2-(4-(2-carboxyethyl)phenethylamino)-5--n-ethylcarboxamidoadenosine and Memory-Disorders

Human and animal studies have converged to suggest that caffeine consumption prevents memory deficits in aging and Alzheimer's disease through the antagonism of adenosine A2A receptors (A2ARs). To test if A2AR activation in the hippocampus is actually sufficient to impair memory function and to begin elucidating the intracellular pathways operated by A2AR, we have developed a chimeric rhodopsin-A2AR protein (optoA2AR), which retains the extracellular and transmembrane domains of rhodopsin (conferring light responsiveness and eliminating adenosine-binding pockets) fused to the intracellular loop of A2AR to confer specific A2AR signaling. The specificity of the optoA2AR signaling was confirmed by light-induced selective enhancement of cAMP and phospho-mitogen-activated protein kinase (p-MAPK) (but not cGMP) levels in human embryonic kidney 293 (HEK293) cells, which was abolished by a point mutation at the C terminal of A2AR. Supporting its physiological relevance, optoA2AR activation and the A2AR agonist CGS21680 produced similar activation of cAMP and p-MAPK signaling in HEK293 cells, of p-MAPK in the nucleus accumbens and of c-Fos/phosphorylated-CREB (p-CREB) in the hippocampus, and similarly enhanced long-term potentiation in the hippocampus. Remarkably, optoA2AR activation triggered a preferential p-CREB signaling in the hippocampus and impaired spatial memory performance, while optoA2AR activation in the nucleus accumbens triggered MAPK signaling and modulated locomotor activity. This shows that the recruitment of intracellular A2AR signaling in the hippocampus is sufficient to trigger memory dysfunction. Furthermore, the demonstration that the biased A2AR signaling and functions depend on intracellular A2AR loops prompts the possibility of targeting the intracellular A2AR-interacting partners to selectively control different neuropsychiatric behaviors.

Topics: Adenosine; Adenosine A2 Receptor Agonists; Animals; Cell Membrane; Cyclic AMP Response Element-Binding Protein; Disease Models, Animal; Exploratory Behavior; HEK293 Cells; Hippocampus; Humans; In Vitro Techniques; Light; Memory Disorders; Mice; Mice, Inbred C57BL; Phenethylamines; Phosphorylation; Receptors, Adenosine A2; Signal Transduction; Synaptosomes; Transfection

Caffeine (a non-selective adenosine receptor antagonist) prevents memory deficits in aging and Alzheimer's disease, an effect mimicked by adenosine A2 A receptor, but not A1 receptor, antagonists. Hence, we investigated the effects of adenosine receptor agonists and antagonists on memory performance and scopolamine-induced memory impairment in mice.. We determined whether A2 A receptors are necessary for the emergence of memory impairments induced by scopolamine and whether A2 A receptor activation triggers memory deficits in naïve mice, using three tests to assess short-term memory, namely the object recognition task, inhibitory avoidance and modified Y-maze.. Scopolamine (1.0 mg·kg(-1) , i.p.) impaired short-term memory performance in all three tests and this scopolamine-induced amnesia was prevented by the A2 A receptor antagonist (SCH 58261, 0.1-1.0 mg·kg(-1) , i.p.) and by the A1 receptor antagonist (DPCPX, 0.2-5.0 mg·kg(-1) , i.p.), except in the modified Y-maze where only SCH58261 was effective. Both antagonists were devoid of effects on memory or locomotion in naïve rats. Notably, the activation of A2 A receptors with CGS 21680 (0.1-0.5 mg·kg(-1) , i.p.) before the training session was sufficient to trigger memory impairment in the three tests in naïve mice, and this effect was prevented by SCH 58261 (1.0 mg·kg(-1) , i.p.). Furthermore, i.c.v. administration of CGS 21680 (50 nmol) also impaired recognition memory in the object recognition task.. These results show that A2 A receptors are necessary and sufficient to trigger memory impairment and further suggest that A1 receptors might also be selectively engaged to control the cholinergic-driven memory impairment.

