The roles of purinergic signaling in psychiatric disorders

Abstract

Ecto-purines and ecto-pyrimidines are present in the extracellular space of the central nervous system (CNS). Together with P1 and P2 receptors and nucleotides metabolizing ecto-enzymes, they make signaling system involved in neurotransmission, the modulation of sensory signals, including pain stimuli conduction, and the induction of apoptosis and necrosis of the cells. Purines and pyrimidines have a dual effect: positive (neuroprotective) of nucleosides, and negative (pro-inflammatory and pro-apoptotic) of nucleotides. Adenosine-5'-triphosphate (ATP) in the CNS triggers the pro-inflammatory reactions, predominantly by activation of the P2X7 receptor, which results in production and release of pro-inflammatory cytokines. In contrast to ATP, adenosine acts generally as an anti-inflammatory agent and plays an important role in neuroprotection. Currently, it is believed that the initiation of CNS diseases, including mental disorders, is caused by any imbalance between the concentration of ATP and adenosine in the extracellular space. Genetic tests provide also the evidence for the participation of purinergic signaling in psychiatric disorders. It is believed that any action leading to the effective increase of adenosine concentration: activation of nucleotide metabolizing ecto-enzymes (mainly NTPDases - nucleoside triphosphate diphosphohydrolases), inhibition of adenosine deaminase and/or adenosine kinase activity as well as therapies using P1 receptor agonists (adenosine or its analogues) might be beneficial in therapy of psychiatric disorders.