Lurasidone inhibits NMDA receptor antagonist‐induced functional abnormality of thalamocortical glutamatergic transmission via 5‐HT₇ receptor blockade

Abstract

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.

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

“…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].…”

“…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]. According to the neuronal connectivity in the mPFC, the present study determined the interaction between thalamocortical glutamatergic transmission and mesocortical serotonergic transmission in the mPFC, whereas, unlike catecholamine, hyper thalamocortical glutamatergic transmission induced by inhibition of NMDA-R in the RTN [25,26,49,50] did not affect 5-HT release in the mPFC.…”

“…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].…”