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The Roles of Purinergic Signaling in Psychiatric Disorders Marek Cieślak1, Joanna Czarnecka2* and Katarzyna Roszek2

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The Roles of Purinergic Signaling in Psychiatric Disorders Marek Cieślak1, Joanna Czarnecka2* and Katarzyna Roszek2 Vol. 63, No 1/2016 1–9 http://dx.doi.org/10.18388/abp.2015_1004 Review The roles of purinergic signaling in psychiatric disorders Marek Cieślak1, Joanna Czarnecka2* and Katarzyna Roszek2 1Neurology Clinic, Marek Cieślak, Toruń, Poland; 2Department of Biochemistry, Faculty of Biology and Environment Protection, Nicolaus Copernicus University in Torun, Poland Ecto-purines and ecto-pyrimidines are present in the where they act as signaling molecules in many physio- extracellular space of the central nervous system (CNS). logical and pathological processes. Ecto-nucleotides are Together with P1 and P2 receptors and nucleotides me- involved in neurotransmission, the propagation of in- tabolizing ecto-enzymes, they make signaling system flammatory processes, modulation of sensory signals, in- involved in neurotransmission, the modulation of sen- cluding the conduction of pain stimuli and neuroprotec- sory signals, including pain stimuli conduction, and the tion (Burnstock, 2008; Burnstock et al., 2011). In 1978, induction of apoptosis and necrosis of the cells. Purines the purinoreceptors were divided into P1 metabotropic and pyrimidines have a dual effect: positive (neuropro- receptors activated exclusively by adenosine (Burnstock, tective) of nucleosides, and negative (pro-inflammatory 1978) and P2 receptors activated by adenine nucleotides and pro-apoptotic) of nucleotides. Adenosine-5’-triphos- — ATP, ADP and pyrimidine ones — UTP, UDP. P2 phate (ATP) in the CNS triggers the pro-inflammatory receptors are divided into ionotropic P2X and metabo- reactions, predominantly by activation of the P2X7 re- tropic P2Y receptors, what was corfirmed by cloning ceptor, which results in production and release of pro-in- (Burnstock & Kennedy C, 1985; Ralevic & Burnstock, flammatory cytokines. In contrast to ATP, adenosine acts 1998) (Fig. 1). generally as an anti-inflammatory agent and plays an im- ATP and ADP are released to the extracellular space portant role in neuroprotection. Currently, it is believed mainly through exocytosis, also connexin and pannexin that the initiation of CNS diseases, including mental dis- channels, or cell lysis (Lazarowski, 2012). The concen- orders, is caused by any imbalance between the concen- tration of ecto-nucleotides, and thus nucleotide signaling, tration of ATP and adenosine in the extracellular space. is controlled by ecto-nucleotidases and nucleotide kinas- Genetic tests provide also the evidence for the participa- es. ATP and ADP are hydrolysed by nucleoside triphos- tion of purinergic signaling in psychiatric disorders. It is phate diphosphohydrolases (NTPDases) and ecto-5’-nu- believed that any action leading to the effective increase cleotidase to adenosine — another potent signaling mol- of adenosine concentration: activation of nucleotide me- ecule — Fig. 1. Adenosine is released to the extracellular tabolizing ecto-enzymes (mainly NTPDases — nucleoside space directly from the neurons and astrocytes by nu- triphosphate diphosphohydrolases), inhibition of adeno- cleoside transporters, but its largest amount is produced sine deaminase and/or adenosine kinase activity as well through the ecto-nucleotidases-mediated degradation of as therapies using P1 receptor agonists (adenosine or its ATP (Aliagas et al., 2013). Adenosine outside the cell is analogues) might be beneficial in therapy of psychiatric phosphorylated to AMP by adenosine kinase or deami- disorders. nated to inosine by adenosine deaminase (Wardas, 2008) – Fig. 1. Key words: Ecto-purines, P receptors, central nervous system diseas- The presence of purinergic receptors as well as ec- es, mental disorders, therapy of psychiatric disorders to-enzymes activity were identified in different brain ar- Received: 08 March, 2015; revised: 14 June, 2015; accepted: eas, such as cortex, hippocampus, basal ganglia, mesen- 02 October, 2015; available on-line: 23 October, 2015 cephalon, thalamus, cerebellum, and many others — Ta- ble 1. Studies have shown the presence of purinorecep- tors (P2X2, P2X7 and P2Y2) in the ventricular system PURINERGIC SIGNALING IN THE CENTRAL NERVOUS of the brain — on the cells of choroid plexus of the SYSTEM lateral ventricles and at the surface of neurons contact- ing with CSF (cerebrospinal fluid-contacting neurons, Modern tendencies in scientific research aim at find- CFCN) (Stoeckel et al., 2003; Czarnecka et al., 2011). ing the specific biochemical markers for the pathophysi- Neurons and astrocytes express all subtypes of P recep- ological conditions and diseases. It is commonly believed tors, while microglial cells contain P2X4, P2X7, P2Y6 that finding such a marker