regions by pretreatment with two drugs that can inhibit aberrant glutamatergic activity: the anticonvulsant lamotrigine (10 mg/kg i.p.) and the mGluR2/3 agonist LY354740 (10 mg/kg i.p.). Taken together, our findings corroborate the pivotal role of dysfunctional glutamatergic neurotransmission in the functional response elicited by PCP, while the lack of effect of raclopride argues against a primary role of dopamine D 2 receptor activation in this process. Finally, the thalamic effect of clozapine could be key to elucidating the functional basis of its pharmacological action.