The purine nucleoside adenosine has the critical autacoid function of directly linking cellular excitability to energy availability. The mechanism is activated whenever the rate of adenosine triphosphate (ATP) utilization exceeds the rate of synthesis. In CNS neurons, adenosine is produced by the rapid intracellular hydrolysis of purine nucleotides during neural excitation and then is extruded into extracellular space. The nucleoside is also produced by the extracellular hydrolysis of ATP by ectonucleotidases. Extracellular adenosine interacts with G-protein linked stereospecific receptors to reestablish metabolic homeostasis by exerting extraordinarily potent inhibition of neural excitation via a number of mechanisms. This autacoid mechanism is directly linked to the production of a depression-like behavioral state termed conservation-withdrawal during times of physical stress or severe emotional distress. We review evidence here that adenosine produces a transition to conservation-withdrawal by activation of A2A receptors in the ventral-medial striatum.