title: The role of purinergic signaling in depressive disorders.
abstract: The purinergic signaling system consists of transporters, enzymes and receptors responsible for the synthesis, release, action and extracellular inactivation of adenosine 5'-triphosphate (ATP) and its extracellular breakdown product adenosine. The actions of ATP are mediated ionotropic P2X and metabotropic P2Y receptor subfamilies, whilst the actions of adenosine are mediated by P1 adenosine receptors. Purinergic signaling pathways are widely expressed in the central nervous system (CNS) and participate in its normal and pathological functions. Among P2X receptors, the P2X7 receptor (P2rx7) has received considerable interest in both basic and clinical neuropsychiatric research because of its profound effects in animal CNS pathology and its potential involvement as a susceptibility gene in mood disorders. Although genetic findings were not always consistently replicated, several studies demonstrated that single nucleotide polymorphisms (SNPs) in the human P2X7 gene (P2RX7) show significant association with major depressive disorder and bipolar disorder. Animal studies revealed that the genetic knock-down or pharmacological antagonism leads to reduced depressive-like behavior, attenuated response in mania-model and alterations in stress reactivity. A potential mechanism of P2rx7 activation on mood related behavior is increased glutamate release, activation of extrasynaptic NMDA receptors and subsequent enduring changes in neuroplasticity. In addition, dysregulation of monoaminergic transmission and HPA axis reactivity could also contribute to the observed changes in behavior. Besides P2rx7, the inhibition of adenosine A1 and A2A receptors also mediate antidepressant-like effects in animal experiments. In conclusion, despite contradictions between existing data, these findings point to the therapeutic potential of the purinergic signaling system in mood disorders.
authors.affiliation: Laboratory of Molecular Pharmacology, Institute of Experimental Medicine, Hungarian Academy of Sciences IEM HAS, H-1083 Budapest, Hungary. sperlagh@koki.hu
authors.forename: Beata
authors.initials: B
authors.lastname: Sperlagh
authors.forename: Cecilia
authors.initials: C
authors.lastname: Csolle
authors.forename: Romeo D
authors.initials: RD
authors.lastname: Ando
authors.forename: Flora
authors.initials: F
authors.lastname: Goloncser
authors.forename: Agnes
authors.initials: A
authors.lastname: Kittel
authors.forename: Maria
authors.initials: M
authors.lastname: Baranyi
mesh_terms: D058916:Adenosine A1 Receptor Antagonists / Q000627:therapeutic use; D058917:Adenosine A2 Receptor Antagonists / Q000627:therapeutic use; D000818:Animals; D001714:Bipolar Disorder / Q000378:metabolism; D003866:Depressive Disorder / Q000188:drug therapy / Q000378:metabolism*; D003865:Major Depressive Disorder / Q000378:metabolism; D006801:Humans; D019964:Mood Disorders / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D043682:Receptor, Adenosine A1 / Q000378:metabolism; D043705:Receptor, Adenosine A2A / Q000378:metabolism; D011983:Receptors, Purinergic / Q000378:metabolism; D058486:Receptors, Purinergic P2X7 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D058916:Adenosine A1 Receptor Antagonists; D058917:Adenosine A2 Receptor Antagonists; D043682:Receptor, Adenosine A1; D043705:Receptor, Adenosine A2A; D011983:Receptors, Purinergic; D058486:Receptors, Purinergic P2X7