Adenosine and Brain Function

This chapter describes the role of adenosine in brain function. Adenosine is an endogenous neuromodulator that influences many functions in the central nervous system (CNS). The levels of adenosine increase when there is an imbalance between the rates of energy use and the rates of energy delivery. Increased neuronal activity, and hypoxia or ischemia results in elevated levels of adenosine. Adenosine receptors (ARs) were based on the ability of methylxanthines, such as theophylline and caffeine to act as antagonists. The two receptors, A1 and A2, inhibit and stimulate adenylyl cyclase respectively. The functions of ARs include: (1) regulation of nerve activity, (2) regulation of transmitter release, (3) interaction with other transmitter systems, and (4) various other functions. Increased extracellular adenosine in response to ischemia and hypoxia acts as a neuro-protectant during cerebral ischemia and other neuronal insults. ARs (A1Rs and A2ARs) are expressed at moderate to high levels in the brain areas enriched with dopaminergic innervation, thus providing an anatomical basis for interaction between these neurotransmitter systems. Different features of the phenotypes provide clues to the roles of defects in AR genes in human disease. The chapter discusses the roles of adenosine A2A receptors in neurodegenerative disorders and ARs in psychiatric disorders. Caffeine is used to improve wakefulness and the main actions of caffeine are mediated by brain ARs. Adenosine might be an endogenous regulator of sleep–wake cycles, as adenosine analogs induced a sleep-like state. In addition, ARs may play many roles in pathways that contribute to pain. Clearly much additional work is needed to pinpoint the sites and mechanisms of action, as well as the roles in chronic pain states.