Purinergic signalling: From normal behaviour to pathological brain function
Highlights
► Purinergic signalling in normal behaviour: memory, sleep, locomotion, feeding. ► Purinoceptors in trauma, ischemia, stroke: neuroprotective strategies. ► Neurodegenerative diseases: Alzheimer's, Parkinson's, Huntington's, MS, ALS. ► P1 and P2 receptors in mood disorders: depression and anxiety and schizophrenia. ► Purinergic therapeutic treatments for epilepsy, migraine and neuropathic pain.
Section snippets
Background of purinergic signalling
The concept of purinergic neurotransmission was born in 1972 (Burnstock, 1972), after it was shown that adenosine 5′-triphosphate (ATP) was a transmitter in non-adrenergic, non-cholinergic inhibitory nerves in the guinea-pig taenia coli. Subsequently ATP was identified as a co-transmitter in sympathetic and parasympathetic nerves (Burnstock, 1976) and it is now recognised that ATP acts as a co-transmitter in most nerves in both the peripheral and the central nervous systems (CNS) (see
Purinergic signalling in the brain
The actions of adenosine in the CNS have been recognised for many years (see Dunwiddie, 1985, Phillis and Wu, 1981, Snyder, 1985, Williams, 1984). However, consideration of the role(s) of ATP in the CNS received less attention until more recently (see Abbracchio, 1997, Bo and Burnstock, 1994, Burnstock, 1996a, Burnstock, 2003, Burnstock, 2007a, Franke and Illes, 2006, Gibb and Halliday, 1996, Illes and Ribeiro, 2004b, Illes and Zimmermann, 1999, Inoue et al., 1996, Krügel et al., 2004a, Krügel
Trauma, ischemia and stroke
Trauma, ischemia and stroke lead to the release of ATP/adenosine from various cells in the CNS and periphery. These signalling molecules partly aggravate the neuronal and glial damage caused by mechanical trauma/metabolic limitation, and partly serve as protective mechanisms (see Majumder et al., 2007). The P2 receptor antagonist, PPADS, supports recovery from experimental stroke in vivo (Lämmer et al., 2011).
Conclusions and future developments
The dominant purinoceptor subtypes that appear to be involved in normal behaviour are A1, A2A, P2Y1 and P2X7 (Table 1). Short-term memory is interrupted by A1 and A2A receptor agonists, but long-term administration of A1 receptor agonists has been claimed to improve spatial memory. Inhibition of LTP by low levels of adenosine acting on A1 receptors, but increase in LTP by higher concentrations of adenosine acting on A2A receptors, has been described. P2X7 receptors have also been claimed to
Acknowledgements
The authors thank Dr. Gillian E. Knight for her brilliant editorial assistance and Professors Patrizia Popoli and Helmut L. Haas for many helpful discussions.
References (761)
- et al.
Purinoceptors: are there families of P2X and P2Y purinoceptors?
Pharmacol. Ther.
(1994) - et al.
The protective effect of 2-chloroadenosine against the development of amygdala kindling and on amygdala-kindled seizures
Eur. J. Pharmacol.
(1997) - et al.
Effects of repeated administration of selective adenosine A1 and A2A receptor agonists on pentylenetetrazole-induced convulsions in the rat
Eur. J. Pharmacol.
(1995) - et al.
ATP regulates oligodendrocyte progenitor migration, proliferation, and differentiation: involvement of metabotropic P2 receptors
Brain Res. Brain Res. Rev.
(2005) - et al.
The cellular localization of adenosine receptors in rat neostriatum
Neuroscience
(1989) - et al.
Systemic administration of GMP induces anxiolytic-like behavior in rats
Pharmacol. Biochem. Behav.
(2010) - et al.
Purinergic P2 receptors trigger adenosine release leading to adenosine A2A receptor activation and facilitation of long-term potentiation in rat hippocampal slices
Neuroscience
(2003) - et al.
Emerging challenges of assigning P2X7 receptor function and immunoreactivity in neurons
Trends Neurosci.
(2006) - et al.
Ivermectin inhibits AMPA receptor-mediated excitotoxicity in cultured motor neurons and extends the life span of a transgenic mouse model of amyotrophic lateral sclerosis
Neurobiol. Dis.
(2007) - et al.
Conditioned effects of caffeine on performance in humans
Physiol. Behav.
(2010)
Adenosine acting via A1 receptors, controls the transition to status epilepticus-like behaviour in an in vitro model of epilepsy
Neuropharmacology
Caffeine-induced anxiogenesis: the role of adenosine, benzodiazepine and noradrenergic receptors
Pharmacol. Biochem. Behav.
