Role for GDNF in biochemical and behavioral adaptations to drugs of abuse

The present study examined a role for GDNF in adaptations to drugs of abuse . Infusion of GDNF into the ventral tegmental area (VTA), a dopaminergic br ain region important for addiction, blocks certain biochemical adaptations to chronic cocaine or morphine as well as the rewarding effects of cocaine. Conversely, responses to cocaine are enhanced in rats by intra-VTA infusio n of an anti-GDNF antibody and in mice heterozygous for a null mutation in the GDNF gene. Chronic morphine or cocaine exposure decreases levels of pho sphoRet, the protein kinase that mediates GDNF signaling, in the VTA. Toget her, these results suggest a feedback loop, whereby drugs of abuse decrease signaling through endogenous GDNF pathways in the VTA, which then increase s the behavioral sensitivity to subsequent drug exposure.