Regulation of Fear Responses by Striatal and Extrastriatal Adenosine A2A Receptors in Forebrain
Biological Psychiatry. 2014-06-01; 75(11): 855-863
DOI: 10.1016/j.biopsych.2013.05.003
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Wei CJ(1), Augusto E(2), Gomes CA(3), Singer P(4), Wang Y(1), Boison D(5), Cunha
RA(6), Yee BK(4), Chen JF(7).
Author information:
(1)Molecular Neuropharmacology Laboratory, Department of Neurology, and
Department of Pharmacology and Experimental Therapeutics, Boston University
School of Medicine, Boston, Massachusetts.
(2)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.
(3)Center for Neuroscience and Cell Biology, CNC-University of Coimbra, Coimbra,
Portugal.
(4)R.S. Dow Neurobiology Laboratories, Legacy Research Institute, Portland,
Oregon; Laboratory of Behavioural Neurobiology, Swiss Federal Institute of
Technology Zurich, Schwerzenbach, Switzerland.
(5)R.S. Dow Neurobiology Laboratories, Legacy Research Institute, Portland,
Oregon.
(6)Center for Neuroscience and Cell Biology, CNC-University of Coimbra, Coimbra,
Portugal; Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
(7)Molecular Neuropharmacology Laboratory, Department of Neurology, and
Department of Pharmacology and Experimental Therapeutics, Boston University
School of Medicine, Boston, Massachusetts. Electronic address: .
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.
Copyright © 2014. Published by Elsevier Inc.
DOI: 10.1016/j.biopsych.2013.05.003
PMCID: PMC4058554
PMID: 23820821 [Indexed for MEDLINE]
Conflict of interest statement: DISCLOSURES/CONFLICT OF INTEREST The authors
declare no conflict of interest.