Adenosine A_2A receptor antagonists exert motor and neuroprotective effects by distinct cellular mechanisms

Abstract

Interpretation: A 2A R activity in forebrain neurons is critical to the control of motor activity, whereas brain cells other than forebrain neurons (likely glial cells) are important components for protection against acute MPTP toxicity.

Selective inactivation of adenosine A2A receptors in striatal neurons enhances working memory and reversal learning

“…1C, upper panel). These results are entirely consistent with the pattern previously reported using 3 H-SCH58261 (another selective A 2A R antagonist) as the radioligand (Yu et al 2008). In contrast, analysis of st-A 2A R KO and st-WT mice (n ¼ 6 -7 per group) demonstrated that A 2A R expression was completely lost in the striatum (F (1,11) ¼ 177.47, P , 0.0001), but preserved in the cortex and the hippocampus (F's , 1), as well as olfactory bulb (P ¼ 0.16) of st-A 2A R KO mice (Fig.…”

“…1A, upper panel). This expression pattern is consistent with our previous detection of Cre-mediated A 2A R deletion in fb-A 2A R KO mice by PCR analysis and by 3 H-SCH58261 radioligand binding assay (Yu et al 2008). In contrast, in Dlx5/6-cre(+)Rosa26 flox/flox mice, Cre recombination was robust and localized mainly to dorsal and ventral striatum, although sparse recombination was detected in extra-striatal brain regions such as the hippocampus and the cortical mantle (Fig.…”

“…Fb-A 2A R KO and st-A 2A R KO mice have been characterized for their selective A 2A R deletion in the forebrain (i.e., the cortex, the hippocampus, and the striatum) (Bastia et al 2005;Yu et al 2008) or exclusively in striatal (Shen et al 2008a) neurons, as shown in our previous studies. To further characterize the Cre-mediated effects on A 2A R expression in different brain regions in fb-A 2A R KO and st-A 2A R KO mice, we determined Cre expression by X-gal staining of LacZ in a Rosa26 reporter transgenic line, PCR analysis of Cre-mediated A 2A R deletion in brain, and 3 H-ZM241385 (a selective A 2A R antagonist) radioligand binding of A 2A R density in the brain.…”

What Knock-Out Animals Tell Us About the Effects of Caffeine

“…Thus, the A 2A R is required for the psychomotor stimulant of caffeine. Furthermore, using recently developed brain region and cell-type specific A 2A R KO mice, we demonstrated that it is the A 2A Rs in forebrain neurons that are responsible for caffeineinduced psychomotor activity [23]. Thus, there is clear and strong evidence that the A 2A R located on forebrain neurons is the molecular target by which caffeine exerts its psychomotor effect.…”

Concluding Remarks

“…Notably, this information will be revealed in animal studies. While A 2A receptors emerge as the most likely candidate to mediate the effects of caffeine on neurodegeneration and memory impairment (see discussion in [9]), there seems to be a different involvement of distinct adenosine A 2A receptors in behavior and neuroprotective effects [26]. Similarly, more detailed information on the pharmacokinetics of caffeine is necessary, with particular emphasis on the brain distribution of caffeine [27].…”