Effect of lurasidone treatment on chronic mild stress-induced behavioural deficits in male rats: The potential role for glucocorticoid receptor signalling

Abstract

Background: Stress represents one of the main precipitating factors for psychiatric diseases, characterised by an altered function of glucocorticoid receptors (GR), known to play a role in mood and cognitive function. We investigated the ability of the antipsychotic lurasidone to modulate the involvement of genomic and non-genomic GR signalling in the behavioural alterations due to chronic stress exposure Methods: Male Wistar rats were exposed to seven weeks of chronic mild stress (CMS) and treated with lurasidone (3 mg/kg/day) starting from the second week of stress for more five weeks. Gene expression and protein analyses were conducted in dorsal hippocampus. Results: Seven weeks of CMS induced anhedonia and cognitive impairment, which were normalised by lurasidone. At molecular level, CMS rats showed an increase of GR protein levels by 60% ( p<0.001 vs. CTRL/VEH) in the membrane compartment, which was paralleled by an up-regulation of phosphoSINAPSYN Ia/b by 88% ( p<0.01 vs. CTRL/VEH) and of the mitochondrial marker Cox3 by 21% ( p<0.05 vs. CTRL/VEH). Moreover, while exposure to the novel object recognition test increased the nuclear translocation of GRs by 96% ( p<0.01 vs. CTRL/VEH/Naïve) and their transcriptional activity in non-stressed rats, such mechanisms were impaired in CMS rats. Interestingly, the genomic and non-genomic alterations of GR, induced by CMS, were normalised by lurasidone. Conclusion: Our results further support the role of glucocorticoid signalling in the dysfunction associated with stress exposure. We provide novel insights on the mechanism of lurasidone, suggesting its effectiveness on different domains associated with psychiatric disorders.

Chronic Restraint Stress Inhibits the Response to a Second Hit in Adult Male Rats: A Role for BDNF Signaling

“…Exposure to 4 weeks of CRS induced a cognitive impairment as assessed by the novel object recognition (NOR) test. Indeed, as previously observed [23,24], we found a significant decrease in the NOR discrimination index in all the rats exposed to chronic stress (−32%, p < 0.05 vs. No stress, T value = 2.446) in comparison to non-stressed animals ( Figure S1).…”

Anti-stress Properties of Atypical Antipsychotics

“…Exposure of adult rats to chronic mild stress (CMS) can induce anhedonic-like behaviors that are successfully normalized through the chronic administration of several AAPDs, such as lurasidone, cariprazine, and olanzapine [ 110 , 114 , 134 , 135 ], suggesting their potential in ameliorating emotional disturbance, which represents a major burden in different psychiatric disorders. Moreover, we have recently demonstrated that chronic lurasidone administration is also able to revert the cognitive deficit induced by CMS exposure [ 113 ] and a similar effect was also detected with olanzapine that was able to improve the impairments in visual and spatial performances [ 136 ]. Furthermore, chronic olanzapine administration ameliorates other behavioral alterations following CMS exposure, including deficits in coat state and grooming behavior in the splash test, while decreasing the attack frequency in the resident intruder test and the immobility time in the tail suspension test [ 137 ].…”

“…Thus, studying the effects of acute and chronic stress occurring during adulthood is crucial to identify those alterations that may be modulated by pharmacological intervention. For instance, chronic mild stress (CMS) exposure induces several behavioral alterations, including anhedonia and cognitive impairment [ 110 , 111 , 112 , 113 ]. These behavioral alterations are associated with a wide range of molecular changes affecting specific systems that are altered in schizophrenia as well as in other mental disorders.…”

“…For instance, we have shown that CMS exposure reduces the expression of neuroplastic proteins [ 114 ] and alters synaptic mechanisms involved in the glutamatergic function and local protein synthesis [ 111 ]. Moreover, exposure to CMS is associated with alterations in the glucocorticoid signaling [ 113 ], enhanced expression of inflammatory markers as well as an imbalance of redox mechanisms [ 38 , 110 ], all of which have been associated with schizophrenia.…”

“…Although the HPA axis does not represent a direct target of AAPDs, several drugs may modulate key brain regions linked to the stress response [ 117 , 138 ]. For instance, we have recently demonstrated that chronic administration of lurasidone can prevent the increase of GR membrane levels that followed CMS exposure, as well as to restore the transcription of GR-responsive genes [ 113 ].…”