Juvenile exposure to methylphenidate reduces cocaine reward and alters netrin-1 receptor expression in adulthood

The guidance cue netrin-1 acting on mesocorticolimbic dopamine (DA) neurons through its receptor DCC (deleted in colorectal cancer) has been implicated in the neuronal plasticity induced by psychostimulant drugs. We examined in C57/BL6 mice the effects of repeated juvenile methylphenidate (MPH) exposure on cocaine-reward sensitivity in adulthood and determined whether early MPH treatment alters adult expression of DCC in mesocorticolimbic DA regions. By using place conditioning, we show that adult mice exposed to MPH during the juvenile period are less sensitive to cocaine-reward compared to saline-controls. Furthermore, by means of immunoblotting, we demonstrate that early MPH treatment attenuates adult DCC expression in the ventral tegmental area (VTA) selectively. These results support previous evidence that developmental MPH treatment diminishes cocaine-reward in adulthood and are the first to suggest that DCC in the VTA may participate in this enduring effect.

► Modulation of brain reward circuitry by early exposure to methylphenidate (MPH).
► MPH treatment early in life reduces cocaine reward in adult C57BL mice.
► DCC, a receptor for the guidance cue netrin-1, is expressed by dopamine neurons.
► Reduced DCC function protects against drug-induced plasticity.
► Early MPH exposure reduces adult DCC expression in the ventral tegmental area.