Lurasidone is an atypical mood-stabilizing antipsychotic agent with unique receptorbinding\nprofile, including 5-HT7 receptor (5-HT7R) antagonism. Effects of 5-HT7R antagonism on\ntransmitter systems of schizophrenia and mood disorders, however, have not been well clarified.\nThus, this study examined the mechanisms underlying the clinical effects of lurasidone by\nmeasuring mesocortical serotonergic transmission. Following systemic and local administrations of\nlurasidone, MK801 and 5-HT receptor modulators, we determined releases of 5-HT in dorsal raphe\nnucleus (DRN), mediodorsal thalamic nucleus (MDTN) and medial prefrontal cortex (mPFC) and\nGamma-aminobutyric acid (GABA) in DRN using multiprobe microdialysis with ultra-high-performance\nliquid chromatography (UHPLC). Serotonergic and GABAergic neurons in the DRN are\npredominantly regulated by inhibitory 5-HT1A receptor (5-HT1AR) and excitatory 5-HT7R,\nrespectively. Lurasidone acutely generates GABAergic disinhibition by 5-HT7R antagonism, but\nconcomitant its 5-HT1AR agonism prevents serotonergic hyperactivation induced by 5-HT7R\ninhibition. During treatments with 5-HT1AR antagonist in DRN, lurasidone dose-dependently\nincreased 5-HT release in the DRN, MDTN and mPFC. Contrary, lurasidone chronically enhanced\nserotonergic transmission and GABAergic disinhibition in the DRN by desensitizing both 5-HT1AR\nand 5-HT7R. These effects of lurasidone acutely prevented MK801-evoked 5-HT release by\nGABAergic disinhibition via N-methyl-D-aspartate (NMDA)/glutamate receptor (NMDA-R)-\nmediated inhibition of 5-HT1AR function, but enhanced MK801-induced 5-HT release by\ndesensitizing 5-HT1AR and 5-HT7R. These results indicate that acutely lurasidone fails to affect 5-\nHT release, but chronically enhances serotonergic transmission by desensitizing both 5-HT1AR and\n5-HT7R. These unique properties of lurasidone ameliorate the dysfunctions of NMDA-R and\naugment antidepressive effects.
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