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Adenosine A2A Receptors and Parkinson’s Disease

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Adenosine Receptors in Health and Disease

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 193))

Abstract

The drug treatment of Parkinson’s disease (PD) is accompanied by a loss of drug efficacy, the onset of motor complications, lack of effect on non-motor symptoms, and a failure to modify disease progression. As a consequence, novel approaches to therapy are sought, and adenosine A2A receptors (A2AARs) provide a viable target. A2AARs are highly localized to the basal ganglia and specifically to the indirect output pathway, which is highly important in the control of voluntary movement. A2AAR antagonists can modulate γ-aminobutyric acid (GABA) and glutamate release in basal ganglia and other key neurotransmitters that modulate motor activity. In both rodent and primate models of PD, A2AAR antagonists produce alterations in motor behavior, either alone or in combination with dopaminergic drugs, which suggest that they will be effective in the symptomatic treatment of PD. In clinical trials, the A2AAR antagonist istradefylline reduces “off” time in patients with PD receiving optimal dopaminergic therapy. However, these effects have proven difficult to demonstrate on a consistent basis, and further clinical trials are required to establish the clinical utility of this drug class. Based on preclinical studies, A2AAR antagonists may also be neuroprotective and have utility in the treatment of neuropsychiatric disorders. We are only now starting to explore the range of potential uses of A2AAR antagonists in central nervous system disorders, and their full utility is still to be uncovered.

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Abbreviations

AIMs:

Abnormal involuntary movements

A2AAR:

Adenosine A2A receptor

AUC:

Area under the curve

AMPA:

Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid

BG:

Basal ganglia

COMT:

Catechol-O-methyl transferase

CPu:

Caudate-putamen

CGI:

Clinical global impression

DA:

Dopamine

DYN:

Dynorphin

ENK:

Enkephalin

GABA:

γ-Aminobutyric acid

GAD67:

Glutamic acid decarboxylase

GP:

Globus pallidus

GPe:

Globus pallidus, external segment

GPi:

Globus pallidus, internal segment

5-HT:

5-Hydroxytryptamine

LOCF:

Last observation carried forward

KO:

Knockout

l-DOPA:

3,4-Dihydroxy-l-phenylalanine

LTP/LDP:

Long-term potentiation/long-term depression

mGlu5:

Metabotropic glutamate subtype 5

MAO B:

Monoamine oxidase B

6-OHDA:

6-Hydroxydopamine

MPTP:

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine

PD:

Parkinson’s disease

STN:

Subthalamus

SNr:

Substantia nigra pars reticulata

TJM:

Tremulous jaw movement

UPDRS:

Unified Parkinson’s disease rating scale

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Authors and Affiliations

  1. Department of Toxicology and Center of Excellence for Neurobiology of Addiction, University of Cagliari, via Ospedale 72, 09124, Cagliari, Italy

    Micaela Morelli & Anna R. Carta

  2. Neurodegenerative Diseases Research Centre, School of Health and Biomedical Sciences, King’s College, London, SE1 1UL, UK

    Peter Jenner

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  1. Micaela Morelli
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  2. Anna R. Carta
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  3. Peter Jenner
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Correspondence to Micaela Morelli .

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  1. Endacea, Inc.,, Davis Drive 2, Research Triangle Park, 27709-2076, U.S.A.

    Constance N. Wilson

  2. Health Sciences Center, West Virginia University, Health Sciences S. 2267, Morgantown, 26506-9104, U.S.A.

    S. Jamal Mustafa

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Morelli, M., Carta, A.R., Jenner, P. (2009). Adenosine A2A Receptors and Parkinson’s Disease. 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_18

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