TY - JOUR
T1 - Alcohol consumption alters Gdnf promoter methylation and expression in rats
AU - Maier, Hannah Benedictine
AU - Neyazi, Meraj
AU - Neyazi, Alexandra
AU - Hillemacher, Thomas
AU - Pathak, Hansi
AU - Rhein, Mathias
AU - Bleich, Stefan
AU - Goltseker, Koral
AU - Sadot-Sogrin, Yossi
AU - Even-Chen, Oren
AU - Frieling, Helge
AU - Barak, Segev
N1 - Publisher Copyright:
© 2019 Elsevier Ltd
PY - 2020/2
Y1 - 2020/2
N2 - Alcohol use disorder is one of the most disabling diseases worldwide. Glial-cell derived neurotrophic factor (Gdnf) shows promising results concerning the inhibition of alcohol consumption in rodent models. We investigated the epigenetic regulation of Gdnf following ethanol consumption and withdrawal in a rat model. 32 Wistar rats underwent 7 weeks of intermittent access to alcohol in a 2-bottle choice (IA2BC). Whole blood, Nucleus Accumbens (NAc) and Ventral Tegmental Area (VTA) were collected immediately after the last 24 h of an alcohol-drinking session (alcohol group, AG) or 24 h after withdrawal (withdrawal group, WG). MRNA levels were measured using real-time quantitative PCR. Bisulfite-conversion of DNA and capillary sequencing was used to determine methylation levels of the core promoter (CP) and the negative regulatory element (NRE). The CP of the AG in the NAc was significantly less methylated compared to controls (p < 0.05). In the NAc, mRNA expression was significantly higher in the WG (p < 0.05). In the WG, mRNA expression levels in the VTA were significantly lower (p < 0.05) and showed significantly less methylation in the NRE in the VTA (p < 0.001) and the NAc (p < 0.01) compared to controls. Changes in the cerebral mRNA expression correspond to alterations in DNA methylation of the Gdnf promoter in a rodent model. Our results hold clinical relevance since differences in Gdnf mRNA expression and DNA methylation could be a target for pharmacological interventions.
AB - Alcohol use disorder is one of the most disabling diseases worldwide. Glial-cell derived neurotrophic factor (Gdnf) shows promising results concerning the inhibition of alcohol consumption in rodent models. We investigated the epigenetic regulation of Gdnf following ethanol consumption and withdrawal in a rat model. 32 Wistar rats underwent 7 weeks of intermittent access to alcohol in a 2-bottle choice (IA2BC). Whole blood, Nucleus Accumbens (NAc) and Ventral Tegmental Area (VTA) were collected immediately after the last 24 h of an alcohol-drinking session (alcohol group, AG) or 24 h after withdrawal (withdrawal group, WG). MRNA levels were measured using real-time quantitative PCR. Bisulfite-conversion of DNA and capillary sequencing was used to determine methylation levels of the core promoter (CP) and the negative regulatory element (NRE). The CP of the AG in the NAc was significantly less methylated compared to controls (p < 0.05). In the NAc, mRNA expression was significantly higher in the WG (p < 0.05). In the WG, mRNA expression levels in the VTA were significantly lower (p < 0.05) and showed significantly less methylation in the NRE in the VTA (p < 0.001) and the NAc (p < 0.01) compared to controls. Changes in the cerebral mRNA expression correspond to alterations in DNA methylation of the Gdnf promoter in a rodent model. Our results hold clinical relevance since differences in Gdnf mRNA expression and DNA methylation could be a target for pharmacological interventions.
KW - Alcohol addiction
KW - Epigenetics
KW - Glial cell line-derived neurotrophic factor (Gdnf)
KW - Neurotrophic factors
KW - Nucleus accumbens
KW - Ventral tegmental area
UR - http://www.scopus.com/inward/record.url?scp=85074456299&partnerID=8YFLogxK
U2 - 10.1016/j.jpsychires.2019.10.020
DO - 10.1016/j.jpsychires.2019.10.020
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C2 - 31710958
AN - SCOPUS:85074456299
SN - 0022-3956
VL - 121
SP - 1
EP - 9
JO - Journal of Psychiatric Research
JF - Journal of Psychiatric Research
ER -
