Adenosine augmentation ameliorates psychotic and cognitive endophenotypes of schizophrenia
Hai-Ying Shen, … , Benjamin K. Yee, Detlev Boison
Hai-Ying Shen, … , Benjamin K. Yee, Detlev Boison
Published June 18, 2012
Citation Information: J Clin Invest. 2012;122(7):2567-2577. https://doi.org/10.1172/JCI62378.
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Research Article Neuroscience

Adenosine augmentation ameliorates psychotic and cognitive endophenotypes of schizophrenia

Abstract

An emerging theory of schizophrenia postulates that hypofunction of adenosine signaling may contribute to its pathophysiology. This study was designed to test the “adenosine hypothesis” of schizophrenia and to evaluate focal adenosine-based strategies for therapy. We found that augmentation of adenosine by pharmacologic inhibition of adenosine kinase (ADK), the key enzyme of adenosine clearance, exerted antipsychotic-like activity in mice. Further, overexpression of ADK in transgenic mice was associated with attentional impairments linked to schizophrenia. We observed that the striatal adenosine A2A receptor links adenosine tone and psychomotor response to amphetamine, an indicator of dopaminergic signaling. Finally, intrastriatal implants of engineered adenosine-releasing cells restored the locomotor response to amphetamine in mice overexpressing ADK, whereas the same grafts placed proximal to the hippocampus of transgenic mice reversed their working memory deficit. This functional double dissociation between striatal and hippocampal adenosine demonstrated in Adk transgenic mice highlights the independent contributions of these two interconnected brain regions in the pathophysiology of schizophrenia and thus provides the rationale for developing local adenosine augmentation therapies for the treatment of schizophrenia.

Authors

Hai-Ying Shen, Philipp Singer, Nikki Lytle, Catherine J. Wei, Jing-Quan Lan, Rebecca L. Williams-Karnesky, Jiang-Fan Chen, Benjamin K. Yee, Detlev Boison

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Figure 3

A2AR mechanistically links ADK expression with psychomotor activity.

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A2AR mechanistically links ADK expression with psychomotor activity. (...
(A and C–F) Psychomotor response to amphetamine (Amph; 2.5 mg/kg, i.p.), in combination with selective AR agonists, was assessed in the open field and indexed as distance traveled. (A) Amphetamine-induced hyperlocomotion, as seen in WT mice following saline (Sal) treatment, is abrogated in Adk-tg mice (n = 10–12 per genotype, F = 45.545, P < 0.01). (B) Membrane binding assay showed no significant change in binding densities of A2AR (3H-ZM241385) and A1R (3H-DPCPX) on whole-membrane preparations from striatum or cortex, comparing expression levels of untreated naive Adk-tg and WT mice (n = 7–15/genotype/region, F values = 0.330–1.432, P > 0.05). (C) A1R agonist pretreatment (CCPA, 0.25 mg/kg, i.p.) attenuated amphetamine-induced psychomotor activity in both WT and Adk-tg mice (n = 8–9/genotype/treatment, F = 48.212, P < 0.01). (E) A2AR agonist pretreatment (CGS-21680 [CGS], 0.5 mg/kg, i.p.) attenuated amphetamine-induced psychomotor activity in WT mice (n = 8 per group, P < 0.01); conversely, it potentiated the amphetamine effect in Adk-tg mice (n = 8–9, F = 13.358, P < 0.01). (D and F) CCPA injection alone did not affect motor activity in both genotypes (n = 7–8 per, P > 0.05), while CGS-21680 alone slightly but significantly attenuated basal locomotion (n = 8–12 per genotype, P < 0.05); this effect was comparable in Adk-tg and WT mice. Data are mean ± SEM. ##P < 0.01, versus WT with same treatment; *P < 0.05, **P < 0.01 versus vehicle (Veh) pretreatment within the corresponding genotypes, based on 2-way ANOVA. Arrows indicate injection time points.