Genetic blockade of adenosine A2A receptors induces cognitive impairments and anatomical changes related to psychotic symptoms in mice

Abstract Schizophrenia is a chronic severe mental disorder with a presumed neurodevelopmental origin, and no effective treatment. Schizophrenia is a multifactorial disease with genetic, environmental and neurochemical etiology. The main theories on the pathophysiology of this disorder include altera...

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Bibliographic Details
Published in:European neuropsychopharmacology 2016-07, Vol.26 (7), p.1227-1240
Main Authors: Moscoso-Castro, Maria, Gracia-Rubio, Irene, Ciruela, Francisco, Valverde, Olga
Format: Article
Language:English
Subjects:
Adenosine A2A
BDNF
Cognition
Internal Medicine
Psychiatry
Psychotic behavior
Schizophrenia
Ventricles enlargement
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Summary:Abstract Schizophrenia is a chronic severe mental disorder with a presumed neurodevelopmental origin, and no effective treatment. Schizophrenia is a multifactorial disease with genetic, environmental and neurochemical etiology. The main theories on the pathophysiology of this disorder include alterations in dopaminergic and glutamatergic neurotransmission in limbic and cortical areas of the brain. Early hypotheses also suggested that nucleoside adenosine is a putative affected neurotransmitter system, and clinical evidence suggests that adenosine adjuvants improve treatment outcomes, especially in poorly responsive patients. Hence, it is important to elucidate the role of the neuromodulator adenosine in the pathophysiology of schizophrenia. A2A adenosine receptor (A2A R) subtypes are expressed in brain areas controlling motivational responses and cognition, including striatum, and in lower levels in hippocampus and cerebral cortex. The aim of this study was to characterize A2A R knockout (KO) mice with complete and specific inactivation of A2A R, as an animal model for schizophrenia. We performed behavioral, anatomical and neurochemical studies to assess psychotic-like symptoms in adult male and female KO and wild-type (WT) littermates. Our results show impairments in inhibitory responses and sensory gating in A2A R KO animals. Hyperlocomotion induced by d -amphetamine and MK-801 was reduced in KO animals when compared to WT littermates. Moreover, A2A R KO animals show motor disturbances, social and cognitive alterations. Finally, behavioral impairments were associated with enlargement of brain lateral ventricles and decreased BDNF levels in the hippocampus. These data highlight the role of adenosine in the pathophysiology of schizophrenia and provide new possibilities for the therapeutic management of schizophrenia.
ISSN:0924-977X
1873-7862
DOI:10.1016/j.euroneuro.2016.04.003