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Lurasidone inhibits NMDA receptor antagonist‐induced functional abnormality of thalamocortical glutamatergic transmission via 5‐HT 7 receptor blockade
Author(s) -
Okada Motohiro,
Fukuyama Kouji,
Ueda Yuto
Publication year - 2019
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.14804
Subject(s) - glutamatergic , nmda receptor , glutamate receptor , pharmacology , dopamine , chemistry , neuroscience , receptor , biology , biochemistry
Background and Purpose Lurasidone is an atypical mood‐stabilizing antipsychotic with a unique receptor‐binding profile, including 5‐HT 7 receptor antagonism; however, the detailed effects of 5‐HT 7 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‐HT 7 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‐HT 7 receptor in the MDTN. These effects on thalamo‐insular glutamatergic transmission may contribute to the antipsychotic and mood‐stabilizing actions of lurasidone.