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New generation prostate cancer therapy may impact motivation for exploration, spatial learning and dopaminergic transmission in aged castrated mice
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  • Celeste Nicola,
  • Martine Dubois,
  • Cynthia Campart,
  • Tareq Al Sagheer,
  • Laurence Desrues,
  • Damien Schapman,
  • Ludovic Galas,
  • Marie Lange,
  • Florence Joly,
  • Hélène CASTEL
Celeste Nicola
University of Rouen Normandie
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Martine Dubois
University of Rouen Normandie
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Cynthia Campart
University of Rouen Normandie
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Tareq Al Sagheer
University of Rouen Normandie
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Laurence Desrues
University of Rouen Normandie
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Damien Schapman
University of Rouen Normandie
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Ludovic Galas
PRIMACEN
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Marie Lange
Centre F. Baclesse
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Florence Joly
Centre F. Baclesse
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Hélène CASTEL
University of Rouen Normandie

Corresponding Author:[email protected]

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Abstract

Background and Purpose: Cognitive side effects after cancer treatment threatening quality of life (QoL) constitute a major challenge in oncology. Abiraterone acetate plus prednisone (AAP) and enzalutamide (ENZ) are next generation therapy (NGT) administered with androgen deprivation therapy to metastatic castration-resistant prostate cancer (mCRPC) patients. NGT significantly improved mCRPC overall survival but neurological side effects such as fatigue and cognitive impairment have been recently reported. Experimental Approach: We developed a behavioral 17 months-aged and castrated mouse model receiving per os AAP or ENZ during 5 days per week for six consecutive weeks. After behavioral tests, brain and plasma were collected for immunohistochemical studies. Spontaneous activity, cognitive functions and emotional reactivity, as well as neurobiological functions were investigated. Key Results: ENZ exposure reduced spontaneous activity and exploratory behavior associated with a decreased tyrosine hydroxylase (TH)-dopaminergic activity in the substantia nigra pars compacta and the ventral tegmental area. A decrease in TH+-DA afferent fibers and Phospho-DARPP32-related dopaminergic neuronal activities in the striatum and the ventral hippocampus, highlighted ENZ-induced dopaminergic regulation whithin the nigrostriatal and mesolimbocortical pathways. ENZ and AAP treatments did not substantially modify spatial learning and memory or behavioral flexibility performances, but ENZ led to a thygmotaxis behavior impacting the cognitive score, and reduced c-fos-related activity of NeuN+-neurons in the dorsal hippocampus. Conclusion and Implications: These results establish the consequences of the mCRPC treatment ENZ in aged castrated mouse motivation to exploration and cognition, of particular importance for future management of patients elderly postrate cancer patients and their QoL.