title: Deletion of striatal adenosine A(2A) receptor spares latent inhibition and prepulse inhibition but impairs active avoidance learning.
abstract: 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 (i) the antagonistic interaction with the dopamine D(2) receptor, and (ii) the regulation of glutamate release and N-methyl-d-aspartate receptor function, striatal A(2A)R 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 A(2A)Rs in 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 - 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 A(2A)Rs - a finding that may undermine the hypothesized importance of A(2A)R in the genesis and/or treatment of schizophrenia.
authors.affiliation: Laboratory of Behavioral Neurobiology, ETH Zurich, Schorenstrasse 16, 8603 Schwerzenbach, Switzerland. psinger@downeurobiology.org
authors.forename: Philipp
authors.initials: P
authors.lastname: Singer
authors.forename: Catherine J
authors.initials: CJ
authors.lastname: Wei
authors.forename: Jiang-Fan
authors.initials: JF
authors.lastname: Chen
authors.forename: Detlev
authors.initials: D
authors.lastname: Boison
authors.forename: Benjamin K
authors.initials: BK
authors.lastname: Yee
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001362:Avoidance Learning / Q000502:physiology*; D003213:Conditioning, Psychological / Q000502:physiology; D003342:Corpus Striatum / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000235:genetics; D007266:Inhibition, Psychological; D007859:Learning Disabilities / Q000235:genetics* / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000235:genetics; D011571:Psychoacoustics; D043705:Receptor, Adenosine A2A / Q000172:deficiency*; D012022:Reflex, Acoustic / Q000235:genetics; D055139:Sensory Gating / Q000235:genetics*; D013649:Taste / Q000235:genetics
chemical_list: C501120:Dlx5 protein, mouse; D018398:Homeodomain Proteins; D043705:Receptor, Adenosine A2A