Lurasidone Exerts Antidepressant Properties in the Chronic Mild Stress Model through the Regulation of Synaptic and Neuroplastic Mechanisms in the Rat Prefrontal Cortex

Abstract

Background:Major depression is associated with several alterations, including reduced neuronal plasticity and impaired synaptic function, which represent an important target of pharmacological intervention.Methods:In the present study, we have investigated the ability of the antipsychotic drug lurasidone to modulate behavioral and neuroplastic alterations in the chronic mild stress model of depression.Results:Rats that show reduced sucrose consumption after 2 weeks of chronic mild stress have reduced expression of the pool of Bdnf transcripts with the long 3′ untranslated region (3′-UTR) that may be targeted to the synaptic compartment, suggesting the contribution of the neurotrophin to the behavioral dysfunction produced by chronic mild stress. The downregulation of Bdnf expression persisted also after 7 weeks of chronic mild stress, whereas chronic lurasidone treatment improved anhedonia in chronic mild stress rats and restored Bdnf mRNA levels in the prefrontal cortex. Moreover, chronic lurasidone treatment was able to normalize chronic mild stress-induced defects of Psd95 and Gfap as well as changes in molecular regulators of protein translation at the synapse, including mTOR and eEF2.Conclusions:These results demonstrate that lurasidone shows antidepressant properties in the chronic mild stress model through the modulation of synaptic and neuroplastic proteins. Such changes may contribute to the amelioration of functional capacities, which are deteriorated in patients with major depression and stress-related disorders.

Stress-induced anhedonia is associated with the activation of the inflammatory system in the rat brain: Restorative effect of pharmacological intervention

“…Moreover, we have recently reported that the ability of lurasidone to normalize the anhedonic-like phenotype induced by CMS may be also due to the modulation of synaptic and neuroplastic mechanisms [57].…”

Synaptic plasticity and depression: new insights from stress and rapid-acting antidepressants

“…Studies to identify the receptor subtype indicate that a selective muscarinic 1 antagonist produces antidepressant actions similar to scopolamine in rodent models 173,174 . Preclinical studies also report that other putative antidepressant agents increase or are dependent on mTORC1 signaling 175–178 . Together, these studies provide additional supporting evidence that the mTORC1 dendritic translational cascade and synapse formation may represent a common final pathway for a wide range of rapid acting, efficacious antidepressants.…”

Chronic Stress Exposure Reduces Parvalbumin Expression in the Rat Hippocampus through an Imbalance of Redox Mechanisms: Restorative Effect of the Antipsychotic Lurasidone

“…We have previously shown that CMS is able to induce depressive-like behaviors such as anhedonia (Rossetti et al, 2016) as well as cognitive impairment (Calabrese et al, 2017), which are associated with alterations in key molecular players for psychiatric disorders (Luoni et al, 2014; Calabrese et al, 2016b; Molteni et al, 2016). We also investigated the effect of a chronic treatment with lurasidone in counteracting the CMS-induced alterations in rat hippocampus.…”