Genetic deletion of A2A adenosine receptors in the striatum selectively impairs habit formation.

A(2A) receptors are a major class of G-protein-coupled receptors for adenosine. Highly expressed in the striatum, on the projection neurons giving rise to the striatopallidal or "indirect" pathway, they have been implicated in sleep, addiction, and other processes, yet their role in the control of striatal circuits and behavior remains unclear. Using established assays from the instrumental learning paradigm, we showed that mice with striatum-specific deletion of A(2A) receptors were selectively impaired in habit formation. After training that generated habitual lever pressing in wild-type controls, the performance of striatum-specific A(2A) knock-out mice remained goal directed, being highly sensitive to outcome devaluation and reversal of the action-outcome contingency. These data demonstrate a critical role for A(2A) receptors on striatopallidal medium spiny projection neurons in shaping behavior and decision making, providing the first instance of a selective alteration in instrumental learning after striatum-specific genetic manipulations.