EXPOSURE TO CHRONIC STRESS IMPAIRS MOTIVATION AND SOCIABILITY IN RATS: RESTORATIVE PROPERTIES OF CHRONIC LURASIDONE TREATMENT

Abstract Background Stress is one of the most important factors for the etiology of mental disorders. On these bases, exposure to stress is used to investigate neurobiological mechanisms associated with specific psychopathologic mechanisms and to establish the potential for pharmacological intervention to ameliorate such alterations. We have previously demonstrated that chronic treatment with the second- generation antipsychotic drug lurasidone is able to normalize consummatory anhedonia induced by stress exposure in a preclinical model of depression [1] [2]. Aims & Objectives In the present study we used two stress paradigms to investigate the ability of lurasidone in ameliorating motivational anhedonia as well as reduced sociability, which represent key psychopathologic domains with a strong impact on patient functioning. Methods Sprague-Dawley male rats were exposed to an unavoidable chronic stress (UCS) protocol for 3 weeks in order to disrupt the motivation to acquire a reward-directed behavior [3]. Motivational anhedonia was assessed using sucrose self-administration in operant chambers provided with one active lever delivering a sucrose pellet. Rats were tested in fixed-ratio (FR) sessions (FR-1 and FR-5) as well as in the progressive ratio (PR) task. After having established the behavioral deficit, the animals (n=10/experimental group) were then divided into two subgroups that continued (or did not) stress exposure and received vehicle or lurasidone (3 mg/kg) once daily. Next, to verify their reactivity to avoidable aversive stimuli, stressed animals were exposed to the escape test. Sociability impairment was investigated using the social defeat stress model. Results We confirmed that exposure of rats to UCS was able to produce a significant reduction in the competence to acquire self-administration, at FR1 and FR5 schedules. Moreover, UCS rats show impaired motivation in the progressive ratio protocol (-50% in breaking point, p<0.001 vs. control/vehicle). After two weeks of drug administration, lurasidone treatment was able to rescue the motivation in stressed rats. In addition, we found that animals exposed to UCS and treated with vehicle show a significant impairment in the emotional reactivity to negative stimuli and that such changes were restored by chronic treatment with the antipsychotic drug. Furthermore, chronic lurasidone treatment was able to restore sociability in rats exposed to the social defeat paradigm. Discussion & Conclusion In summary, these novel data provide support for the ability of lurasidone treatment to ameliorate key psychopathologic domains, including impaired motivation and reduced sociability, which represent core elements for the disability associated with mental disorders. References [1]Luoni A. et al., Int J Neuropsychopharmacol. 18(4):1–12, 2015. [2]Rossetti A.C. et al., Int J Neuropsychopharmacol. 21(9):883-893, 2018. [3]Scheggi, S. et al., Neuroscience, 291, 189–202, 2015.