Dose-dependent modulation of social and motivational behavior by lurasidone in a rat model of social defeat

: Chronic psychosocial stress is a key risk factor for psychiatric disorders, often causing motivational and social impairments poorly responsive to conventional pharmacotherapies. The present study investigated the effects of chronic lurasidone treatment on behavioral and molecular alterations induced by prolonged social defeat (SD) stress in adult male rats. Rats underwent resident-intruder SD paradigm for approximately seven weeks and treated orally with lurasidone (1 or 3 mg/kg/day) during the final three weeks. Motivational drive was assessed using sucrose self-administration under fixed and progressive ratio schedules, while sociability was evaluated through social interaction tests. Molecular analysis quantified DARPP-32 dopaminergic response to social stimuli and gene expression [immediate early genes (Arc, c-Fos, Npas4, Zif268) and glucocorticoid-responsive genes (Sgk1, Fkbp5, Dusp1, Nr4a1)] across corticolimbic regions, including the nucleus accumbens and prefrontal cortex. SD stress caused anhedonia and social withdrawal. Treatment with lurasidone at 3 mg/kg, but not 1 mg/kg, effectively restored motivational performance, as indicated by normalized breaking points in the progressive ratio task. Both doses ameliorated the stress-induced social deficits, and DARPP-32 responses, although with different magnitudes. At the molecular level, SD disrupted activity-dependent and glucocorticoid-responsive transcription and functional coupling between brain regions. Lurasidone reinstated coordinated network activation, particularly during social stimulation, suggesting a dose- and context-dependent facilitation of neuronal plasticity. Overall, chronic lurasidone treatment counteracts stress-induced impairments in motivation and sociability through the restoration of corticolimbic network activity. Such effects may underlie its clinical efficacy in addressing negative and motivational symptoms across affective and psychotic disorders.