PMID- 23820821 OWN - NLM STAT- MEDLINE DCOM- 20141216 LR - 20220317 IS - 1873-2402 (Electronic) IS - 0006-3223 (Print) IS - 0006-3223 (Linking) VI - 75 IP - 11 DP - 2014 Jun 1 TI - Regulation of fear responses by striatal and extrastriatal adenosine A2A receptors in forebrain. PG - 855-63 LID - S0006-3223(13)00411-3 [pii] LID - 10.1016/j.biopsych.2013.05.003 [doi] AB - BACKGROUND: Adenosine A2A receptors (A2ARs) are enriched in the striatum but are also present at lower levels in the extrastriatal forebrain (i.e., hippocampus, cortex), integrating dopamine, glutamate, and brain-derived neurotrophic factor (BDNF) signaling, and are thus essential for striatal neuroplasticity and fear and anxiety behavior. METHODS: We tested two brain region-specific A2AR knockout lines with A2ARs selectively deleted either in the striatum (st-A2AR KO) or the entire forebrain (striatum, hippocampus, and cortex [fb-A2AR KO]) on fear and anxiety-related responses. We also examined the effect of hippocampus-specific A2AR deletion by local injection of adeno-associated virus type 5 (AAV5)-Cre into floxed-A2AR knockout mice. RESULTS: Selectively deleting A2ARs in the striatum increased Pavlovian fear conditioning (both context and tone) in st-A2AR KO mice, but extending the deletion to the rest of the forebrain apparently spared context fear conditioning and attenuated tone fear conditioning in fb-A2AR KO mice. Moreover, focal deletion of hippocampal A2ARs by AAV5-Cre injection selectively attenuated context (but not tone) fear conditioning. Deletion of A2ARs in the entire forebrain in fb-A2AR KO mice also produced an anxiolytic phenotype in both the elevated plus maze and open field tests, and increased the startle response. These extrastriatal forebrain A2AR behavioral effects were associated with reduced BDNF levels in the fb-A2AR KO hippocampus. CONCLUSIONS: This study provides evidence that inactivation of striatal A2ARs facilitates Pavlovian fear conditioning, while inactivation of extrastriatal A2ARs in the forebrain inhibits fear conditioning and also affects anxiety-related behavior. CI - Copyright (c) 2014. Published by Elsevier Inc. FAU - Wei, Catherine J AU - Wei CJ AD - Molecular Neuropharmacology Laboratory, Department of Neurology, and Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, Massachusetts. FAU - Augusto, Elisabete AU - Augusto E AD - Molecular Neuropharmacology Laboratory, Department of Neurology, and Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, Massachusetts; Center for Neuroscience and Cell Biology, CNC-University of Coimbra, Coimbra, Portugal; Faculty of Medicine, University of Coimbra, Coimbra, Portugal. FAU - Gomes, Catarina A AU - Gomes CA AD - Center for Neuroscience and Cell Biology, CNC-University of Coimbra, Coimbra, Portugal. FAU - Singer, Philipp AU - Singer P AD - R.S. Dow Neurobiology Laboratories, Legacy Research Institute, Portland, Oregon; Laboratory of Behavioural Neurobiology, Swiss Federal Institute of Technology Zurich, Schwerzenbach, Switzerland. FAU - Wang, Yumei AU - Wang Y AD - Molecular Neuropharmacology Laboratory, Department of Neurology, and Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, Massachusetts. FAU - Boison, Detlev AU - Boison D AD - R.S. Dow Neurobiology Laboratories, Legacy Research Institute, Portland, Oregon. FAU - Cunha, Rodrigo A AU - Cunha RA AD - Center for Neuroscience and Cell Biology, CNC-University of Coimbra, Coimbra, Portugal; Faculty of Medicine, University of Coimbra, Coimbra, Portugal. FAU - Yee, Benjamin K AU - Yee BK AD - R.S. Dow Neurobiology Laboratories, Legacy Research Institute, Portland, Oregon; Laboratory of Behavioural Neurobiology, Swiss Federal Institute of Technology Zurich, Schwerzenbach, Switzerland. FAU - Chen, Jiang-Fan AU - Chen JF AD - Molecular Neuropharmacology Laboratory, Department of Neurology, and Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, Massachusetts. Electronic address: chenjf@bu.edu. LA - eng GR - R01 NS048995/NS/NINDS NIH HHS/United States GR - R01 MH083973/MH/NIMH NIH HHS/United States GR - R01NS48995/NS/NINDS NIH HHS/United States GR - R01NS073947/NS/NINDS NIH HHS/United States GR - R01DA19362/DA/NIDA NIH HHS/United States GR - R01 DA019362/DA/NIDA NIH HHS/United States GR - R01NS41083-10/NS/NINDS NIH HHS/United States GR - R01 NS041083/NS/NINDS NIH HHS/United States GR - R01MH083973/MH/NIMH NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, Non-P.H.S. DEP - 20130629 PL - United States TA - Biol Psychiatry JT - Biological psychiatry JID - 0213264 RN - 0 (Receptor, Adenosine A2A) SB - IM MH - Animals MH - Anxiety/metabolism MH - Conditioning, Classical MH - Corpus Striatum/*metabolism MH - Fear/*physiology MH - Hippocampus/metabolism MH - Mice MH - Mice, Inbred C57BL MH - Mice, Knockout MH - Prosencephalon/*metabolism MH - Receptor, Adenosine A2A/genetics/*metabolism MH - Reflex, Startle PMC - PMC4058554 MID - NIHMS570223 OTO - NOTNLM OT - Adenosine A(2A) receptor OT - BDNF OT - anxiety OT - cortex OT - fear conditioning OT - hippocampus OT - startle response OT - striatum COIS- DISCLOSURES/CONFLICT OF INTEREST The authors declare no conflict of interest. EDAT- 2013/07/04 06:00 MHDA- 2014/12/17 06:00 PMCR- 2014/12/01 CRDT- 2013/07/04 06:00 PHST- 2012/03/26 00:00 [received] PHST- 2013/04/15 00:00 [revised] PHST- 2013/05/02 00:00 [accepted] PHST- 2013/07/04 06:00 [entrez] PHST- 2013/07/04 06:00 [pubmed] PHST- 2014/12/17 06:00 [medline] PHST- 2014/12/01 00:00 [pmc-release] AID - S0006-3223(13)00411-3 [pii] AID - 10.1016/j.biopsych.2013.05.003 [doi] PST - ppublish SO - Biol Psychiatry. 2014 Jun 1;75(11):855-63. doi: 10.1016/j.biopsych.2013.05.003. Epub 2013 Jun 29.