Purinergic system dysfunction in mood disorders: a key target for developing improved therapeutics

Uric acid and purines (such as adenosine) regulate mood, sleep, activity, appetite, cognition, memory, convulsive threshold, social interaction, drive, and impulsivity. A link between purinergic dysfunction and mood disorders was first proposed a century ago. Interestingly, a recent nationwide popul...

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Bibliographic Details
Published inProgress in neuro-psychopharmacology & biological psychiatry Vol. 57; pp. 117 - 131
Main Authors Ortiz, Robin, Ulrich, Henning, Zarate, Carlos A., Machado-Vieira, Rodrigo
Format Journal Article
LanguageEnglish
Published England Elsevier Inc 03.03.2015
Subjects
Adenosine - physiology
Adenosine Triphosphate - physiology
Animals
Biomarkers - metabolism
Bipolar disorder
Depression
Guanosine - physiology
Humans
Mania
Models, Neurological
Molecular Targeted Therapy
Mood Disorders - drug therapy
Mood Disorders - genetics
Mood Disorders - metabolism
Mood Disorders - physiopathology
Neuroimaging
Psychotropic Drugs - pharmacology
Psychotropic Drugs - therapeutic use
Purines
Receptors, Purinergic - genetics
Receptors, Purinergic - metabolism
Treatment
Uric acid
NPPs
BD
GTP
GWAS
NF-kB
HPST
CNS
Bipolar disorder
E-NTPDases
cAMP
MDD
MRS
ALPs
UTP
Purines
GDP
e5NT
SNPs
TSPO
DMPA
PPADS
IRP-NIMH-NIH
TCAs
PKC
Depression
Uric acid
SSRI
31P
Treatment
EHNA
XO
ECT
GABA
Mania
SAH
YMRS
ATP
CHA
PET
ADA
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Abstract Uric acid and purines (such as adenosine) regulate mood, sleep, activity, appetite, cognition, memory, convulsive threshold, social interaction, drive, and impulsivity. A link between purinergic dysfunction and mood disorders was first proposed a century ago. Interestingly, a recent nationwide population-based study showed elevated risk of gout in subjects with bipolar disorder (BD), and a recent meta-analysis and systematic review of placebo-controlled trials of adjuvant purinergic modulators confirmed their benefits in bipolar mania. Uric acid may modulate energy and activity levels, with higher levels associated with higher energy and BD spectrum. Several recent genetic studies suggest that the purinergic system – particularly the modulation of P1 and P2 receptor subtypes – plays a role in mood disorders, lending credence to this model. Nucleotide concentrations can be measured using brain spectroscopy, and ligands for in vivo positron emission tomography (PET) imaging of adenosine (P1) receptors have been developed, thus allowing potential target engagement studies. This review discusses the key role of the purinergic system in the pathophysiology of mood disorders. Focusing on this promising therapeutic target may lead to the development of therapies with antidepressant, mood stabilization, and cognitive effects. •Purines and their metabolites regulate mood, cognition, and behavior.•P1 and P2 receptor function and SNPs play a role in mood disorders.•We review purinergic pathophysiology in mood disorders.•We review the potential therapeutic role of purinergic agents in mood disorders.
AbstractList Uric acid and purines (such as adenosine) regulate mood, sleep, activity, appetite, cognition, memory, convulsive threshold, social interaction, drive, and impulsivity. A link between purinergic dysfunction and mood disorders was first proposed a century ago. Interestingly, a recent nationwide population-based study showed elevated risk of gout in subjects with bipolar disorder (BD), and a recent meta-analysis and systematic review of placebo-controlled trials of adjuvant purinergic modulators confirmed their benefits in bipolar mania. Uric acid may modulate energy and activity levels, with higher levels associated with higher energy and BD spectrum. Several recent genetic studies suggest that the purinergic system - particularly the modulation of P1 and P2 receptor subtypes - plays a role in mood disorders, lending credence to this model. Nucleotide concentrations can be measured using brain spectroscopy, and ligands for in vivo positron emission tomography (PET) imaging of adenosine (P1) receptors have been developed, thus allowing potential target engagement studies. This review discusses the key role of the purinergic system in the pathophysiology of mood disorders. Focusing on this promising therapeutic target may lead to the development of therapies with antidepressant, mood stabilization, and cognitive effects.Uric acid and purines (such as adenosine) regulate mood, sleep, activity, appetite, cognition, memory, convulsive threshold, social interaction, drive, and impulsivity. A link between purinergic dysfunction and mood disorders was first proposed a century ago. Interestingly, a recent nationwide population-based study showed elevated risk of gout in subjects with bipolar disorder (BD), and a recent meta-analysis and systematic review of placebo-controlled trials of adjuvant purinergic modulators confirmed their benefits in bipolar mania. Uric acid may modulate energy and activity levels, with higher levels associated with higher energy and BD spectrum. Several recent genetic studies suggest that the purinergic system - particularly the modulation of P1 and P2 receptor subtypes - plays a role in mood disorders, lending credence to this model. Nucleotide concentrations can be measured using brain spectroscopy, and ligands for in vivo positron emission tomography (PET) imaging of adenosine (P1) receptors have been developed, thus allowing potential target engagement studies. This review discusses the key role of the purinergic system in the pathophysiology of mood disorders. Focusing on this promising therapeutic target may lead to the development of therapies with antidepressant, mood stabilization, and cognitive effects.
