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

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 center dot kg(-1)) administration increased insular release of l-glutamate, dopamine, and noradrenaline but decreased GABA release. Systemic lurasidone (1 mg center dot kg(-1)) administration also increased insular release of l-glutamate, dopamine, and noradrenaline but without affecting GABA. Local lurasidone administration into the insula (3 mu M) did not affect MK-801-induced insular release of l-glutamate or catecholamine, whereas local lurasidone administration into the MDTN (1 mu M) 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.