PMID- 29890020 OWN - NLM STAT- MEDLINE DCOM- 20200803 LR - 20210731 IS - 1369-1600 (Electronic) IS - 1355-6215 (Print) IS - 1355-6215 (Linking) VI - 24 IP - 5 DP - 2019 Sep TI - Accumbens brain-derived neurotrophic factor (BDNF) transmission inhibits cocaine seeking. PG - 860-873 LID - 10.1111/adb.12638 [doi] AB - Brain-derived neurotrophic factor (BDNF) regulates a variety of physiological processes, and several studies have explored the role of BDNF in addiction-related brain regions like the nucleus accumbens core (NAcore). We sought to understand the rapid effects of endogenous BDNF on cocaine seeking. Rats were trained to self-administer cocaine and extinguished. We then microinjected two inhibitors of BDNF stimulation of tropomyosin receptor kinase B (TrkB), the non-competitive receptor antagonist ANA-12 and TrkB/Fc, a fusion protein that binds BDNF and prevents TrkB stimulation. Blocking TrkB or inactivating BDNF in NAcore potentiated active lever pressing, showing that endogenous BDNF tone was present and supplying inhibitory tone on cue-induced reinstatement. To determine if exogenous BDNF also negatively regulated reinstatement, BDNF was microinjected into NAcore 15 minutes before cue-induced reinstatement. BDNF decreased cocaine seeking through TrkB receptor binding, but had no effect on inactive lever pressing, spontaneous or cocaine-induced locomotion, or on reinstated sucrose seeking. BDNF-infusion potentiated within trial extinction when microinjected in the NAcore during cue- and context + cue induced reinstatement, and the inhibition of lever pressing lasted at least 3 days post injection. Although decreased reinstatement endured for 3 days when BDNF was administered prior to a reinstatement session, when microinjected before an extinction session or in the home cage, BDNF did not alter subsequent cued-reinstatement. Together, these data show that endogenous BDNF acts on TrKB to provide inhibitory tone on reinstated cocaine seeking, and this effect was recapitulated by exogenous BDNF. CI - (c) 2018 Society for the Study of Addiction. FAU - Bobadilla, Ana-Clara AU - Bobadilla AC AUID- ORCID: 0000-0002-4273-1237 AD - Department of Neuroscience, Medical University of South Carolina, Charleston, SC, USA. FAU - Garcia-Keller, Constanza AU - Garcia-Keller C AD - Department of Neuroscience, Medical University of South Carolina, Charleston, SC, USA. FAU - Chareunsouk, Victoria AU - Chareunsouk V AD - Department of Neuroscience, Medical University of South Carolina, Charleston, SC, USA. FAU - Hyde, Jeffrey AU - Hyde J AD - Department of Neuroscience, Medical University of South Carolina, Charleston, SC, USA. AD - Western Washington University, Department of Psychology and Program in Behavioral Neuroscience, Bellingham, WA, USA. FAU - Medina Camacho, Daniela AU - Medina Camacho D AD - Department of Neuroscience, Medical University of South Carolina, Charleston, SC, USA. FAU - Heinsbroek, Jasper A AU - Heinsbroek JA AD - Department of Neuroscience, Medical University of South Carolina, Charleston, SC, USA. FAU - Kalivas, Peter W AU - Kalivas PW AD - Department of Neuroscience, Medical University of South Carolina, Charleston, SC, USA. LA - eng GR - P50 DA015369/DA/NIDA NIH HHS/United States GR - DA015369/National Institute of Health NIH/International GR - R01 DA003906/DA/NIDA NIH HHS/United States GR - R37 DA003906/DA/NIDA NIH HHS/United States GR - R01 DA012513/DA/NIDA NIH HHS/United States GR - DA12513/National Institute of Health NIH/International GR - DA003906/National Institute of Health NIH/International GR - DA003906; DA12513; DA015369/National Institute of Health NIH/International GR - French Fyssen Foundation/International PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20180611 PL - United States TA - Addict Biol JT - Addiction biology JID - 9604935 RN - 0 (ANA 12 compound) RN - 0 (Azepines) RN - 0 (Bdnf protein, rat) RN - 0 (Benzamides) RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Dopamine Uptake Inhibitors) RN - 0 (Sweetening Agents) RN - 57-50-1 (Sucrose) RN - EC 2.7.10.1 (Ntrk2 protein, rat) RN - EC 2.7.10.1 (Receptor, trkB) RN - I5Y540LHVR (Cocaine) SB - IM MH - Analysis of Variance MH - Animals MH - Azepines/pharmacology MH - Benzamides/pharmacology MH - Brain-Derived Neurotrophic Factor/antagonists & inhibitors/pharmacology/*physiology MH - Cocaine/pharmacology MH - Cocaine-Related Disorders/*physiopathology MH - Conditioning, Psychological/drug effects MH - Cues MH - Dopamine Uptake Inhibitors/pharmacology MH - Drug-Seeking Behavior/*physiology MH - Male MH - Motor Activity/drug effects MH - Nucleus Accumbens/drug effects MH - Rats, Sprague-Dawley MH - Receptor, trkB/antagonists & inhibitors/pharmacology MH - Reinforcement Schedule MH - Self Administration MH - Sucrose/pharmacology MH - Sweetening Agents/pharmacology PMC - PMC8320750 MID - NIHMS1711647 OTO - NOTNLM OT - BDNF OT - cocaine seeking OT - nucleus accumbens OT - rats OT - self-administration OT - sucrose-seeking COIS- Disclosure The authors declare no conflict of interest. EDAT- 2018/06/12 06:00 MHDA- 2020/08/04 06:00 PMCR- 2021/07/29 CRDT- 2018/06/12 06:00 PHST- 2018/01/31 00:00 [received] PHST- 2018/04/27 00:00 [revised] PHST- 2018/05/01 00:00 [accepted] PHST- 2018/06/12 06:00 [pubmed] PHST- 2020/08/04 06:00 [medline] PHST- 2018/06/12 06:00 [entrez] PHST- 2021/07/29 00:00 [pmc-release] AID - 10.1111/adb.12638 [doi] PST - ppublish SO - Addict Biol. 2019 Sep;24(5):860-873. doi: 10.1111/adb.12638. Epub 2018 Jun 11.