Uric acid and purines (such as adenosine) regulate mood, sleep, activity, appetite, cognition, memory, convulsive threshold, social interaction, drive, and impulsivity. A link between purinergic dysfunction and mood disorders was first proposed a century ago. Interestingly, a recent nationwide population-based study showed elevated risk of gout in subjects with bipolar disorder (BD), and a recent meta-analysis and systematic review of placebo-controlled trials of adjuvant purinergic modulators confirmed their benefits in bipolar mania. Uric acid may modulate energy and activity levels, with higher levels associated with higher energy and BD spectrum. Several recent genetic studies suggest that the purinergic system - particularly the modulation of P1 and P2 receptor subtypes - plays a role in mood disorders, lending credence to this model. Nucleotide concentrations can be measured using brain spectroscopy, and ligands for in vivo positron emission tomography (PET) imaging of adenosine (P1) receptors have been developed, thus allowing potential target engagement studies. This review discusses the key role of the purinergic system in the pathophysiology of mood disorders. Focusing on this promising therapeutic target may lead to the development of therapies with antidepressant, mood stabilization, and cognitive effects.
Uric acid and purines (such as adenosine) regulate mood, sleep, activity, appetite, cognition, memory, convulsive threshold, social interaction, drive, and impulsivity. A link between purinergic dysfunction and mood disorders was first proposed a century ago. Interestingly, a recent nationwide population-based study showed elevated risk of gout in subjects with bipolar disorder (BD), and a recent meta-analysis and systematic review of placebo-controlled trials of adjuvant purinergic modulators confirmed their benefits in bipolar mania. Uric acid may modulate energy and activity levels, with higher levels associated with higher energy and BD spectrum. Several recent genetic studies suggest that the purinergic system - particularly the modulation of P1 and P2 receptor subtypes - plays a role in mood disorders, lending credence to this model. Nucleotide concentrations can be measured using brain spectroscopy, and ligands for in vivo positron emission tomography (PET) imaging of adenosine (P1) receptors have been developed, thus allowing potential target engagement studies. This review discusses the key role of the purinergic system in the pathophysiology of mood disorders. Focusing on this promising therapeutic target may lead to the development of therapies with antidepressant, mood stabilization, and cognitive effects. Abbreviations * BD, Bipolar disorder * PET, positron emission tomography * ATP, adenosine triphosphate * CNS, Central nervous system * cAMP, cyclic adenosine monophosphate * GABA, gamma aminobutyric acid * E-NTPDases, ectonucleoside triphosphate diphosphohydrolases * NPPs, nucleotide pyrophosphatase/phosphodiesterase * ALPs, alkaline phosphatases * e5NT, ecto-5'-nucleotidase * UTP, uridine triphosphate * GTP, guanosine triphosphate * SAH, S-adenosyl-L-homocysteine * ADA, adenosine deaminase * XO, xanthine oxidase * NF-kB, nuclear factor kappa-light-chain-enhancer * GDP, guanosine diphosphate * MDD, major depressive disorder * PPADS, pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid * ECT, electroconvulsive therapy * TCAs, tricyclic antidepressants * CHA, N6-cyclohexyladenosine * DMPA, N6-[2-(3,5-dimethoxyphenyl)-2-(methylphenyl)ethyl]adenosine * EHNA, erythro-9-(2-hydroxy-3nonyl) adenine * PKC, protein kinase C * SNPs, single nucleotide polymorphisms * GWAS, genome-wide association studies * SSRI, selective serotonin reuptake inhibitor * super(31)P, Phosphorous-31 * TSPO, translocator protein * MRS, magnetic resonance spectroscopy * HPST, hypoxanthine-guanine phosphoribosyltransferase * YMRS, Young Mania Rating Scale * IRP-NIMH-NIH, Intramural Research Program at the National Institute of Mental Health, National Institutes of Health
Uric acid and purines (such as adenosine) regulate mood, sleep, activity, appetite, cognition, memory, convulsive threshold, social interaction, drive, and impulsivity. A link between purinergic dysfunction and mood disorders was first proposed a century ago. Interestingly, a recent nationwide population-based study showed elevated risk of gout in subjects with bipolar disorder (BD), and a recent meta-analysis and systematic review of placebo-controlled trials of adjuvant purinergic modulators confirmed their benefits in bipolar mania. Uric acid may modulate energy and activity levels, with higher levels associated with higher energy and BD spectrum. Several recent genetic studies suggest that the purinergic system – particularly the modulation of P1 and P2 receptor subtypes – plays a role in mood disorders, lending credence to this model. Nucleotide concentrations can be measured using brain spectroscopy, and ligands for in vivo positron emission tomography (PET) imaging of adenosine (P1) receptors have been developed, thus allowing potential target engagement studies. This review discusses the key role of the purinergic system in the pathophysiology of mood disorders. Focusing on this promising therapeutic target may lead to the development of therapies with antidepressant, mood stabilization, and cognitive effects. •Purines and their metabolites regulate mood, cognition, and behavior.•P1 and P2 receptor function and SNPs play a role in mood disorders.•We review purinergic pathophysiology in mood disorders.•We review the potential therapeutic role of purinergic agents in mood disorders.
