Adenosine and Kynurenic Acid Interactions: Possible Relevance for Schizophrenia Treatment?

Schizophrenia is a severe and chronic mental disorder, mainly characterized by the presence of the so-called “positive” (delusions, hallucinations, disorganized thinking) and “negative” (anhedonia, blunted affect, social withdrawal) symptoms, as well as cognitive dysfunctions. Although several interrelated causes have been associated with the development of the pathology, it is generally accepted that the hyperfunction of dopaminergic and/or hypofunction of glutamatergic transmission (i.e., the so-called “combined glutamate/dopamine hypothesis of schizophrenia”) might underlie the symptoms of schizophrenia (Howes et al., 2015; Snyder and Gao, 2020). Clinical indications demonstrate that positive symptoms respond well to conventional antipsychotic medications, which mainly act as dopamine D2 receptor (D2R) antagonists, while negative symptoms and cognitive impairments are more difficult to be counteracted. Several non-D2R related mechanisms of action of antipsychotic drugs have been proposed over the last decades, but none has conclusively been proven effective. Furthermore, while the newer antipsychotic drugs produce fewer motor side effects than conventional “first generation” drugs, safety and tolerability concerns about weight gain and endocrinopathies often limit their use (Li et al., 2016). Thus, there is an urgent necessity for more effective and better-tolerated antipsychotic drugs, as well as to identify new molecular targets and develop mechanistically novel compounds that can address the various symptom dimensions of schizophrenia. Due to the complexity of the pathology, it seems likely, however, that a multi-target strategy, i.e., the use of multifunctional drugs or a combination of drugs affecting distinct targets, will lead to more effective therapeutic approaches. Based on this background and recent findings, the present opinion paper was conceived to critically review possible interactions between adenosine and kynurenic acid (KYNA) in this context. These two neuromodulators may be pathophysiologically associated with schizophrenia, and a deeper understanding of their interactions may lead to the development of innovative strategies for the treatment of schizophrenia.