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Glial cell line-derived neurotrophic factor (GDNF) is a potent neurotrophic factor for midbrain dopamine (DA) neurons, while the DA neurons in the ventral tegmental area (VTA) is a crucial part of the neural circuits associated with drug addiction. Recently, more and more evidence suggests that GDNF plays an important role in negatively regulating the neuroadaptations induced by chronic exposure to drugs, which was thought to be the neurobiological basis of drug addiction, but the underlying mechanism is still unknown. More recently, the neural cell adhesion molecule (NCAM), which plays an important role in the process of neural plasticity, has been identified as an alternative signaling receptor for GDNF. The purpose of this study was to investigate whether NCAM was involved in the effects of GDNF on the neuroadaptations induced by chronic morphine exposure. Immunostaining results showed that NCAM was widely expressed in the VTA of rats, including all the DA neurons. The results also showed that the phosphorylation of NCAM-associated FAK, but not the total NCAM, was upregulated by GDNF, and this upregulation was inhibited by pre-treatment with the NCAM function-blocking antibody. Moreover, pre-treatment with the antibody could antagonize the effect of GDNF on inhibiting the neuroadaptations induced by chronic morphine exposure, including the decreases of the number and length of neurites and the size of cell bodies of VTA dopamine neurons, as well as the increase of tyrosine hydroxylase in the VTA dopamine neurons. These results suggest that NCAM signaling is involved in the negative regulatory effects of GDNF on chronic morphine-induced neuroadaptations.

Glial cell line-derived neurotrophic factor (GDNF) is a potent protective factor for dopaminergic (DA) neurons, but the signaling mechanisms underlying the effect of GDNF on these neurons remain obscure. Here, both our in vivo and in vitro studies demonstrate that the majority of DA neurons express the NF-κB-inducing kinase (NIK), which is the essential kinase for mediating activation of the new alternative NF-κB signaling pathway. Additionally, we also show that GDNF induced the time/dose-dependent phosphorylation of IκB kinase α (IKKα) and p100, facilitated the processing of p100 to p52 and accelerated the translocation of NF-κB dimmers into the nuclei of DA neurons. We furtherly found that the dimmer which translocate into the nucleus was RelA/p52 not RelB/p52. Meanwhile, the attenuation of 6-OHDA-induced DA neuronal apoptosis due to GDNF was reversed subsequent to the inhibition of p100 expression by RNAi while the neuroprotective effect of GDNF on injured DA neurons was strengthened by the overexpression of p100. Our data, therefore, indicate that a new alternative NF-κB signaling pathway, which was not the classic pathway but different from the non-canonical pathway, exists in DA neurons and mediates the neuroprotective effect of GDNF on these neurons., (Copyright © 2011 Elsevier B.V. All rights reserved.)