The Adenosine Receptor: A Homeostatic Neuromodulator for Fine-Tuning Control of Cognition

Abstract

There is a convergence of neurochemical studies showing the dual roles of neuromodulation and homeostatic function by adenosine receptors (AR), with animal studies demonstrating the strong pro-cognitive impact upon AR antagonism in healthy and diseased brains, with the epidemiological evidence in support of caffeine and AR drugs used for the therapeutic modulation of cognition. This perspective led to the proposal that the adenosine and AR may uniquely position to modulate cognitive behaviors in normal and disease conditions. This review first describes the ability of AR to integrate dopamine and glutamate signaling and to modulate synaptic plasticity by acting through the inhibitory A1 and facilitating A2A receptors (A2AR). It is followed by the discussion on the animal studies demonstrating the strong pro-cognitive effects of AR (mainly the A2A receptor) antagonism on a variety of cognitive behaviors. These studies reveal several novel insights into the mechanism underlying AR control of cognition: temporally precise interaction of adenosine with dopamine and glutamate signaling at the striatum, striatopallidal A2ARs function as a common “break” mechanism to constrain cognition, and selective modulation of distinct phases of working memory information processing. We further describe the evidence for the aberrantly increased adenosine-AR signaling under pathological conditions. Accordingly, blocking the aberrant AR signaling reverses cognitive impairments in animal models of neurodegenerative disorders. AR modification of neurodegenerative proteins (including α-synuclein, β-amyloid, and phosphorylation of Tau) and neuroprotection against synaptic loss are discussed as the potential mechanisms underlying AR control of cognitive deficits. Last, translational potential of A2AR antagonists and caffeine for cognitive improvement is highlighted with non-human primate studies and epidemiological findings. As caffeine is regularly consumed by >50% world population and A2AR antagonists are in phase III clinical trials for Parkinson’s disease with noted safety profiles, this convergence of molecular, animal, and epidemiological evidence supporting AR control of cognition will stimulate necessary clinical investigations to explore AR-targeting drugs as a novel strategy to ameliorate cognitive deficits in neuropsychiatric disorders.