We studied the influence of the cGMP pathway on cocaine self-administration by rats. When injected in the medial prefrontal cortex, three distinct activators of this pathway reduced the number of self-injections triggered by rats, suggesting a reduction of the reinforcing properties of cocaine and a lesser motivation of the animals for the drug. Immunohistochemical studies revealed that this behavioural effect was accompanied by a reduced expression of epigenetic markers (MeCP2, HDAC2), as well as inceased levels of histone acetylation. Complementary results indicate that the cGMP pathway is indeed able to regulate proteins implied in epigenetic mechanisms. The uncovering of an implication of these types of regulations leads us to suggest original hypotheses about the processes underlying the reduction of the reinforcing properties of cocaine.
