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

Following early clinical leads, the adenosine A2AR receptor (A2AR) 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 A2AR's unique modulatory action over glutamatergic in addition to dopaminergic signaling. Through (i) the antagonistic interaction with the dopamine D2 receptor, and (ii) the regulation of glutamate release and N-methyl-d-aspartate receptor function, striatal A2AR is ideally positioned to fine-tune the dopamine-glutamate balance, the disturbance of which is implicated in the pathophysiology of schizophrenia. However, the precise function of striatal A2ARs in the regulation of schizophrenia-relevant behavior is poorly understood. Here, we tested the impact of conditional striatum-specific A2AR knockout (st-A2AR-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-A2AR-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 – namely, 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 A2ARs – a finding that may undermine the hypothesized importance of A2AR in the genesis and/or treatment of schizophrenia.

► Deficient adenosine A2A receptor function has been implicated in schizophrenia.
► Loss of striatal A2A receptor did not impair prepulse inhibition or latent inhibition.
► Striatal A2A receptors are not critical for schizophrenia attentional deficits.
► Active avoidance learning is however uniquely sensitive to loss of striatal A2A receptor.