[Frontiers in Bioscience 13, 2614-2632, January 1, 2008] 2614 Adenosine receptor antagonists for cognitive dysfunction: a review of animal studies Reinaldo Naoto Takahashi, Fabricio Alano Pamplona, Rui Daniel Schroder Prediger Departamento de Farmacologia, Centro de Ciencias Biologicas, Universidade Federal de Santa Catarina, Campus Trindade, Florianopolis-SC 88049-900, Brazil TABLE OF CONTENTS 1. Abstract 2. Introduction 3. Basic aspects of adenosine as a neuromodulator relevant for cognitive functions 4. Effects of adenosine receptor antagonists on cognitive deficits in aged rodents and models of Alzheimer's disease 5. Effects of adenosine receptor antagonists on learning and memory impairments in rodent models of Parkinson's disease 6. Cognitive effects of adenosine receptor antagonists on the spontaneously hypertensive rat (SHR) strain, a rodent model of attention deficit hyperactivity disorder (ADHD) 7. Summary and perspective 8. Acknowledgements 9. References 1. ABSTRACT Over the last decade, adenosine receptors in the central nervous system have been implicated in the modulation of cognitive functions. Despite the general view that endogenous adenosine modulates cognition through the activation of adenosine A 1 receptors, evidence is now emerging on a possible role of A 2A receptors in learning and memory. The present review attempts to examine results reported in different studies using diverse animal models, to provide a comprehensive picture of the recent evidence of a relationship between adenosinergic function and memory deficits. The present data suggest that caffeine (a nonselective adenosine receptor antagonist) and selective adenosine A 2A receptor antagonists can improve memory performance in rodents evaluated through different tasks. They might also afford protection against memory dysfunction elicited in experimental models of aging, Alzheimer's disease, Parkinson's disease and, in spontaneously hypertensive rats (SHR), a putative genetic model of attention deficit hyperactivity disorder (ADHD). 2. INTRODUCTION Adenosine, an established neuromodulator, plays an important role in the regulation of synaptic transmission and neuronal excitability in the central nervous system (CNS) (1). The relevance of adenosine receptors was initially recognized on the basis of the ability of caffeine, the most widely consumed psychoactive substance, to act as a dual antagonist at A 1 and A 2 receptors (2). Four adenosine receptor subtypes (A 1 , A 2A , A 2B and A 3 ) have been cloned and characterized from several mammalian species. They are all metabotropic G protein-coupled receptors (3) and were divided into two broad groups: A 1 and A 3 receptors usually couple to “inhibitory” G-proteins (Gi and Go); and A 2A and A 2B receptors couple to “stimulatory” G-proteins (Gs) (4). However, all adenosine receptors are fundamentally pleiotropic receptors, as they can potentially couple to different G proteins and to different transducing systems, according to their degree of activation and their particular cellular and subcellular localization (5).