 |
 Previous Article | Next Article 
The Journal of Neuroscience, August 1, 2000, 20(15):5848-5852
Rescue of Locomotor Impairment in Dopamine D2 Receptor-Deficient
Mice by an Adenosine A2A Receptor Antagonist
Shiro
Aoyama1, 2,
Hiroshi
Kase2, and
Emiliana
Borrelli1
1 Institut de Génétique et de Biologie
Moléculaire et Cellulaire, BP163, 67404 Illkirch Cedex, C.U. de
Strasbourg, France, and 2 Pharmaceutical Research
Institute, Kyowa Hakko Kogyo Co., Ltd., Nagaizumi-cho Shizuoka,
411-8731 Japan
In Parkinson's disease a degeneration of dopaminergic neurons of
the nigrostriatal pathway is observed. Loss of dopaminergic regulation
of striatal neuron activity results in altered motor functions.
Adenosine A2A (A2AR) and dopamine D2 (D2R) receptors are colocalized in
striatal medium spiny neurons. It has been proposed that adenosine
binding to A2AR lowers the affinity of dopamine for D2R, thus
modulating the function of this receptor. Absence of D2R in knockout
mice (D2R /) results in impaired locomotion and coordinated
movements. This indicates that absence of dopamine in Parkinson's
disease might principally affect D2R-mediated effects with regard to
locomotor functions. A2AR-selective antagonists have been demonstrated
to have anti- parkinsonian activities in various models of Parkinson's
disease in rodents and nonhuman primates. In this article, D2R/
mice were used to explore the possibility that an A2AR antagonist might
reestablish their motor impairment. Interestingly, blockade of A2AR
rescues the behavioral parameters altered in D2R/ mice. In
addition, the level of expression of enkephalin and substance P, which
were altered in D2R/, were also reestablished to normal levels
after A2AR antagonist treatment. These results show that A2AR and D2R
have antagonistic and independent activities in controlling neuronal
and motor functions in the basal ganglia. They also provide evidence
that selective A2AR antagonists can exhibit their anti-parkinsonian
activities through a nondopaminergic mechanism.
Key words:
adenosine A2 receptor; dopamine D2 receptor; striatum; KW-6002; Parkinson's disease; knockout mice
Copyright © 2000 Society for Neuroscience 0270-6474/00/20155848-05$05.00/0
This article has been cited by other articles:
|
|
|
|
 
F. S. Jones, J. Jing, A. H. Stonehouse, A. Stevens, and G. M. Edelman
Caffeine Stimulates Cytochrome Oxidase Expression and Activity in the Striatum in a Sexually Dimorphic Manner
Mol. Pharmacol.,
September 1, 2008;
74(3):
673 - 684.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Stacy, D. Silver, T. Mendis, J. Sutton, A. Mori, P. Chaikin, and N. M. Sussman
A 12-week, placebo-controlled study (6002-US-006) of istradefylline in Parkinson disease
Neurology,
June 3, 2008;
70(23):
2233 - 2240.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. A. Vortherms and V. J. Watts
Sensitization of Neuronal A2A Adenosine Receptors after Persistent D2 Dopamine Receptor Activation
J. Pharmacol. Exp. Ther.,
January 1, 2004;
308(1):
221 - 227.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Fuxe, L.F. Agnati, K. Jacobsen, J. Hillion, M. Canals, M. Torvinen, B. Tinner-Staines, W. Staines, D. Rosin, A. Terasmaa, et al.
Receptor heteromerization in adenosine A2A receptor signaling: Relevance for striatal function and Parkinson's disease
Neurology,
December 9, 2003;
61(90116):
S19 - 23.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
S.N. Schiffmann, D. Dassesse, P. d'Alcantara, C. Ledent, S. Swillens, and M. Zoli
A2A receptor and striatal cellular functions: Regulation of gene expression, currents, and synaptic transmission
Neurology,
December 9, 2003;
61(90116):
S24 - 29.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
P. Jenner
A2A antagonists as novel non-dopaminergic therapy for motor dysfunction in PD
Neurology,
December 9, 2003;
61(90116):
S32 - 38.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
H. Kase
Industry forum: Progress in pursuit of therapeutic A2A antagonists: The adenosine A2A receptor selective antagonist KW6002: Research and development toward a novel nondopaminergic therapy for Parkinson's disease
Neurology,
December 9, 2003;
61(90116):
S97 - 100.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
L. F. Agnati, S. Ferre, C. Lluis, R. Franco, and K. Fuxe
Molecular Mechanisms and Therapeutical Implications of Intramembrane Receptor/Receptor Interactions among Heptahelical Receptors with Examples from the Striatopallidal GABA Neurons
Pharmacol. Rev.,
September 1, 2003;
55(3):
509 - 550.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. S. Kim and R. D. Palmiter
Adenosine receptor blockade reverses hypophagia and enhances locomotor activity of dopamine-deficient mice
PNAS,
February 4, 2003;
100(3):
1346 - 1351.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J.-F. Chen, R. Moratalla, F. Impagnatiello, D. K. Grandy, B. Cuellar, M. Rubinstein, M. A. Beilstein, E. Hackett, J. S. Fink, M. J. Low, et al.
The role of the D2 dopamine receptor (D2R) in A2A adenosine receptor (A2AR)-mediated behavioral and cellular responses as revealed by A2A and D2 receptor knockout mice
PNAS,
February 13, 2001;
98(4):
1970 - 1975.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
