Abstract
The adenosine receptors (ARs) in the nervous system act as a kind of “go-between” to regulate the release of neurotransmitters (this includes all known neurotransmitters) and the action of neuromodulators (e.g., neuropeptides, neurotrophic factors). Receptor–receptor interactions and AR–transporter interplay occur as part of the adenosine’s attempt to control synaptic transmission. A2AARs are more abundant in the striatum and A1ARs in the hippocampus, but both receptors interfere with the efficiency and plasticity-regulated synaptic transmission in most brain areas. The omnipresence of adenosine and A2A and A1 ARs in all nervous system cells (neurons and glia), together with the intensive release of adenosine following insults, makes adenosine a kind of “maestro” of the tripartite synapse in the homeostatic coordination of the brain function. Under physiological conditions, both A2A and A1 ARs play an important role in sleep and arousal, cognition, memory and learning, whereas under pathological conditions (e.g., Parkinson’s disease, Alzheimer’s disease, amyotrophic lateral sclerosis, stroke, epilepsy, drug addiction, pain, schizophrenia, depression), ARs operate a time/circumstance window where in some circumstances A1AR agonists may predominate as early neuroprotectors, and in other circumstances A2AAR antagonists may alter the outcomes of some of the pathological deficiencies. In some circumstances, and depending on the therapeutic window, the use of A2AAR agonists may be initially beneficial; however, at later time points, the use of A2AAR antagonists proved beneficial in several pathologies. Since selective ligands for A1 and A2A ARs are now entering clinical trials, the time has come to determine the role of these receptors in neurological and psychiatric diseases and identify therapies that will alter the outcomes of these diseases, therefore providing a hopeful future for the patients who suffer from these diseases.
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Abbreviations
- AC:
-
Adenylate cyclase
- ACh:
-
Acetylcholine
- ADO:
-
Adenosine
- ADP:
-
Adenosine 5′-diphosphate
- AK:
-
Adenosine kinase
- AMP:
-
Adenosine 5′-monophosphate
- AMPA:
-
α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
- AOPCP:
-
α, β-Methylene ADP
- Ap5A:
-
Diadenosine pentaphosphate
- AR:
-
Adenosine receptor
- ATP:
-
Adenosine 5′-triphosphate
- BDNF:
-
Brain-derived neurotrophic factor
- BRET:
-
Bioluminescence resonance energy transfer
- CamK:
-
Calmodulin-dependent kinase
- cAMP:
-
Cyclic adenosine 5′-monophosphate
- CB:
-
Cannabinoid
- CGRP:
-
Calcitonin gene-related peptide
- DA:
-
Dopamine
- DARPP:
-
Dopamine- and cAMP-regulated phosphoprotein
- DPCPX:
-
1,3-Dipropyl-8-cyclopentylxanthine
- ENT:
-
Equilibrative nucleoside transporter
- ERK:
-
Extracellular signal-regulated kinase
- GABA:
-
γ-Aminobutyric acid
- GAT:
-
GABA transporter
- GLU:
-
Glutamate
- GDNF:
-
Glial cell line-derived neurotrophic factor
- GPCRs:
-
G-protein-coupled receptors
- HEK cells:
-
Human embryonic kidney cells
- HFS:
-
High-frequency stimulation
- IL-6:
-
Interleukin 6
- IP3:
-
Inositol triphosphate
- i.v.:
-
Intravenous
- KO:
-
Knockout
- LFS:
-
Low-frequency stimulation
- LTD:
-
Long-term depression
- LTP:
-
Long-term potentiation
- MAPK:
-
Mitogen-activated protein kinase
- mGluR:
-
Metabotropic glutamate receptor (mGlu1–8 refer to mGluR subtypes)
- NAc:
-
Nucleus accumbens
- nAChR:
-
Nicotinic acetylcholine receptor
- NBTI:
-
Nitrobenzylthioinosine
- NGF:
-
Nerve growth factor
- NMDA:
-
N-Methyl-d-aspartate
- NT:
-
Neurotransmitter
- NTR:
-
Neurotransmitter receptor
- NPY:
-
Neuropeptide Y
- NR:
-
NMDA receptor subunit
- NT-3:
-
Neurotrophin 3
- NTDase:
-
Ecto-5′-nucleotidase
- NTPDase:
-
Ectonucleoside triphosphate diphosphohydrolase
- PDE:
-
Phosphodiesterase
- PKA:
-
Protein kinase A
- PKC:
-
Protein kinase C
- PLC:
-
Phospholipase C
- PTX:
-
Pertussis toxin
- REM:
-
Rapid eye movement
- Trk receptors:
-
Tropomyosin-related kinase receptors
- VIP:
-
Vasoactive intestinal peptide
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Acknowledgements
The work in the authors’ laboratory is supported by research grants from Fundação para a Ciência e Tecnologia (FCT), Gulbenkian Foundation and the European Union (COST B30).
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Sebastião, A.M., Ribeiro, J.A. (2009). Adenosine Receptors and the Central Nervous System. In: Wilson, C., Mustafa, S. (eds) Adenosine Receptors in Health and Disease. Handbook of Experimental Pharmacology, vol 193. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-540-89615-9_16
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