PMID- 30056122 OWN - NLM STAT- MEDLINE DCOM- 20190220 LR - 20190915 IS - 1873-7064 (Electronic) IS - 0028-3908 (Print) IS - 0028-3908 (Linking) VI - 140 DP - 2018 Sep 15 TI - Increasing Brain-Derived Neurotrophic Factor (BDNF) in medial prefrontal cortex selectively reduces excessive drinking in ethanol dependent mice. PG - 35-42 LID - S0028-3908(18)30429-5 [pii] LID - 10.1016/j.neuropharm.2018.07.031 [doi] AB - The neurotrophin Brain-Derived Neurotrophic Factor (BDNF) has been implicated in a number of neuropsychiatric disorders, including alcohol use disorder. Studies have shown that BDNF activity in cortical regions, such as the medial prefrontal cortex (mPFC) mediates various ethanol-related behaviors. We previously reported a significant down-regulation in Bdnf mRNA in mPFC following chronic ethanol exposure compared to control mice. The present study was conducted to extend these findings by examining whether chronic ethanol treatment reduces BDNF protein expression in mPFC and whether reversing this deficit via direct injection of BDNF or viral-mediated overexpression of BDNF in mPFC alters voluntary ethanol consumption in dependent and nondependent mice. Repeated cycles of chronic intermittent ethanol (CIE) exposure was employed to model ethanol dependence, which produces robust escalation of ethanol intake. Results indicated that CIE treatment significantly increased ethanol intake and this was accompanied by a significant decrease in BDNF protein in mPFC that lasted at least 72 h after CIE exposure. In a separate study, once dependence-related increased drinking was established, bilateral infusion of BDNF (0, 0.25, 0.50 mug) into mPFC significantly decreased ethanol intake in a dose-related manner in dependent mice but did not affect moderate drinking in nondependent mice. In a third study, viral-mediated overexpression of BDNF in mPFC prevented escalation of drinking in dependent mice but did not alter intake in nondependent mice. Collectively, these results provide evidence that adaptations in cortical (mPFC) BDNF activity resulting from chronic ethanol exposure play a role in mediating excessive ethanol drinking associated with dependence. CI - Published by Elsevier Ltd. FAU - Haun, Harold L AU - Haun HL AD - Charleston Alcohol Research Center, Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, SC, 29425, USA; Department of Neuroscience, Medical University of South Carolina, Charleston, SC, 29425, USA. FAU - Griffin, William C AU - Griffin WC AD - Charleston Alcohol Research Center, Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, SC, 29425, USA. FAU - Lopez, Marcelo F AU - Lopez MF AD - Charleston Alcohol Research Center, Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, SC, 29425, USA. FAU - Solomon, Matthew G AU - Solomon MG AD - Charleston Alcohol Research Center, Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, SC, 29425, USA; Department of Neuroscience, Medical University of South Carolina, Charleston, SC, 29425, USA. FAU - Mulholland, Patrick J AU - Mulholland PJ AD - Charleston Alcohol Research Center, Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, SC, 29425, USA; Department of Neuroscience, Medical University of South Carolina, Charleston, SC, 29425, USA. FAU - Woodward, John J AU - Woodward JJ AD - Charleston Alcohol Research Center, Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, SC, 29425, USA; Department of Neuroscience, Medical University of South Carolina, Charleston, SC, 29425, USA. FAU - McGinty, Jacqueline F AU - McGinty JF AD - Department of Neuroscience, Medical University of South Carolina, Charleston, SC, 29425, USA. FAU - Ron, Dorit AU - Ron D AD - Department of Neurology, University of California at San Francisco School of Medicine, San Francisco, CA, 94158, USA. FAU - Becker, Howard C AU - Becker HC AD - Charleston Alcohol Research Center, Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, SC, 29425, USA; Department of Neuroscience, Medical University of South Carolina, Charleston, SC, 29425, USA; RHJ Department of Veterans Affairs Medical Center, Charleston, SC, 20401, USA. Electronic address: beckerh@musc.edu. LA - eng GR - T32 AA007474/AA/NIAAA NIH HHS/United States GR - U24 AA020929/AA/NIAAA NIH HHS/United States GR - U01 AA014095/AA/NIAAA NIH HHS/United States GR - P50 AA010761/AA/NIAAA NIH HHS/United States GR - I01 BX000813/BX/BLRD VA/United States GR - R37 AA016848/AA/NIAAA NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, U.S. Gov't, Non-P.H.S. DEP - 20180726 PL - England TA - Neuropharmacology JT - Neuropharmacology JID - 0236217 RN - 0 (Brain-Derived Neurotrophic Factor) RN - 3K9958V90M (Ethanol) SB - IM MH - Alcohol Drinking/physiopathology/*prevention & control MH - Alcoholism/metabolism/*prevention & control MH - Animals MH - Brain-Derived Neurotrophic Factor/*biosynthesis/genetics/*metabolism MH - Dose-Response Relationship, Drug MH - Ethanol/administration & dosage/adverse effects MH - Genetic Vectors/administration & dosage MH - Male MH - Mice MH - Microinjections MH - Prefrontal Cortex/*metabolism PMC - PMC6113096 MID - NIHMS1501967 OTO - NOTNLM OT - BDNF OT - Ethanol dependence OT - Ethanol drinking OT - Medial prefrontal cortex OT - Mice EDAT- 2018/07/30 06:00 MHDA- 2019/03/21 06:00 PMCR- 2019/09/15 CRDT- 2018/07/30 06:00 PHST- 2018/05/21 00:00 [received] PHST- 2018/07/05 00:00 [revised] PHST- 2018/07/26 00:00 [accepted] PHST- 2018/07/30 06:00 [pubmed] PHST- 2019/03/21 06:00 [medline] PHST- 2018/07/30 06:00 [entrez] PHST- 2019/09/15 00:00 [pmc-release] AID - S0028-3908(18)30429-5 [pii] AID - 10.1016/j.neuropharm.2018.07.031 [doi] PST - ppublish SO - Neuropharmacology. 2018 Sep 15;140:35-42. doi: 10.1016/j.neuropharm.2018.07.031. Epub 2018 Jul 26.