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.

ObjectivesTo explore the mechanisms of reduced suicide mortality in Japan, which decreased from 25.7 to 16.5 per 100 000 people following the comprehensive suicide prevention programme from 2009 to 2018, the present study determined the relationship between regional suicide mortality, socioeconomic data (GDP per capita, unemployment rates) and financial support for regional suicide prevention programmes.Design and settingStepwise multiple regression analysis was used to determine the effects of regional GDP per capita, unemployment rates and implementation amount of financial support for regional suicide prevention programmes (Emergency Fund to Enhance Community-Based Suicide Countermeasures—EFECBSC) on age and gender disaggregated suicide mortalities in Japan between 2009 and 2018. Data on each prefecture’s complete unemployment rates, GDP per capita and implementation amount of EFECBSC sub-divisions were derived from an official Japanese governmental database.ResultsBoth prefectural enlightenment and intervention model programmes were found to lead to a decrease in male suicide mortality, but were less effective in reducing female suicide mortality. Municipal enlightenment and intervention model programmes were also less effective in reducing suicide mortality. Municipal development programmes for listener and leader led to a greater decrease in suicide mortality for both men and women compared with such programmes at the prefectural level. Contrary to our expectations, reduced complete unemployment rate only reduced suicide mortality in the older male population without affecting female suicide mortality.ConclusionThe study findings suggest an inverse relationship between financial support and suicide mortality in Japan. Furthermore, independent factors in the reduction of suicide mortality rates provide important information for planning evidence-based and cost-effective regional suicide prevention programmes.

A glutamate/NMDA receptor (NMDA-R) antagonist, amantadine (AMA) exhibits a broad spectrum of clinically important properties, including antiviral, antiparkinsonian, neuroprotective, neuro-reparative and cognitive-enhancing effects. However, both clinical and pre-clinical studies have demonstrated that noncompetitive NMDA-R antagonists induce severe schizophrenia-like cognitive deficits. Therefore, this study aims to clarify the clinical discrepancy between AMA and noncompetitive NMDA-R antagonists by comparing the effects of AMA with those of a noncompetitive NMDA-R antagonist, MK801, on rat tripartite glutamatergic synaptic transmission using microdialysis and primary cultured astrocytes. Microdialysis study demonstrated that the stimulatory effects of AMA on L-glutamate release differed from those of MK801 in the globus pallidus, entorhinal cortex and entopeduncular nucleus. The stimulatory effect of AMA on L-glutamate release was modulated by activation of cystine/glutamate antiporter (Sxc). Primary cultured astrocytes study demonstrated that AMA also enhanced glutathione synthesis via Sxc activation. Furthermore, carbon-monoxide induced damage of the astroglial glutathione synthesis system was repaired by AMA but not MK801. Additionally, glutamate/AMPA receptor (AMPA-R) antagonist, perampanel enhanced the protective effects of AMA. The findings of microdialysis and cultured astrocyte studies suggest that a combination of Sxc activation with inhibitions of ionotropic glutamate receptors contributes to neuroprotective, neuro-reparative and cognitive-enhancing activities that can mitigate several neuropsychiatric disorders.

Several mood-stabilizing atypical antipsychotics and antidepressants weakly block serotonin (5-HT) receptor type-7 (5-HT7R); however, the contributions of 5-HT7R antagonism to clinical efficacy and pathophysiology are yet to be clarified. A novel mood-stabilizing antipsychotic agent, lurasidone exhibits predominant binding affinity to 5-HT7R when compared with other monoamine receptors. To date, we have failed to discover the superior clinical efficacy of lurasidone on schizophrenia, mood, or anxiety disorders when compared with conventional mood-stabilizing atypical antipsychotics; however, numerous preclinical findings have indicated the possible potential of 5-HT7R antagonism against several neuropsychiatric disorders, as well as the generation of novel therapeutic options that could not be expected with conventional atypical antipsychotics. Traditional experimental techniques, electrophysiology, and microdialysis have demonstrated that the effects of 5-HT receptor type-1A (5-HT1AR) and 5-HT7R on neurotransmission are in contrast, but the effect of 5-HT1AR is more predominant than that of 5-HT7R, resulting in an insufficient understanding of the 5-HT7R function in the field of psychopharmacology. Accumulating knowledge regarding the pharmacodynamic profiles of 5-HT7R suggests that 5-HT7R is one of the key players in the establishment and remodeling of neural development and cytoarchitecture during the early developmental stage to the mature brain, and dysfunction or modulation of 5-HT7R is linked to the pathogenesis/pathophysiology of neuropsychiatric and neurodevelopmental disorders. In this review, to explore candidate novel applications for the treatment of several neuropsychiatric disorders, including mood disorders, schizophrenia, and other cognitive disturbance disorders, we discuss perspectives of psychopharmacology regarding the effects of 5-HT7R antagonism on transmission and intracellular signaling systems, based on preclinical findings.

To improve and plan regional suicide prevention programmes that utilise more cost-effective governmental financial support compared with previous programmes, the present study determined the effects of the amount of financial support provided for regional suicide prevention programmes, such as the Emergency Fund to Enhance Community-Based Suicide Countermeasures (EFECBSC), on the trends of suicide mortalities caused by six major suicide motives between 2009 and 2018, using forward multiple regression analysis. The ranking order of motives for male suicide was health, economy, family, employment, romance and school (in that order), whereas the ranking order for females was health, family, economy, romance, employment and school. Male suicide mortality caused by economy-related motives was significantly/inversely related to prefectural intervention programmes, whereas mortality caused by health-related motives was also significantly/inversely related to prefectural intervention programmes, but significantly/positively related to prefectural personal consultation support programmes. Contrary to males, female suicide mortality caused by health-related motives was significantly/inversely related to the municipal development programmes of leaders/listeners, whereas mortality caused by family- and school-related motives was significantly/positively related to prefectural and municipal telephone consultation support programmes, respectively. Contrary to our expectations, school-aged female suicide mortality caused by school-related motives was significantly/positively related to prefectural personal consultation support, enlightenment and municipal telephone consultation support programmes. These results indicate that Japanese regional suicide prevention programmes probably affect the suppression of male suicide mortality. However, these programmes are possibly ineffective, or at least partially, have an adverse effect, in regard to the suicide mortalities of female and school-aged populations. Therefore, we should work to improve regional suicide prevention programmes, making them more cost-effective and targeted towards female and school-aged populations in the future.