Cystine/Glutamate Antiporter and Aripiprazole Compensate NMDA Antagonist-Induced Dysfunction of Thalamocortical L-Glutamatergic Transmission

Abstract

To explore pathophysiology of schizophrenia, this study analyzed the regulation mechanisms that are associated with cystine/glutamate antiporter (Sxc), group-II (II-mGluR), and group-III (III-mGluR) metabotropic glutamate-receptors in thalamo-cortical glutamatergic transmission of MK801-induced model using dual-probe microdialysis. L-glutamate release in medial pre-frontal cortex (mPFC) was increased by systemic- and local mediodorsal thalamic nucleus (MDTN) administrations of MK801, but was unaffected by local administration into mPFC. Perfusion into mPFC of activators of Sxc, II-mGluR, and III-mGluR, and into the MDTN of activators of Sxc, II-mGluR, and GABAA receptor inhibited MK801-evoked L-glutamate release in mPFC. Perfusion of aripiprazole (APZ) into MDTN and mPFC also inhibited systemic MK801-evoked L-glutamate release in mPFC. Inhibition of II-mGluR in mPFC and MDTN blocked inhibitory effects of Sxc-activator and APZ on MK801-evoked L-glutamate release; however, their inhibitory effects were blocked by the inhibition of III-mGluR in mPFC but not in MDTN. These results indicate that reduced activation of the glutamate/NMDA receptor (NMDAR) in MDTN enhanced L-glutamate release in mPFC possibly through GABAergic disinhibition in MDTN. Furthermore, MDTN-mPFC glutamatergic transmission receives inhibitory regulation of Sxc/II-mGluR/III-mGluR functional complex in mPFC and Sxc/II-mGluR complex in MDTN. Established antipsychotic, APZ inhibits MK801-evoked L-glutamate release through the activation of Sxc/mGluRs functional complexes in both MDTN and mPFC.

Memantine protects thalamocortical hyper‐glutamatergic transmission induced by NMDA receptor antagonism via activation of system xc−

“…However, local administration of MK801 into the mPFC did not affect glutamate levels in the mPFC . In contrast with observations in the mPFC, inhibition of NMDAR in the MDTN induced by local administration of MK801 into the MDTN increased glutamate release in the mPFC (mPFC MK801‐induced glutamate rise) . The present study showed that perfusion of MK801 into the MDTN also increased glutamate release from the mPFC without affecting that in the MDTN.…”

“…The present study showed that perfusion of MK801 into the MDTN also increased glutamate release from the mPFC without affecting that in the MDTN. These results suggest that the major mechanisms of systemic NMDAR antagonist‐induced glutamate release in the mPFC are generated by enhanced thalamocortical glutamatergic transmission outside of the mPFC …”

“…Several microdialysis studies show that systemic administration of the noncompetitive NMDAR antagonists phencyclidine, ketamine, and MK801 increased glutamate release in the mPFC . However, local administration of MK801 into the mPFC did not affect glutamate levels in the mPFC .…”

“…Moreover, thalamocortical glutamatergic terminals activate catecholaminergic terminals, but do not make contact with cortical GABAergic neurons . However, a large proportion of the GABAergic neurons in the frontal cortex are regulated by excitatory glutamatergic transmission from other cortical regions via activation of NMDAR . Given these anatomical observations, we characterized the mechanisms of systemic MK801‐induced glutamate release in the mPFC by determining the effects of MK801 perfusions into the MDTM and the mPFC on GABA release from both regions.…”

“…After stabilization of levels of l ‐glutamate and GABA, dialysate was collected for 60 minutes as pretreatment periods of MK801 or MEM, and for 180 minutes as post‐administration periods of MK801 or MEM. The concentration of each agent was mainly prepared using a protocol from previous reports …”