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Adenosine A_2A receptors (A_2AR) are a sub-type of receptors enriched in basal ganglia, activated by the neuromodulator adenosine, which interact with dopamine D₂ receptors. Although this reciprocal antagonistic interaction is well-established in motor function, the outcome in dopamine-related behaviors remains uncertain, in particular in depression and anxiety. We have demonstrated an upsurge of A_2AR associated to aging and chronic stress. Furthermore, Alzheimer’s disease patients present A_2AR accumulation in cortical areas together with depressive signs. We now tested the impact of overexpressing A_2AR in forebrain neurons on dopamine-related behavior, namely depression. Adult male rats overexpressing human A_2AR under the control of CaMKII promoter [Tg(CaMKII-hA2AR)] and aged-matched wild-types (WT) of the same strain (Sprague-Dawley) were studied. The forced swimming test (FST), sucrose preference test (SPT), and the open-field test (OFT) were performed to evaluate behavioral despair, anhedonia, locomotion, and anxiety. Tg(CaMKII-hA2AR) animals spent more time floating and less time swimming in the FST and presented a decreased sucrose preference at 48 h in the SPT. They also covered higher distances in the OFT and spent more time in the central zone than the WT. The results indicate that Tg(CaMKII-hA2AR) rats exhibit depressive-like behavior, hyperlocomotion, and altered exploratory behavior. This A_2AR overexpression may explain the depressive signs found in aging, chronic stress, and Alzheimer’s disease.