Regulation of Fear Responses by Striatal and Extrastriatal Adenosine A2A Receptors in Forebrain

Background: Adenosine A(2A) receptors (A(2A)Rs) 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 A(2A)R knockout lines with A(2A)Rs selectively deleted either in the striatum (st-A(2A)R KO) or the entire forebrain (striatum, hippocampus, and cortex [fb-A(2A)R KO]) on fear and anxiety-related responses. We also examined the effect of hippocampus-specific A(2A)R deletion by local injection of adeno-associated virus type 5 (AAV5)-Cre into floxed-A(2A)R knockout mice. Results: Selectively deleting A(2A)Rs in the striatum increased Pavlovian fear conditioning (both context and tone) in st-A(2A)R KO mice, but extending the deletion to the rest of the forebrain apparently spared context fear conditioning and attenuated tone fear conditioning in fb-A(2A)R KO mice. Moreover, focal deletion of hippocampal A(2A)Rs by AAV5-Cre injection selectively attenuated context (but not tone) fear conditioning. Deletion of A2ARs in the entire forebrain in fb-A(2A)R 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 A(2A)R behavioral effects were associated with reduced BDNF levels in the fb-A(2A)R KO hippocampus. Conclusions: This study provides evidence that inactivation of striatal A(2A)Rs facilitates Pavlovian fear conditioning, while inactivation of extrastriatal A(2A)Rs in the forebrain inhibits fear conditioning and also affects anxiety-related behavior.