Stress, Brain Adenosine Signaling, and Fatigue-Related Behavioral Processes

Abstract

This chapter reviews the role of adenosine in stress-induced behaviors such as fatigue and behavioral depression, as characterized by the state of conservation-withdrawal. Evidence is provided that adenosine A2A receptors mediate these behaviors as seen in a variety of animal models of depression: learned helplessness, behavioral despair, reserpine-induced depression, sickness behavior, and cytokine-induced behavioral depression. A2A receptors are colocalized with dopamine D2 receptors on the indirect pathway of the striatum where they modulate the binding affinity of dopamine to the D2 receptor. The striatum is segregated into functionally distinct regions, ranging from control of sensorimotor behaviors in the dorsal striatum to the motivational aspects of ongoing behavior in the ventral striatum. Preliminary evidence suggests that adenosine A2A receptors in the core of the ventral striatum mediate behavioral depression in the learned helplessness paradigm. Activation of A2A receptors in this region blocks the dopaminergic signal from the ventral tegmental area, resulting in the uncoupling of motivation from ongoing behavior.