Associate editor: A.L. Morrow
GDNF — A potential target to treat addiction

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Abstract

The glial cell line-derived neurotrophic factor (GDNF) is a secreted protein, best known for its role in the development of the central and peripheral nervous systems and the survival of adult dopaminergic neurons. More recently, accumulating evidence suggests that GDNF plays a unique role in negatively regulating the actions of drugs of abuse. In this article, we review these data and highlight the possibility that the GDNF pathway may be a promising target for the treatment of addiction.

Introduction

GDNF is a distant member of the transforming growth factor β superfamily that was originally isolated from the rat B49 glial cell line (Lin et al., 1993). GDNF is expressed throughout the central nervous system during development (Schaar et al., 1993, Stromberg et al., 1993, Choi-Lundberg and Bohn, 1995, Nosrat et al., 1996), and is also expressed in the adult brain, albeit in more restricted areas. High levels of the growth factor are found in the striatum (dorsal striatum and nucleus accumbens), thalamus, cortex and hippocampus (Springer et al., 1994, Choi-Lundberg and Bohn, 1995, Nosrat et al., 1996, Pochon et al., 1997, Trupp et al., 1997, Golden et al., 1998, Golden et al., 1999, Barroso-Chinea et al., 2005). Although GDNF is expressed in astrocytes, in the adult brain GDNF is mainly expressed and detected in neurons (Pochon et al., 1997, Barroso-Chinea et al., 2005). As described below, a major site of action of GDNF is the midbrain in which the growth factor is expressed at low levels under basal conditions (Golden et al., 1998, Semba et al., 2004, He et al., 2005). The major source of GDNF to the midbrain is the striatum where GDNF is retrogradely transported by dopaminergic neurons of the substantia nigra pars compacta (SNc) and the ventral tegmental area (VTA) (Tomac et al., 1995b, Lapchak et al., 1997, Kordower et al., 2000, Ai et al., 2003, Barroso-Chinea et al., 2005).

Section snippets

GDNF-mediated signaling

The main pathway by which GDNF transduces its signal is via the activation of the Rearranged during transfection receptor (Ret) (Jing et al., 1996, Treanor et al., 1996, Trupp et al., 1996, Eketjall et al., 1999). Ret is the product of the c-ret proto-oncogene and is a receptor tyrosine kinase (Tsui-Pierchala et al., 2002a). Activation of the GDNF pathway is initiated via the ligation of GDNF to its co-receptor, GDNF family receptor α1 (GFRα1), which is a glycosylphosphatidylinositol

GDNF's functions

GDNF promotes survival of mesencephalic dopamine neurons in culture (Lin et al., 1993) and plays an essential role in the development and survival of motor neurons, the development of sympathetic and sensory neurons, and kidneys (Moore et al., 1996, Pichel et al., 1996, Sanchez et al., 1996), as well as in hippocampal synaptogenesis (Ledda et al., 2007). GDNF was also shown to promote survival and re-growth of dopaminergic neurons in the adult brain following injury (Beck et al., 1995, Tomac et

GDNF and addiction

As described above, GFRα1 and Ret are highly expressed in VTA dopaminergic neurons. Dopaminergic neurons within the VTA are a critical component of the neural circuitry implicated in addictive behaviors. All drugs of abuse increase the level of extracellular dopamine in the NAc of rodents (Di Chiara & Imperato, 1988) and humans (Volkow et al., 2007), and alteration of the dopaminergic transmission modulates self-administration of drug of abuse and relapse (Koob et al., 1998, Hyman et al., 2006

GDNF as a possible target to treat addiction

Taken together, the data described above support a selective role for GDNF in the regulation of drugs of abuse-related behaviors and suggest that upregulation of the GDNF pathway may be a valuable strategy to combat several forms of addiction. However, it is unlikely that GDNF itself could be used as a therapeutic agent. GDNF is a 24 kDa protein that cannot readily cross the blood-brain barrier (Kastin et al., 2003, Kilic et al., 2003), and its delivery to the brain requires intracerebral or

Summary

The present reviewed data suggest that GDNF negatively regulates the actions of drugs of abuse, as reducing endogenous GDNF levels or inhibition of the GDNF pathway increases several biochemical and behavioral adaptations to psychostimulants, opioids and ethanol, whereas GDNF administration in the mesolimbic system results in opposite effects. The mechanisms of action of GDNF to counter these adaptations associated with addiction are currently unknown. The rapid MAPK-mediated effect of GDNF on

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    This work was supported by NIH-NIAAA R01 AA014366-02 (D.R.) and the State of California for Medical Research on Alcohol and Substance Abuse through the University of California, San Francisco (D.R.).

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