Background and Purpose Lurasidone is an atypical mood‐stabilizing antipsychotic with a unique receptor‐binding profile, including 5‐HT7 receptor antagonism; however, the detailed effects of 5‐HT7 receptor antagonism on various transmitter systems relevant to schizophrenia, particularly the thalamo‐insular glutamatergic system and the underlying mechanisms, are yet to be clarified. Experimental Approach We examined the mechanisms underlying the clinical effects of lurasidone by measuring the release of l‐glutamate, GABA, dopamine, and noradrenaline in the reticular thalamic nucleus (RTN), mediodorsal thalamic nucleus (MDTN) and insula of freely moving rats in response to systemic injection or local infusion of lurasidone or MK‐801 using multiprobe microdialysis with ultra‐HPLC. Key Results Systemic MK‐801 (0.5 mg·kg−1) administration increased insular release of l‐glutamate, dopamine, and noradrenaline but decreased GABA release. Systemic lurasidone (1 mg·kg−1) administration also increased insular release of l‐glutamate, dopamine, and noradrenaline but without affecting GABA. Local lurasidone administration into the insula (3 μM) did not affect MK‐801‐induced insular release of l‐glutamate or catecholamine, whereas local lurasidone administration into the MDTN (1 μM) inhibited MK‐801‐induced insular release of l‐glutamate and catecholamine, similar to the 5‐HT7 receptor antagonist SB269970. Conclusions and Implications The present results indicate that MK‐801‐induced insular l‐glutamate release is generated by activation of thalamo‐insular glutamatergic transmission via MDTN GABAergic disinhibition resulting from NMDA receptor inhibition in the MDTN and RTN. Lurasidone inhibited this MK‐801‐evoked insular l‐glutamate release through inhibition of excitatory 5‐HT7 receptor in the MDTN. These effects on thalamo‐insular glutamatergic transmission may contribute to the antipsychotic and mood‐stabilizing actions of lurasidone.

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.

Background and Purpose: The mechanisms causing spontaneous epileptic seizures, including carbamazepine-resistant/zonisamide -sensitive seizures and comorbidity in autosomal dominant sleep-related hypermotor epilepsy (ADSHE) are unclear. This study investigated functional abnormalities in thalamocortical transmission in transgenic rats bearing rat S286L-mutant Chrna4 (S286L-TG) of α4 subunit of the nicotinic ACh receptor (nAChR) that corresponds to the human S284L-mutant CHRNA4.Experimental Approach: Effects of carbamazepine and zonisamide on epileptic discharges of S286L-TG rat were measured using telemetry electrocorticogram.Transmission abnormalities of L-glutamate and GABA in thalamocortical pathway of S286L-TG rats were investigated using multiprobe microdialysis and ultra-highperformance liquid-chromatography.Key Results: Epileptic discharges in S286L-TG rats were reduced by zonisamide but not by carbamazepine, similar to that of S284L-ADSHE patients. Carbamazepine unaffected functional abnormality in transmission of S286L-TG rats. However, zonisamide was able to compensate for the attenuated S286L-mutant nAChR induced GABA release in frontal-cortex, without affecting attenuated thalamocortical glutamatergic transmission. Excitatory effects of S286L-mutant nAChR on thalamocortical transmission were attenuated compared with those of wild-type nAChR. Loss-of-function of S286L-nAChR enhanced transmission in thalamocortical motor pathway by predominantly attenuating GABAergic transmission. However, it attenuated transmission in thalamocortical cognitive pathway by reducing inhibitory GABAergic and excitatory glutamatergic transmission. Conclusion and Implications:Our results suggest that functional abnormalities of S286L-nAChR are associated with intra-frontal and thalamocortical transmission, possibly contributing to the pathogenesis of ADSHE-seizure and comorbidity of S284L-ADSHE. Selective compensation of impaired GABAergic transmission by zonisamide (but not by carbamazepine) in frontal cortex may be involved, at least partially, in carbamazepine-resistant ADSHE-seizure of S284L-ADSHE patients. thalamic nucleus; SHE, sporadic form sleep-related hypermotor epilepsy; S286L-TG, transgenic rat bearing rat Chrna4 missense S286L mutation; ZNS, zonisamide.

Deficiencies in N‐methyl‐d‐aspartate (NMDA)/glutamate receptor (NMDAR) signaling have been considered central to the cognitive impairments of schizophrenia; however, an NMDAR antagonist memantine (MEM) improves cognitive impairments of Alzheimer's disease and schizophrenia. These mechanisms of paradoxical clinical effects of NMDAR antagonists remain unclear. To explore the mechanisms by which MK801 and MEM affect thalamocortical transmission, we determined interactions between local administrations of MK801, MEM, system xc− (Sxc), and metabotropic glutamate receptors (mGluRs) on extracellular glutamate and GABA levels in the mediodorsal thalamic nucleus (MDTN) and medial prefrontal cortex (mPFC) using dual‐probe microdialysis with ultra‐high‐pressure liquid chromatography. Effects of MK801 and MEM on Sxc activity were also determined using primary cultured astrocytes. Sxc activity was enhanced by MEM, but was unaffected by MK801. MK801 enhanced thalamocortical glutamatergic transmission by GABAergic disinhibition in the MDTN. In the MDTN and the mPFC, MEM weakly increased glutamate release by activating Sxc, whereas MEM inhibited thalamocortical glutamatergic transmission. Paradoxical effects of MEM were induced following secondary activation of inhibitory II‐mGluR and III‐mGluR by exporting glutamate from astroglial Sxc. The present results suggest that the effects of therapeutically relevant concentrations of MEM on thalamocortical glutamatergic transmission are predominantly caused by activation of Sxc rather than inhibition of NMDAR. These demonstrations suggest that the combination between reduced NMDAR and activated Sxc contribute to the neuroprotective effects of MEM. Furthermore, activation of Sxc may compensate for the cognitive impairments that are induced by hyperactivation of thalamocortical glutamatergic transmission following activation of Sxc/II‐mGluR in the MDTN and Sxc/II‐mGluR/III‐mGluR in the mPFC.

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.