Elsevier

Progress in Neurobiology

Volume 95, Issue 2, October 2011, Pages 229-274
Progress in Neurobiology

Purinergic signalling: From normal behaviour to pathological brain function

https://doi.org/10.1016/j.pneurobio.2011.08.006Get rights and content

Abstract

Purinergic neurotransmission, involving release of ATP as an efferent neurotransmitter was first proposed in 1972. Later, ATP was recognised as a cotransmitter in peripheral nerves and more recently as a cotransmitter with glutamate, noradrenaline, GABA, acetylcholine and dopamine in the CNS. Both ATP, together with some of its enzymatic breakdown products (ADP and adenosine) and uracil nucleotides are now recognised to act via P2X ion channels and P1 and P2Y G protein-coupled receptors, which are widely expressed in the brain. They mediate both fast signalling in neurotransmission and neuromodulation and long-term (trophic) signalling in cell proliferation, differentiation and death. Purinergic signalling is prominent in neurone–glial cell interactions. In this review we discuss first the evidence implicating purinergic signalling in normal behaviour, including learning and memory, sleep and arousal, locomotor activity and exploration, feeding behaviour and mood and motivation. Then we turn to the involvement of P1 and P2 receptors in pathological brain function; firstly in trauma, ischemia and stroke, then in neurodegenerative diseases, including Alzheimer's, Parkinson's and Huntington's, as well as multiple sclerosis and amyotrophic lateral sclerosis. Finally, the role of purinergic signalling in neuropsychiatric diseases (including schizophrenia), epilepsy, migraine, cognitive impairment and neuropathic pain will be considered.

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.

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