Ketamine is clinically used as an anesthetic, a fast-acting antidepressant, and recreationally used for its dissociative properties. Addictive drugs, such as cocaine, increase dopamine (DA) levels in the nucleus accumbens (NAc). This facilitates synaptic plasticity in the mesolimbic system, which causes behavioral adaptations, eventually driving the transition to compulsion1-4. The addiction liability of ketamine is a matter of much debate, also because of its complex pharmacology that among several targets includes N-methyl-d-aspartic acid (NMDA) receptor (NMDAR) antagonism5,6. Here we show that ketamine fails to induce synaptic plasticity typically observed with addictive drugs in mice despite inducing robust DA transients in the NAc. Ketamine nevertheless supported reinforcement via disinhibition of DA neurons in the ventral tegmental area (VTA). This effect was mediated by NMDAR antagonism in VTA γ-aminobutyric acid (GABA) neurons but quickly terminated by type 2 DA receptors (D2R) on DA neurons. The rapid off-kinetics of the DA transients along with the NMDARs antagonism precluded the induction of synaptic plasticity in the VTA and NAc, and failed to elicit locomotor sensitization and uncontrolled self-administration. In summary, ketamine’s dual-action leads to a unique constellation for DA-driven positive reinforcement yet low addiction liability.