Positive autoregulation of GDNF levels in the ventral tegmental area mediates long-lasting inhibition of excessive alcohol consumption

S Barak,D Ron,V Kharazia,S Ahmadiantehrani

doi:10.1038/tp.2011.57

Abstract

Glial cell line-derived neurotrophic factor (GDNF) is an essential growth factor for the survival and maintenance of the midbrain dopaminergic (DA-ergic) neurons. Activation of the GDNF pathway in the ventral tegmental area (VTA), where the GDNF receptors are expressed, produces a long-lasting suppression of excessive alcohol consumption in rats. Previous studies conducted in the DA-ergic-like cells, SHSY5Y, revealed that GDNF positively regulates its own expression, leading to a long-lasting activation of the GDNF signaling pathway. Here we determined whether GDNF activates a positive autoregulatory feedback loop in vivo within the VTA, and if so, whether this mechanism underlies the long-lasting suppressive effects of the growth factor on excessive alcohol consumption. We found that a single infusion of recombinant GDNF (rGDNF; 10 μg) into the VTA induces a long-lasting local increase in GDNF mRNA and protein levels, which depends upon de novo transcription and translation of the polypeptide. Importantly, we report that the GDNF-mediated positive autoregulatory feedback loop accounts for the long-lasting inhibitory actions of GDNF in the VTA on excessive alcohol consumption. Specifically, the long-lasting suppressive effects of a single rGDNF infusion into the VTA on excessive alcohol consumption were prevented when protein synthesis was inhibited, as well as when the upregulation of GDNF expression was prevented using short hairpin RNA to focally knock down GDNF mRNA in the VTA. Our results could have implications for the development of long-lasting treatments for disorders in which GDNF has a beneficial role, including drug addiction, chronic stress and Parkinson's disease.

Highlights

Glial cell line-derived neurotrophic factor (GDNF) is a secreted growth factor that was initially identified in a glialderived cell line[1] GDNF is expressed throughout the central nervous system during development, and high levels of GDNF mRNA are present in the adult neurons in brain regions such as the striatum, thalamus, cortex and hippocampus.[2]
Remarkably higher levels of phosphorylated and thus activated ERK1/2 (pERK1/2) were detected in the recombinant GDNF (rGDNF)-infused side, predominantly in DA-ergic neurons, as compared with the vehicle-infused side. These results suggest that a single infusion of rGDNF into the ventral tegmental area (VTA) leads to an increase in the level of GDNF and to a long-lasting activation of the GDNF-mediated extracellular-regulated protein kinase 1/2 (ERK1/2) activation in the VTA
We further show that the long-lasting elevation in GDNF levels depends upon de novo translation of this growth factor

Summary

Introduction

Glial cell line-derived neurotrophic factor (GDNF) is a secreted growth factor that was initially identified in a glialderived cell line[1] GDNF is expressed throughout the central nervous system during development, and high levels of GDNF mRNA are present in the adult neurons in brain regions such as the striatum, thalamus, cortex and hippocampus.[2]. GDNF is an important factor for the survival, regeneration and maintenance of DA-ergic midbrain neurons,[1,2] and an increase in the GDNF levels has been suggested to be beneficial for Parkinson’s disease[2,12] and chronic stress.[13]. Activation of the GDNF pathway in the VTA has recently been suggested to negatively regulate the intake of drugs of abuse, including alcohol.[14,15] for alcohol, activation of the GDNF signaling pathway in the VTA results in a fast (minutes), and a very sustained (at least 48 h), reduction in excessive, ‘binge-like,’ alcohol consumption in rats.[16,17] The rapid actions of GDNF are mediated by the rapid stimulation of VTA DA-ergic neurons and the reversal of alcohol-induced DA deficiency in the nucleus accumbens (NAc).[7,18] the long-lasting suppressive actions of GDNF on alcohol consumption are not likely to be mediated by the recombinant growth factor, which degrades within several hours.

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Results

Conclusion