Author Machado-Vieira, Rodrigo
Ortiz, Robin
Ulrich, Henning
Zarate, Carlos A.
AuthorAffiliation b Departament of Biochemistry, University of Sao Paulo, Sao Paulo, Brazil
c Laboratory of Neuroscience, LIM27, University of Sao Paulo, Brazil
a Experimental Therapeutics and Pathophysiology Branch, National Institute of Mental Health, Division of Intramural Research Programs, National Institutes of Health, Bethesda, MD, USA
AuthorAffiliation_xml – name: c Laboratory of Neuroscience, LIM27, University of Sao Paulo, Brazil
– name: a Experimental Therapeutics and Pathophysiology Branch, National Institute of Mental Health, Division of Intramural Research Programs, National Institutes of Health, Bethesda, MD, USA
– name: b Departament of Biochemistry, University of Sao Paulo, Sao Paulo, Brazil
Author_xml – sequence: 1
  givenname: Robin
  surname: Ortiz
  fullname: Ortiz, Robin
  email: robinortiz.mail@gmail.com
  organization: Experimental Therapeutics and Pathophysiology Branch, National Institute of Mental Health, Division of Intramural Research Programs, National Institutes of Health, Bethesda, MD, USA
– sequence: 2
  givenname: Henning
  surname: Ulrich
  fullname: Ulrich, Henning
  email: henning@iq.usp.br
  organization: Departament of Biochemistry, University of Sao Paulo, Sao Paulo, Brazil
– sequence: 3
  givenname: Carlos A.
  surname: Zarate
  fullname: Zarate, Carlos A.
  email: zaratec@mail.nih.gov
  organization: Experimental Therapeutics and Pathophysiology Branch, National Institute of Mental Health, Division of Intramural Research Programs, National Institutes of Health, Bethesda, MD, USA
– sequence: 4
  givenname: Rodrigo
  surname: Machado-Vieira
  fullname: Machado-Vieira, Rodrigo
  email: machadovieirar@mail.nih.gov
  organization: Experimental Therapeutics and Pathophysiology Branch, National Institute of Mental Health, Division of Intramural Research Programs, National Institutes of Health, Bethesda, MD, USA
BackLink https://www.ncbi.nlm.nih.gov/pubmed/25445063$$D View this record in MEDLINE/PubMed
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BD
GTP
GWAS
NF-kB
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CNS
Bipolar disorder
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MDD
MRS
ALPs
UTP
Purines
GDP
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Snippet Uric acid and purines (such as adenosine) regulate mood, sleep, activity, appetite, cognition, memory, convulsive threshold, social interaction, drive, and...
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SubjectTerms Adenosine - physiology
Adenosine Triphosphate - physiology
Animals
Biomarkers - metabolism
Bipolar disorder
Depression
Guanosine - physiology
Humans
Mania
Models, Neurological
Molecular Targeted Therapy
Mood Disorders - drug therapy
Mood Disorders - genetics
Mood Disorders - metabolism
Mood Disorders - physiopathology
Neuroimaging
Psychotropic Drugs - pharmacology
Psychotropic Drugs - therapeutic use
Purines
Receptors, Purinergic - genetics
Receptors, Purinergic - metabolism
Treatment
Uric acid
Title Purinergic system dysfunction in mood disorders: a key target for developing improved therapeutics
URI https://dx.doi.org/10.1016/j.pnpbp.2014.10.016
https://www.ncbi.nlm.nih.gov/pubmed/25445063
https://www.proquest.com/docview/1652430777
https://www.proquest.com/docview/1660385748
https://pubmed.ncbi.nlm.nih.gov/PMC4262688
Volume 57
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