Exploring the anti-anhedonic properties of lurasidone and saffron extract long-term administration: behavioral and molecular insights in a rat model of chronic stress-induced anhedonia.

Anhedonia, a core symptom in depressive disorders, represents a clinically significant challenge as it is associated to poor prognosis, low treatment response, and increased suicide risk. While several pharmacological treatments have been proposed, none is approved to target specifically anhedonia and, thus there is an urgent need to identify novel compounds. In this context, I used preclinical models of anhedonia induced by exposure to chronic unavoidable stress (CUS) to investigate in male rats the antidepressant-like and pro-motivational effects of two distinct compounds: lurasidone, a second-generation antipsychotic, and saffron extract, a natural compound with potential antidepressant properties. The CUS exposure led to a marked reduction in the motivation to operate for positive stimuli (sucrose pellets) during sucrose self-administration (SSA) protocols and in competence to escape negative stimuli. Long-term administration of lurasidone (at the dose of 3mg/kg/day) and saffron extract (at the dose of 40 mg/kg/day) restored behavioral responses to positive and negative stimuli. Conversely, lurasidone administration at the dose of 10 mg/kg/day only ameliorated the reactivity to negative stimuli but not the responses to reward-associated cues. Neither treatment showed anxiolytic properties in the elevated plus maze (EPM) test. At the end of in vivo experiments, I studied the molecular mechanisms that may underlie the behavioral effects of long-term lurasidone and saffron extract administration, focusing on selected brain regions involved in reward circuits, the medial prefrontal cortex (mPFC) and nucleus accumbens (NAc). The results show that both long-term treatments completely restored the dopaminergic impairments in response to hedonic stimuli induced by exposure to CUS protocol and modulated neuroplastic changes via BDNF–TrkB signaling in the mPFC and NAc. Importantly, both lurasidone and saffron extract administration restored the increase in phosphorylation levels of DARPP-32 in response to rewarding stimuli, a key regulator of dopamine signaling in the mPFC and NAc, further underscoring its role in the modulation of reward-related pathways. The results suggest that both these treatments activate the BDNF–TrkB signaling pathways in the NAc and mPFC, supporting the hypothesis that the induction of neuroplastic changes has an essential role in the development of positive effects of several treatments in stress-induced disorders. In addition, the results suggest that lurasidone treatment also regulates activity-dependent genes (e.g. Npas4 and Arc), and stabilized interneuronal activity, as indicated by the effects on parvalbumin (PVB) and somatostatin (SST) expression. These findings demonstrate that lurasidone and saffron extract counteract stress-induced depressive-like symptoms, in particular motivational anhedonia, suggesting their clinical use as therapeutic strategies for treating anhedonia and associated disorders.