Master’s thesis

Le résumé fourni par la source

Adenosine plays a central role in maintaining healthy communication between brain cells, yet its balance can easily shift during stress, disease, or chronic receptor stimulation. Previous studies have shown that adenosine elevation during and after cerebral ischemia alters the expression and distribution of adenosine receptors. In this thesis, we examined how chronic activation of the adenosine A1 receptor (A1R) affects receptor homeostasis, downstream Casein Kinase 2 (CK2), and the equilibrative nucleoside transporter 1 (ENT1) and its phosphorylated form (pENT1) in the rat brain. Specifically, we focused on the hippocampus region and the substantia nigra pars compacta, two areas deeply involved in learning and memory processes and motor function, respectively. Rats were treated for five days with the A1R agonist N6-Cyclopentyladenosine (CPA) to model chronic receptor activation and to explore its broader consequences. Behavioral testing revealed that chronic CPA treatment impaired hippocampal-dependent spatial memory, increased anxiety-like behavior, reduced motor performance, and produced enhanced depressive-like immobility. These behavioral shifts were accompanied by distinct molecular changes. Imaging and protein analyses showed that prolonged A1R activation led to reduced expression of A1R, upregulated adenosine A2A receptor (A2AR), lowered levels of the kinase CK2, and altered regulation of the nucleoside transporter ENT1 and its phosphorylated form, pENT1. These effects were blunted by co-administration of CPA with either the A1R antagonist (DPCPX) or the A2AR antagonist (Istradefylline, or KW-6002). Moreover, the results obtained from lipid raft and non-raft fractions indicated similar downregulation of A1R, CK2 and ENT1 after CPA treatments in both membrane microdomains, and pretreatment with either DPCPX or Istradefylline abrogated these changes. Together, these findings show that chronic A1R activation sets off a cascade of changes, beginning with receptor desensitization and extending to CK2-dependent disturbances in ENT1 signaling, that ultimately result in cognitive, emotional, and motor deficits. This work provides new insight into how prolonged shifts in adenosine signaling may contribute to neurological dysfunction and highlights the interconnected nature of receptor regulation, intracellular kinases, and nucleoside transport in the brain.

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