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.
Key Words
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Article info
Publication history
Published online: July 01, 2013
Accepted:
May 2,
2013
Received in revised form:
April 15,
2013
Received:
March 26,
2012
Footnotes
Authors BKY and J-FC contributed equally to this work.
Identification
Copyright
© 2014 Published by Elsevier Inc.
