Neuroimaging studies using positron emission tomo graphy suggest that reduced dopamine (DA) D2 receptor (D2R)availability in the striatum is associated with increased vulnerabili ty to drug addiction in humans and experimental animals.Howev er, the role of D3 R in the neurobiology of addiction remains un clear.Here we report that D3R-knockout (D3-/-) mice display enhanced cocaine (and sucrose) taking observed during the ac quisition and maintenance of cocaine self-administration and en hanced motivation for cocaine (and sucrose) seeking observed during progressive-ratio cocaine self-administration and extinction from cocaine self-administration.This increased vulnerability to cocaine was accompanied by decreased DA response to cocaine secondary to increased basal levels of extracellular DA in the nu cleus accumbens, suggesting that enhanced cocaine-taking and co caine-seeking behavior could be a compensatory response to de creased cocaine reward in D3-/-mice.In addition, D3-/-mice also displayed up-regulation of DA transporter in the striatum,suggesting that a neureadaptative change occurred D3-/-mice to restore elevated basal levels of extracellular DA.These findings,for the first time, suggest that deletion of D3 R increases vulnera bility to cocaine-taking and cocaine-seeking behavior.Thus, re duced D3R availability in the brain constitutes an important risk factor for the development of cocaine addiction.