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 A.sub.2A receptors (A.sub.2ARs). To test if A.sub.2AR activation in the hippocampus is actually sufficient to impair memory function and to begin elucidating the intracellular pathways operated by A.sub.2AR, we have developed a chimeric rhodopsin-A.sub.2AR protein (optoA.sub.2AR), which retains the extracellular and transmembrane domains of rhodopsin (conferring light responsiveness and eliminating adenosine-binding pockets) fused to the intracellular loop of A.sub.2AR to confer specific A.sub.2AR signaling. The specificity of the optoA.sub.2AR 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 A.sub.2AR. Supporting its physiological relevance, optoA.sub.2AR activation and the A.sub.2AR 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, optoA.sub.2AR activation triggered a preferential p-CREB signaling in the hippocampus and impaired spatial memory performance, while optoA.sub.2AR activation in the nucleus accumbens triggered MAPK signaling and modulated locomotor activity. This shows that the recruitment of intracellular A.sub.2AR signaling in the hippocampus is sufficient to trigger memory dysfunction. Furthermore, the demonstration that the biased A.sub.2AR signaling and functions depend on intracellular A.sub.2AR loops prompts the possibility of targeting the intracellular A.sub.2AR-interacting partners to selectively control different neuropsychiatric behaviors. Molecular Psychiatry (2015) 20, 1339-1349; doi: 10.1038/mp.2014.182; published online 17 February 2015