Clozapine Normalizes a Glutamatergic Transmission Abnormality Induced by an Impaired NMDA Receptor in the Thalamocortical Pathway via the Activation of a Group III Metabotropic Glutamate Receptor

Abstract

Pharmacological mechanisms of gold-standard antipsychotics against treatment-refractory schizophrenia, such as clozapine (CLZ), remain unclear. We aimed to explore the mechanisms of CLZ by investigating the effects of MK801 and CLZ on tripartite synaptic transmission in the thalamocortical glutamatergic pathway using multi-probe microdialysis and primary cultured astrocytes. l-glutamate release in the medial prefrontal cortex (mPFC) was unaffected by local MK801 administration into mPFC but was enhanced in the mediodorsal thalamic nucleus (MDTN) and reticular thalamic nucleus (RTN) via GABAergic disinhibition in the RTN–MDTN pathway. The local administration of therapeutically relevant concentrations of CLZ into mPFC and MDTN increased and did not affect mPFC l-glutamate release. The local administration of the therapeutically relevant concentration of CLZ into mPFC reduced MK801-induced mPFC l-glutamate release via presynaptic group III metabotropic glutamate receptor (III-mGluR) activation. However, toxic concentrations of CLZ activated l-glutamate release associated with hemichannels. This study demonstrated that RTN is a candidate generator region in which impaired N-methyl-d-aspartate (NMDA)/glutamate receptors likely produce thalamocortical hyperglutamatergic transmission. Additionally, we identified several mechanisms of CLZ relating to its superiority in treatment-resistant schizophrenia and its severe adverse effects: (1) the prevention of thalamocortical hyperglutamatergic transmission via activation of mPFC presynaptic III-mGluR and (2) activation of astroglial l-glutamate release associated with hemichannels. These actions may contribute to the unique clinical profile of CLZ.

Vortioxetine Subchronically Activates Serotonergic Transmission via Desensitization of Serotonin 5-HT1A Receptor with 5-HT3 Receptor Inhibition in Rats

“…Notably, various pharmacodynamic studies have explored the mechanisms of the psychotropic and rapid-acting antidepressant-like actions of ketamine [46,47]. The inhibition of NMDA-R activates glutamatergic transmission via GABAergic disinhibition in the cortex and subcortical regions, including the RTN and DRN [25,28,34,[37][38][39][40][48][49][50]. Indeed, in this study, MK801 (NMDA-R antagonist) drastically increased 5-HT release via GABAergic disinhibition in the DRN [28,34].…”

“…Study-4 was designed to determine the effects of subchronic systemic administrations of effective doses of escitalopram (5 mg/kg/d) and vortioxetine (2.5 mg/kg/d) for 7 d on serotonergic and GABAergic transmissions in the mPFC induced by the inhibition of NMDA-R in the DRN using 5 µM MK801 [25][26][27]. After a 24 h stop of subchronic administrations of escitalopram and vortioxetine, a perfusion medium in the mPFC, the DRN, and the RTN was commenced with MRS. After confirming the stabilization of levels of 5-HT and GABA in the mPFC, the perfusion medium in the DRN or RTN was switched to MRS containing 5 µM MK801 (Figure 7).…”

“…In our recent studies, hyperactivation of thalamocortical glutamatergic transmission has been considered as contributing to the cognitive impairment of several neuropsychiatric disorders [25,26,[49][50][51]. Under physiological conditions, the MDTN regulates a wide range of cognitive processes, and the enhancement of the sensitivity and reliability of MDTN signaling contributes to the augmentation of flexibility and stability against environmental changes [25][26][27].…”

“…In our recent studies, hyperactivation of thalamocortical glutamatergic transmission has been considered as contributing to the cognitive impairment of several neuropsychiatric disorders [25,26,[49][50][51]. Under physiological conditions, the MDTN regulates a wide range of cognitive processes, and the enhancement of the sensitivity and reliability of MDTN signaling contributes to the augmentation of flexibility and stability against environmental changes [25][26][27]. Severe GABAergic disinhibition in the MDTN induced by NMDA-R attenuation in the RTN leads to continuous hyperactivated MDTN glutamatergic activities, resulting in the relative deterioration of sensitivity to the input signaling from other regions, which is functionally similar to the disruption of MDTN activity [25][26][27]50,52].…”

“…Contrary to the effectiveness of esketamine/ketamine, NMDA-R dysfunction is implicated in the pathophysiology of schizophrenia, as evidenced by the induction of schizophrenia-like cognitive impairment, positive and negative symptoms in healthy volunteers and experimental animal models, and the exacerbation of psychosis in schizophrenia patients by noncompetitive NMDA-R antagonists such as phencyclidine and ketamine [23,24]. We have demonstrated that the hyperactivation of thalamocortical glutamatergic transmission induced by the NMDA-R antagonist plays an important role in the cognitive impairment in schizophrenia [25][26][27][28].…”