Adenosinergic perspectives on schizophrenia: Opportunity for an integrative synthesis

All rights are reserved. Adenosine is a homeostatic modulator capable of influencing brain-wide network functioning through receptor-dependent interactions, and receptor-independent biochemical, bioenergetic and epigenetic mechanisms. In the brain, it directly modulates and interferes with dopaminergic and glutamatergic neuronal activities, the dysfunctions of which have been consistently implicated in the pathophysiology of schizophrenia. In addition, adenosinergic mechanisms may also be relevant to the aetiology of schizophrenia due to its importance in early brain development and its interaction with the brain immune response. This chapter aims to integrate these different perspectives on the neurobiology of schizophrenia in relation to the unique functional properties of adenosine within the central nervous system. The rationale of an adenosinergic hypothesis of schizophrenia is outlined with evidence supporting the suggestion that adenosinergic dysfunction might contribute to the emergence of multiple behavioural and cognitive dysfunctions characteristic of schizophrenia. Possible novel therapeutic strategies are explored, especially against negative and cognitive schizophrenia symptoms where current pharmacotherapy remains highly unsatisfactory. Multiple pharmacological targets within the adenosine system are identified, including the high-affinity adenosine receptors (A₁ receptor and A_2A receptor) and the major regulatory enzyme of adenosine metabolism in the brain, adenosine kinase. Preliminary clinical data are encouraging in highlighting the therapeutic potential of these new targets, but preclinical data have also yielded a more complex picture underlining the necessity to consider brain region and receptor subtype specificity in order to maximize benefits and minimize possible side-effects of any adenosine-based approach to treat schizophrenia.