Rescue of locomotor impairment in dopamine D2 receptor-deficient mice by an adenosine A2A receptor antagonist.
Identifieur interne : 001307 ( PubMed/Corpus ); précédent : 001306; suivant : 001308Rescue of locomotor impairment in dopamine D2 receptor-deficient mice by an adenosine A2A receptor antagonist.
Auteurs : S. Aoyama ; H. Kase ; E. BorrelliSource :
- The Journal of neuroscience : the official journal of the Society for Neuroscience [ 0270-6474 ] ; 2000.
English descriptors
- KwdEn :
- Adenosine (analogs & derivatives), Adenosine (metabolism), Adenosine (pharmacology), Animals, Antihypertensive Agents (metabolism), Antihypertensive Agents (pharmacology), Antineoplastic Agents (pharmacology), Enkephalins (genetics), Gait (drug effects), Gene Expression (drug effects), Mice, Mice, Inbred C57BL, Mice, Knockout, Motor Activity (drug effects), Parkinson Disease, Secondary (drug therapy), Parkinson Disease, Secondary (physiopathology), Phenethylamines (metabolism), Phenethylamines (pharmacology), Purinergic P1 Receptor Antagonists, Purines (pharmacology), RNA, Messenger (analysis), Radioligand Assay, Receptor, Adenosine A2A, Receptors, Dopamine D2 (genetics), Receptors, Purinergic P1 (genetics), Substance P (genetics), Tritium.
- MESH :
- chemical , analogs & derivatives : Adenosine.
- chemical , analysis : RNA, Messenger.
- chemical , genetics : Enkephalins, Receptors, Dopamine D2, Receptors, Purinergic P1, Substance P.
- chemical , metabolism : Adenosine, Antihypertensive Agents, Phenethylamines.
- chemical , pharmacology : Adenosine, Antihypertensive Agents, Antineoplastic Agents, Phenethylamines, Purines.
- drug effects : Gait, Gene Expression, Motor Activity.
- drug therapy : Parkinson Disease, Secondary.
- physiopathology : Parkinson Disease, Secondary.
- Animals, Mice, Mice, Inbred C57BL, Mice, Knockout, Purinergic P1 Receptor Antagonists, Radioligand Assay, Receptor, Adenosine A2A, Tritium.
Abstract
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.
PubMed: 10908627
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pubmed:10908627Le document en format XML
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<front><div type="abstract" xml:lang="en">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.</div>
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