Central effects of adenosine analogs on locomotor activity in mice and antagonism of caffeine
Brain Res.
Adenosine A2a receptors in the nucleus accumbens mediate locomotor depression
Brain Res. Bull.
Adenosine and sleep–wake regulation
Prog. Neurobiol.
Behavioral profile of P2X7 receptor knockout mice in animal models of depression and anxiety: relevance for neuropsychiatric disorders
Behav. Brain Res.
Cocaine and caffeine: conditioned place preference, locomotor activity, and additivity
Pharmacol. Biochem. Behav.
Immunolocalization of ecto-nucleoside triphosphate diphosphohydrolase 3 in rat brain: implications for modulation of multiple homeostatic systems including feeding and sleep–wake behaviors
Neuroscience
Stimulation of A1 adenosine receptors mimics the electroencephalographic effects of sleep deprivation
Brain Res.
Pathophysiological roles of extracellular nucleotides in glial cells: differential expression of purinergic receptors in resting and activated microglia
Brain Res. Brain Res. Rev.
The cortical stab injury induces beading of fibers expressing ecto-nucleoside triphosphate diphosphohydrolase 3
Neuroscience
Decreased behavioral activation following caffeine, amphetamine and darkness in A3 adenosine receptor knock-out mice
Physiol. Behav.
Adenosine A1 and A3 receptors protect astrocytes from hypoxic damage
Eur. J. Pharmacol.
Adenosine kinase, epilepsy and stroke: mechanisms and therapies
Trends Pharmacol. Sci.
The adenosine kinase hypothesis of epileptogenesis
Prog. Neurobiol.
Therapeutic epilepsy research: from pharmacological rationale to focal adenosine augmentation
Biochem. Pharmacol.
Learning-specific decrease in synaptosomal ATP diphosphohydrolase activity from hippocampus and entorhinal cortex of adult rats
Brain Res.
Effects of suramin on hippocampal apyrase activity and inhibitory avoidance learning of rats
Pharmacol. Biochem. Behav.
2-Chloroadenosine, a preferential agonist of adenosine A1 receptors, enhances the anticonvulsant activity of carbamazepine and clonazepam in mice
Eur. Neuropsychopharmacol.
Expression of ectonucleotidase CD39 by Foxp3+ Treg cells: hydrolysis of extracellular ATP and immune suppression
Blood
Caffeine-induced place and taste conditioning: production of dose-dependent preference and aversion
Pharmacol. Biochem. Behav.
Central noradrenergic neurons signal via ATP to elicit vasopressin responses to haemorrhage
Neuroscience
A 2A adenosine receptor regulates glia proliferation and pain after peripheral nerve injury
Pain
Purinergic receptors
J. Theor. Biol.
Pathophysiology of migraine: a new hypothesis
Lancet
The role of adenosine triphosphate in migraine
Biomed. Pharmacother.
A unifying purinergic hypothesis for the initiation of pain
Lancet
Purine-mediated signalling in pain and visceral perception
Trends Pharmacol. Sci.
Purinergic receptors in the nervous system
Is there a basis for distinguishing two types of P2-purinoceptor?
Gen. Pharmacol.
Cellular distribution and functions of P2 receptor subtypes in different systems
Int. Rev. Cytol.
Purinergic receptors: their role in nociception and primary afferent neurotransmission
Curr. Opin. Neurobiol.
Acute and chronic electroconvulsive shock in rats: effects on peripheral markers of neuronal injury and glial activity
Life Sci.
Role of ventral hippocampal nitric oxide/cGMP pathway in anxiety-related behaviors in rats submitted to the elevated T-maze
Behav. Brain Res.
P2Y2 nucleotide receptors enhance α-secretase-dependent amyloid precursor protein processing
J. Biol. Chem.
ATP in brain function
Purinergic signalling: pathophysiological roles
Jpn. J. Pharmacol.
Dipyridamole in the treatment of schizophrenia: adenosine–dopamine receptor interactions
J. Clin. Pharm. Ther.
Up-regulation of adenosine receptors in the frontal cortex in Alzheimer's disease
Brain Pathol.
Major depression is associated with significant diurnal elevations in plasma interleukin-6 levels, a shift of its circadian rhythm, and loss of physiological complexity in its secretion: clinical implications
J. Clin. Endocrinol. Metab.
Cited by (349)
ATP-P2X7 signaling mediates brain pathology while contributing to viral control in perinatal Zika virus infection
2024, Brain, Behavior, and ImmunityATP-mediated signalling in the central synapses
2023, NeuropharmacologyAssociation between uric acid and cognitive dysfunction: A cross-sectional study with newly diagnosed, drug-naïve with bipolar disorder
2023, Journal of Affective Disorders