may precede the diagnosis of and P2Y12 receptors (Di Virgilio, 2007; Di Virgilio et al., the disease in the future or be of great importance in 2009) and adenosine receptors, excluding subtype A2B differential diagnosis, also in the case of psychiatric dis- (Cieślak et al., 2011). orders. The experimental results indicate that elements ATP and adenosine through P2 and P1 receptors ac- of the purinergic signaling system: purines, purinorecep- tivation, act antagonistically and therefore regulate the tors and purines metabolizing ecto-enzymes are involved CNS functions. Under physiological conditions pro- in psychophysiological processes in health and disease cesses initiated by ATP-mediated P2 receptor activation conditions. Therefore, there are indications that puriner- gic compounds could potentially be markers of psycho- *e-mail: [email protected] pathological processes. Abbreviations: ATP, adenosine-5’-triphosphate; CNS, central nerv- Ecto-purines and ecto-pyrimidines are present in the ous system extracellular space of the central nervous system (CNS), 2 M. Cieślak and others 2016 Figure 1. Metabolism and receptors of extracellular adenosine derivatives. Extracellular ATP (agonist of P2 receptors) may be metabolised by hydrolases: ecto-NTPDases (E-NTPDases), ecto-NPPases (E-NPPases) and ecto-5’nucleotidase (E-5’NU) and by adenylate kinase to ADP (agonist of P2). Adenosine (agonist of P1 receptors) is phosphorylated by adenosine kinase to AMP or degraded by adenosine deaminase (E-ADA) and other enzymes to final product: uric acid. (for example glutamate secretion or inflammatory pro- cell types throughout the CNS. Studies have shown the cesses propagation (Cotrina et al., 2000)) are inhibited by presence of NTPDase activity (mainly NTPDase1), on adenosine formed due to its degradation and activating nerve endings membranes and on the surface of mi- adenosine P1 receptors (Frau et al., 2011). However, the croglia cells (Robson et al., 2006; Sperlagh& Illes, 2007). problem of this antagonism is more complex. Adenosine Expression of ecto-5’-nucleotidase was shown on astro- may in turn stimulate the release of glutamate from as- cytes, oligodendrocytes and microglia (Sperlagh& Illes, trocytes via A2A receptors (Nishizaki, 2004). For synap- 2007; Cieslak et al., 2011). tic transmission, activation of A1 receptors (ADORA1) It was also shown that enzymes activity is different in exerts an inhibitory effect, whereas adenosine via 2A distinct areas of the brain: the neuronal cell membranes receptor subtype (ADORA2A), coupled to a stimula- of the cerebral cortex and hippocampus present the high tory G protein, enhances excitatory neurotransmitter re- activity of NTPDase1 and NTPDase2, while the activity lease. Moreover, the genetic variation of the ADORA2A of these enzymes in the cerebellum and spinal cord (me- gene results in changing the balance of the nucleotide/ dulla oblongata) is minor (Kukulski et al., 2004). nucleoside signaling system (Shinohara 2013). Haplotype It is assumed that purinergic signaling may be import- A causes high expression of the ADORA2A mRNA ant in some psychophysiological and psychopatophysi- and ADORA2A protein, as well as high production of ological states, such as fear and anxiety, and behaviors cAMP in response to adenosine, in an additive manner such as: memory and learning, sleep and wakefulness, (diplotype AA>AB>BB). Thus, the adenosine activation movement, food intake, mood and anxiety, agression and of inhibitory ADORA1 will not compensate the stimula- motivation (Krügel et al., 2001; Burnstock, 2008). Also in tory effect of ADORA2A activation and the equilibrium the case of psychophysiological processes it is important is shifted towards the stimulatory action (Saitoch, 2014). to maintain a balance between the ATP-mediated exci- Generally, there must be a balance between the process- tation and adenosine-mediated excitation or quenching. es of the nervous system stimulation and quenching, and The results of recent studies on the purinergic signal- any disturbance leads to different disturbances disorders ing have already been used in the treatment of certain and diseases of the nervous system. neurological diseases (e.g. Parkinson’s disease and isch- Co-localization of different types of purinergic recep- emic stroke), and may be used in the therapy of multiple tors with ecto-nucleotidases activity on the cell mem- sclerosis, epilepsy and migraine headache (Cieślak et al., branes in the adjacent areas of CNS enables the precise 2008; Burnstock, 2008; Cieślak et al., 2015). The authors regulation of nucleotide/nucleoside concentration, signal- speculate that purinergic signaling may also participate in ing and intercellular cross-talking. the pathophysiology of certain mental disorders. Distribution of ecto-nucleotidases in the brain is well recognized in rats, less is known about the localization BIPOLAR AFFECTIVE DISORDERS
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