Except as a marker of cancer progression, gamma-synuclein (GSyn) had received little attention. Recent data showed however that GSyn modulates cocaine-induced locomotor effects, suggesting that it could also play a role in cocaine reinforcing effects. In the rat, siRNAs targeting GSyn expression were injected in the nucleus accumbens and cocaine reinforcing effects were evaluated by means of intravenous self-administration. A dose-response curve was followed by procedures of progressive ratio, extinction, cocaine- and cue-induced reinstatements. Decrease of GSyn expression increased self-administration over a large range of doses. This effect was associated with an increase in cocaine-induced reinstatement. The present data reveal that GSyn exert a specific negative control on cocaine-induced reinforcing and incentive effects.