Instrumental conditioning allows animals to learn about the consequences of their own actions, but the underpinning molecular mechanisms remain elusive. Here we show that the sphingosine-1-phosphate (S1P) receptor Gpr6 is selectively expressed in the striatopallidal neurons in the striatum. Gpr6-deficient mice showed reduced striatal cyclic AMP production in vitro and selective alterations in instrumental conditioning in vivo. Thus, Gpr6 is the first striatopallidal neuron-specific genetic regulator of instrumental conditioning in a mammal.