An increasing number of studies indicate that leptin can regulate the activity of the mesolimbic dopamine system. The objective of this study was to examine the regulation of the activity of dopamine neurons by leptin. This was accomplished by examining the dopamine D2 receptor-mediated synaptic current that resulted from somatodendritic release of dopamine in brain slices taken from mice that lacked leptin (Lep(ob/ob) mice). Under control conditions, the amplitude and kinetics of the IPSC in wild-type and Lep(ob/ob) mice were not different. However, in the presence of forskolin or cocaine, the facilitation of the dopamine IPSC was significantly reduced in Lep(ob/ob) mice. The application of L-3,4-dihydroxyphenylalanine (L-DOPA) increased the IPSC in Lep(ob/ob) mice significantly more than in wild-type animals and fully restored the responses to both forskolin and cocaine. Treatment of Lep(ob/ob) mice with leptin in vivo fully restored the cocaine-induced increase in the IPSC to wild-type levels. These results suggest that there is a decrease in the content of somatodendritic vesicular dopamine in the Lep(ob/ob) mice. The release of dopamine from terminals may be less affected in the Lep(ob/ob) mice, because the cocaine-induced rise in dopamine in the ventral striatum was not statistically different between wild-type and Lep(ob/ob) mice. In addition, the relative increase in cocaine-induced locomotion was similar for wild-type and Lep(ob/ob) mice. These results indicate that, although basal release is not altered, the amount of dopamine that can be released is reduced in Lep(ob/ob) mice.