Topics: Adenosine; Animals; Avoidance Learning; Dose-Response Relationship, Drug; Infusions, Intraventricular; Locomotion; Male; Maze Learning; Memory Disorders; Memory, Short-Term; Mice; Phenethylamines; Purinergic P1 Receptor Agonists; Purinergic P1 Receptor Antagonists; Pyrimidines; Receptor, Adenosine A1; Receptor, Adenosine A2A; Recognition, Psychology; Scopolamine; Triazoles; Xanthines

Central adenosine A(2A) receptor is a promising target for drugs to treat Parkinson's disease (PD), and the central blockade of adenosine A(1) receptor improves cognitive function. In the present study, we investigated the effect of a novel adenosine A(1) and A(2A) dual antagonist, 5-[5-amino-3-(4-fluorophenyl) pyrazin-2-yl]-1-isopropylpyridine-2(1H)-one (ASP5854), in animal models of PD and cognition. The binding affinities of ASP5854 for human A(1) and A(2A) receptors were 9.03 and 1.76 nM, respectively, with higher specificity and no species differences. ASP5854 also showed antagonistic action on A(1) and A(2A) agonist-induced increases of intracellular Ca(2+) concentration. ASP5854 ameliorated A(2A) agonist 2-[p-(2-carboxyethyl) phenethylamino]-5'-N-ethylcarboxamidoadenosine (CGS21680)- and haloperidol-induced catalepsy in mice, with the minimum effective doses of 0.32 and 0.1 mg/kg, respectively, and it also improved haloperidol-induced catalepsy in rats at doses higher than 0.1 mg/kg. In unilateral 6-hydroxydopamine-lesioned rats, ASP5854 significantly potentiated l-dihydroxyphenylalanine (L-DOPA)-induced rotational behavior at doses higher than 0.032 mg/kg. ASP5854 also significantly restored the striatal dopamine content reduced by 1-metyl-4-phenyl-1,2,3,6-tetrahydropyridine treatment in mice at doses higher than 0.1 mg/kg. Furthermore, in the rat passive avoidance test, ASP5854 significantly reversed the scopolamine-induced memory deficits, whereas the specific adenosine A(2A) antagonist 8-((E)-2-(3,4-dimethoxyphenyl)ethenyl)-1,3-diethyl-7-methyl-3,7-dihydro-1H-purine-2,6-dione (KW-6002; istradefylline) did not. Scopolamine- or 5H-dibenzo[a,d]cyclohepten-5,10-imine (dizocilpine maleate) (MK-801)-induced impairment of spontaneous alternation in the mouse Y-maze test was ameliorated by ASP5854, whereas KW-6002 did not exert improvement at therapeutically relevant dosages. These results demonstrate that the novel, selective, and orally active dual adenosine A(1) and A(2A) receptors antagonist ASP5854 improves motor impairments, is neuroprotective via A(2A) antagonism, and also enhances cognitive function through A(1) antagonism.

Topics: Adenosine; Adenosine A1 Receptor Antagonists; Adenosine A2 Receptor Antagonists; Aminopyridines; Animals; CHO Cells; Cognition Disorders; Cricetinae; Cricetulus; Dopamine; Haloperidol; Humans; Male; Memory Disorders; Mice; Mice, Inbred C57BL; MPTP Poisoning; Phenethylamines; Piperazines; Rats; Rats, Inbred F344; Rats, Wistar; Receptor, Adenosine A1; Receptor, Adenosine A2A; Scopolamine

THE highly selective adenosine A1 receptor agonist N6-cyclohexyladenosine (CHA) significantly increased the number of errors (attempts to pass through two incorrect panels of the three panel-gates at four choice points) in the working memory task with a three-panel runway setup, when injected bilaterally at 0.3 and 1.0 microgram per side into the dorsal hippocampus. Pretreatment with the selective adenosine A1 receptor antagonist 1,3-dipropyl-8-cyclopentylxanthine (DPCPX; 1 mg kg-1, i.p.) prevented the increase in working memory errors induced by intrahippocampal administration of CHA (1.0 microgram per side). CGS-21680, a highly selective agonist for adenosine A2 receptors, had no effect on the number of working memory errors, when administered intrahippocampally at a dose of 1.0 microgram per side. These results suggest that activation of hippocampal adenosine A1 receptors interferes with neural processes involved in working memory function.

Topics: Adenosine; Animals; Hippocampus; Injections; Learning; Male; Memory Disorders; Memory, Short-Term; Phenethylamines; Purinergic P1 Receptor Agonists; Purinergic P2 Receptor Agonists; Rats; Rats, Wistar