lurasidone-hydrochloride and Anhedonia

Stress represents a major contributor to the development of mental illness. Accordingly, exposure of adult rats to chronic stress represents a valuable tool to investigate the ability of a pharmacological intervention to counteract the adverse effects produced by stress exposure.. The aim of this study was to perform a time course analysis of the treatment with the antipsychotic drug lurasidone in normalizing the anhedonic phenotype in the chronic mild stress (CMS) model in order to identify early mechanisms that may contribute to its therapeutic activity.. Male Wistar rats were exposed to CMS or left undisturbed for 7 weeks. After two weeks of stress, both controls and CMS rats were randomly divided into two subgroups that received vehicle or lurasidone for five weeks. Weekly measures of sucrose intake were recorded to evaluate anhedonic behavior, and animals were sacrificed at different weeks of treatment for molecular analyses.. We found that CMS-induced anhedonia was progressively improved by lurasidone treatment. Interestingly, after two weeks of lurasidone treatment, 50% of the animals showed a full recovery of the phenotype, which was associated with increased activation of the prefrontal and recruitment of parvalbumin-positive cells that may lead to a restoration of excitatory/inhibitory balance.. These results suggest that the capacity of lurasidone to normalize anhedonia at an early stage of treatment may depend on its ability to modulate the function of the prefrontal cortex.

Topics: Anhedonia; Animals; Antipsychotic Agents; Lurasidone Hydrochloride; Male; Prefrontal Cortex; Rats; Rats, Wistar; Stress, Psychological

Major depression is a complex disease that originates from the interaction between a genetic background of susceptibility and environmental factors such as stress. At molecular level, it is characterized by dysfunctions of multiple systems including neurotransmitters, hormones, signalling pathways, neurotrophic and neuroplastic molecules and - more recently - inflammatory mediators. Accordingly, in the present study we used the chronic mild stress (CMS) paradigm in the rat to elucidate to what extent brain inflammation may contribute to the development and/or the maintenance of an anhedonic phenotype and how pharmacological intervention may interfere with such behavioral and molecular stress-induced alterations. To this aim, adult male rats were exposed to CMS for 2 weeks and the cerebral expression of several mediators of the inflammatory system was evaluated in the hippocampus and prefrontal cortex of both stressed and control animals in parallel with the sucrose intake. Next, the animals that showed a decreased sucrose consumption were exposed to five further weeks of CMS and treated with the antidepressants imipramine or agomelatine, or the antipsychotic lurasidone. Our results demonstrate that only the stressed animals that were characterized by a deficit in sucrose intake showed increased expression of the pro-inflammatory cytokines IL-1β, IL-6 and up-regulation of markers and mediators of microglia activation such as CD11b, CX3CL1 and its receptor CX3CR1 in comparison with stress-resilient animals. Some of these molecular alterations persisted also after longer stress exposure and were modulated, similarly to the behavioral effects of CMS, by chronic pharmacological treatment. These data suggest that neuroinflammation may have a key role in the pathological consequences of stress exposure, thus contributing to the subject's vulnerability for depression.

Topics: Acetamides; Anhedonia; Animals; Antidepressive Agents; Antipsychotic Agents; Brain; CD11b Antigen; Chemokine CX3CL1; CX3C Chemokine Receptor 1; Gene Expression Profiling; Hippocampus; Imipramine; Interleukin-1beta; Interleukin-6; Lurasidone Hydrochloride; Male; Prefrontal Cortex; Rats, Wistar; Receptors, Chemokine; RNA, Messenger; Stress, Physiological; Transforming Growth Factor beta