Deletion of striatal adenosine A2A receptor spares latent inhibition and prepulse inhibition but impairs active avoidance learning

Laboratory of Behavioral Neurobiology, ETH Zurich, Schorenstrasse 16, 8603 Schwerzenbach, Switzerland
Behavioural brain research (Impact Factor: 3.03). 12/2012; 242(1). DOI: 10.1016/j.bbr.2012.12.024
Source: PubMed


Following early clinical leads, the adenosine A(2A)R receptor (A(2A)R) has continued to attract attention as a potential novel target for treating schizophrenia; especially against the negative and cognitive symptoms of the disease because of A(2A)R's unique modulatory action over glutamatergic in addition to dopaminergic signaling. Through the antagonistic interaction with the dopamine D(2) receptor, and by regulating glutamate release and N-methyl-d-aspartate receptor function, striatal A(2A)R is ideally positioned to fine-tune the dopamine-glutamate balance whose disturbance is implicated in the pathophysiology of schizophrenia. However, the precise function of striatal A(2A)Rsin the regulation of schizophrenia-relevant behavior is poorly understood. Here, we tested the impact of conditional striatum-specific A(2A)R knockout (st-A(2A)R-KO) on latent inhibition (LI) and prepulse inhibition (PPI)-behavior that is tightly regulated by striatal dopamine and glutamate. These are two common cross-species translational tests for the assessment of selective attention and sensorimotor gating deficits reported in schizophrenia patients; and enhanced performance in these tests is associated with antipsychotic drug action. We found that neither LI nor PPI was significantly affected in st-A(2A)R-KO mice; although a deficit in active avoidance learning was identified in these animals. The latter phenotype, however, was not replicated in another form of aversive conditioning-conditioned taste aversion. Hence, the present study shows that neither learned inattention (as measured by LI) nor sensory gating (as indexed by PPI) requires the integrity of striatal A(2A)Rs-a finding that may undermine the hypothesized importance of A(2A)R in the genesis and/or treatment of schizophrenia.

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Available from: Benjamin K Yee
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    • "D2R antagonism, including in the CeA specifically, has been demonstrated to decrease two-way avoid-escape and increase fear (Perez de la Mora et al., 2010; Reis et al., 2004). The D2R interacts antagonistically with the adenosine receptor A2AR by forming heteromers (Boison et al., 2012); because expression of both Drd2 and Adora2a was decreased by CSD it is difficult to predict the functional consequences; nonetheless it is noteworthy that striatum-specific Adora2a knockout mice exhibited decreased activity and two-way avoid-escape (Singer et al., 2013), as observed in CSD mice. Both Adora2a and Gpr88 exhibit enriched expression in the central extended AMYG and dorsal striatum (Becker et al., 2008); accordingly, the decreased expression observed in CSD mice might have occurred primarily in CeA indicating that future studies should analyse CSD effects on gene expression here and in striatal regions. "
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