Oct 9, 2019

Lurasidone Sub-Chronically Activates Serotonergic Transmission via Desensitization of 5-HT1A and 5-HT7 Receptors in Dorsal Raphe Nucleus

Pharmaceuticals
Motohiro OkadaYuto Ueda

Abstract

Lurasidone is an atypical mood-stabilizing antipsychotic agent with unique receptor-binding profile, including 5-HT7 receptor (5-HT7R) antagonism. Effects of 5-HT7R antagonism on transmitter systems of schizophrenia and mood disorders, however, have not been well clarified. Thus, this study examined the mechanisms underlying the clinical effects of lurasidone by measuring mesocortical serotonergic transmission. Following systemic and local administrations of lurasidone, MK801 and 5-HT receptor modulators, we determined releases of 5-HT in dorsal raphe nucleus (DRN), mediodorsal thalamic nucleus (MDTN) and medial prefrontal cortex (mPFC) and γ-aminobutyric acid (GABA) in DRN using multiprobe microdialysis with ultra-high-performance liquid chromatography (UHPLC). Serotonergic and GABAergic neurons in the DRN are predominantly regulated by inhibitory 5-HT1A receptor (5-HT1AR) and excitatory 5-HT7R, respectively. Lurasidone acutely generates GABAergic disinhibition by 5-HT7R antagonism, but concomitant its 5-HT1AR agonism prevents serotonergic hyperactivation induced by 5-HT7R inhibition. During treatments with 5-HT1AR antagonist in DRN, lurasidone dose-dependently increased 5-HT release in the DRN, MDTN and mPFC. Contrary, lurasi...Continue Reading

Mentioned in this Paper

Study
GRIN1
Schizophrenia
Serotonin 5-HT1A Receptor Antagonists
Serotonin
HTR1A
Receptor, Serotonin,5-HT1A
Molecular_function
Dosage Compensation by Hyperactivation of X Chromosome
Lurasidone

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