Lurasidone and fluoxetine reduce novelty-induced hypophagia and NMDA receptor subunit and PSD-95 expression in mouse brain

Abstract

Lurasidone, a novel second-generation antipsychotic agent, exerts antidepressant actions in patients suffering from bipolar type I disorder. Lurasidone acts as a high affinity antagonist at multiple monoamine receptors, particularly 5-HT_2A, 5-HT₇, D₂ and α₂ receptors, and as a partial agonist at 5-HT_1A receptors. Accumulating evidence indicates therapeutic actions by monoaminergic antidepressants are mediated via alterations of glutamate receptor-mediated neurotransmission. Here, we used mice and investigated the effects of chronic oral administration of vehicle, lurasidone (3 or 10 mg/kg) or fluoxetine (20 mg/kg) in the novelty induced hypophagia test, a behavioral test sensitive to chronic antidepressant treatment. We subsequently performed biochemical analyses on NMDA receptor subunits and associated proteins. Both lurasidone and fluoxetine reduced the latency to feed in the novelty-induced hypophagia test. Western blotting experiments showed that both lurasidone and fluoxetine decreased the total levels of NR1, NR2A and NR2B subunits of NMDA receptors and PSD-95 (PostSynaptic Density-95) in hippocampus and prefrontal cortex. Taken together, these data indicate that antidepressant/anxiolytic-like effects of lurasidone, as well as fluoxetine, could involve reduced NMDA receptor-mediated signal transduction, particularly in pathways regulated by PSD-95, in hippocampus and prefrontal cortex.

Introduction

Lurasidone is a novel atypical antipsychotic which alleviates both positive and negative symptoms of schizophrenia (Citrome et al., 2012, Meltzer et al., 2011). In addition, lurasidone has recently also been approved by the food and drug administration (FDA) for treatment of bipolar depression. Lurasidone acts as an antagonist at dopamine D2, serotonin 5-HT_2A and 5-HT₇ and adrenergic α₂ receptors (Cates et al., 2013, Ishiyama et al., 2007) and as a partial agonist at 5-HT_1A receptors (Ishibashi et al., 2010). It possesses antidepressant properties, either when used as a monotherapy (Loebel et al., 2014a) or an adjuvant therapy (Loebel et al., 2014b), for type I bipolar depression. Accordingly, chronic lurasidone administration induces antidepressant-like effects in rodent models (Cates et al., 2013, Luoni et al., 2013, Luoni et al., 2014).

An increasing amount of evidence indicates that serotonergic modulation of glutamatergic neurotransmission is a plausible approach in treating depression and cognitive dysfunction (Pehrson and Sanchez, 2014, Sanacora et al., 2008). It has, for example, been indicated that chronic treatment with different classes of monoaminergic antidepressants decreases N-methyl-d-aspartate receptor (NMDAR) function (Skolnick et al., 1996). Clinical trials have shown that a single, subanesthetic dose of the non-selective NMDAR antagonist, ketamine, has a rapid and sustained antidepressive effect (Sanacora et al., 2008, Zarate et al., 2006). Moreover, preclinical studies in rodents indicate that treatment with an acute, subanesthetic dose of ketamine or Ro25-6981 (a NR2B subunit-specific NMDAR antagonist) have rapid and sustained antidepressive effects at the behavioral level (Autry et al., 2011, Kiselycznyk et al., 2011, Li et al., 2010, Maeng et al., 2008) which are accompanied by altered presynaptic (Muller et al., 2013, Stan et al., 2014) and postsynaptic NMDAR-mediated signaling (Autry et al., 2011, Li et al., 2010, Maeng et al., 2008). Given this background, the current study aimed at exploring the effects of chronic treatment with lurasidone or fluoxetine on antidepressive/anxiolytic-like properties in the novelty-induced hypophagia test, which is sensitive to chronic antidepressant treatment, and in regulating the levels of NMDA receptor subunits and associated proteins, in hippocampus and prefrontal cortex of mice.