Striatopallidal adenosine A_2A receptor modulation of goal-directed behavior: Homeostatic control with cognitive flexibility

Dysfunction of goal-directed behaviors under stressful or pathological conditions results in impaired decision-making and loss of flexibility of thoughts and behaviors, which underlie behavioral deficits ranging from depression, obsessive-compulsive disorders and drug addiction. Tackling the neuromodulators fine-tuning this core behavioral element may facilitate the development of effective strategies to control these deficits present in multiple psychiatric disorders. The current investigation of goal-directed behaviors has concentrated on dopamine and glutamate signaling in the corticostriatal pathway. In accordance with the beneficial effects of caffeine intake on mood and cognitive dysfunction, we now propose that caffeine's main site of action - adenosine A_2A receptors (A_2AR) - represent a novel target to homeostatically control goal-directed behavior and cognitive flexibility. A_2AR are abundantly expressed in striatopallidal neurons and colocalize and interact with dopamine D2, NMDA and metabotropic glutamate 5 receptors to integrate dopamine and glutamate signaling. Specifically, striatopallidal A_2AR (i) exert an overall “break” control of a variety of cognitive processes, making A_2AR antagonists a novel strategy for improving goal-directed behavior; (ii) confer homeostatic control of goal-directed behavior by acting at multiple sites with often opposite effects, to enhance cognitive flexibility; (iii) integrate dopamine and adenosine signaling through multimeric A_2AR-D₂R heterocomplexes allowing a temporally precise fine-tuning in response to local signaling changes. As the U.S. Food and Drug Administration recently approved the A_2AR antagonist Nourianz® (istradefylline) to treat Parkinson's disease, striatal A_2AR-mediated control of goal-directed behavior may offer a new and real opportunity for improving deficits of goal-directed behavior and enhance cognitive flexibility under various neuropsychiatric conditions.