GDNF is an Endogenous Negative Regulator of Ethanol‐Mediated Reward and of Ethanol Consumption After a Period of Abstinence

Abstract

Background We previously found that activation of the glial cell line-derived neurotrophic factor (GDNF) pathway in the ventral tegmental area (VTA) reduces ethanol-drinking behaviors. In this study, we set out to assess the contribution of endogenous GDNF or its receptor GFRα1 to the regulation of ethanol-related behaviors. Methods GDNF and GFRα1 heterozygote mice (HET) and their wild-type littermate controls (WT) were used for the studies. Ethanol-induced hyperlocomotion, sensitization, and conditioned place preference (CPP), as well as ethanol consumption before and after a period of abstinence were evaluated. Blood ethanol concentration (BEC) was also measured. Results We observed no differences between the GDNF HET and WT mice in the level of locomotor activity or in sensitization to ethanol-induced hyperlocomotion after systemic injection of a nonhypnotic dose of ethanol and in BEC. However, GDNF and GFRα1 mice exhibited increased place preference to ethanol as compared with their WT littermates. The levels of voluntary ethanol or quinine consumption were similar in the GDNF HET and WT mice, however, a small but significant increase in saccharin intake was observed in the GDNF HET mice. No changes were detected in voluntary ethanol, saccharin or quinine consumption of GFRα1 HET mice as compared with their WT littermates. Interestingly, however, both the GDNF and GFRα1 HET mice consumed much larger quantities of ethanol after a period of abstinence from ethanol as compared with their WT littermates. Furthermore, the increase in ethanol consumption after abstinence was found to be specific for ethanol as similar levels of saccharin intake were measured in the GDNF and GFRα1 HET and WT mice after abstinence. Conclusions Our results suggest that endogenous GDNF negatively regulates the rewarding effect of ethanol and ethanol-drinking behaviors after a period of abstinence.

From Signaling Pathways to Behavior

“…Moreover, because of the growth factor's ability to induce its own mRNA expression He & Ron, 2006), the reduction of alcohol drinking persists for up to 48 hours following a single intra-VTA infusion of the growth factor Carnicella et al, 2008;. Interestingly, we found that the GDNF heterozygote knockout (HET) mice consumed more alcohol than their WT littermates after a period of abstinence and exhibit increased CPP for alcohol (Carnicella, Ahmadiantehrani, Janak, & Ron, 2009), suggesting an important role for the endogenous growth factor in the regulation of alcohol intake. To this end, we recently demonstrated that both the mRNA and protein levels of GDNF are increased in the VTA of rats after the first week of the 20% 2BC alcohol-drinking procedure (Ahmadiantehrani, Barak, & Ron, 2013).…”

Selective chemical genetic inhibition of protein kinase C epsilon reduces ethanol consumption in mice

“…Blood samples were stored at −80°C, until BECs were determined using an NAD-ADH enzymatic assay (Carnicella et al, 2009). …”

Opportunities for the Development of Neuroimmune Therapies in Addiction

“…Glial cell line-derived neurotrophic factor (GDNF) is a protein that is essential for the maintenance and survival of dopamine (DA) neurons (Boger et al, 2006) and can inhibit microglial activation (Rocha, Cristovão, Campos, Fonseca, & Baltazar, 2012). Additionally, preclinical evidence suggests that infusion of GDNF into the ventral tegmental area (VTA) blocks the acquisition and expression of alcohol-induced conditioned place preference (Barak, Ahmadiantehrani, Kharazia, & Ron, 2011;Barak, Carnicella, Yowell, & Ron, 2011), rapidly reduces alcohol intake (Carnicella, Ahmadiantehrani, Janak, & Ron, 2009, Carnicella, Amamoto, & Ron, 2009Carnicella, Kharazia, Jeanblanc, Janak, & Ron, 2008), and blocks alcohol reinstatement following extinction (Carnicella et al, 2008). Furthermore, endogenous levels of GDNF have been found to negatively regulate the rewarding effect of alcohol after a period of abstinence (Carnicella, Ahmadiantehrani, et al, 2009;Carnicella, Amamoto, et al, 2009).…”

“…Additionally, preclinical evidence suggests that infusion of GDNF into the ventral tegmental area (VTA) blocks the acquisition and expression of alcohol-induced conditioned place preference (Barak, Ahmadiantehrani, Kharazia, & Ron, 2011;Barak, Carnicella, Yowell, & Ron, 2011), rapidly reduces alcohol intake (Carnicella, Ahmadiantehrani, Janak, & Ron, 2009, Carnicella, Amamoto, & Ron, 2009Carnicella, Kharazia, Jeanblanc, Janak, & Ron, 2008), and blocks alcohol reinstatement following extinction (Carnicella et al, 2008). Furthermore, endogenous levels of GDNF have been found to negatively regulate the rewarding effect of alcohol after a period of abstinence (Carnicella, Ahmadiantehrani, et al, 2009;Carnicella, Amamoto, et al, 2009). In one human study, GDNF serum levels measured peripherally were found to be significantly reduced in alcohol-dependent patients versus healthy controls and to be negatively associated with measures of tolerance and withdrawal (Heberlein et al, 2010).…”