Cocaine is a psychostimulant and a drug widely abused by humans. Cocaine elicits its effects primarily by blocking the activity of the dopamine (DA) transporter, leading to elevated levels of extracellular DA in areas receiving dopaminergic innervation, with the consequent activation of DA receptors. Cocaine, however, also elevates other neurotransmitter levels, leading to a general activation of interconnected brain circuitries. Studies aimed at unraveling the molecular mechanisms underlying the effects of cocaine have shown a leading role of DA D1 receptors in the cascade of cellular events elicited by this drug. In this study, we have analyzed the acute response to cocaine in animals deleted for the expression of DA D2 receptors (D2R), an inhibitor of DA signaling. Importantly, we show that although D1 receptor-mediated functions are preserved and even enhanced in D2R−/− mutants, the behavioral response to acute cocaine administration is severely altered. In addition, c-fos response to acute cocaine administration, in contrast to wild-type mice, is absent in D2R−/− mutants. Our findings show that the absence of D2R, very likely through a presynaptic mechanism, uncovers an inhibitory signaling pathway normally masked by the activity of this receptor on brain circuitries engaged by abused drugs.