Persistent behavioral sensitization to chronic L-DOPA requires A2A adenosine receptors

被引:99
作者
Fredduzzi, S
Moratalla, R
Monopoli, A
Cuellar, B
Xu, K
Ongini, E
Impagnatiello, F
Schwarzschild, MA
Chen, JF
机构
[1] Massachusetts Gen Hosp, Mol Neurobiol Lab, Boston, MA 02129 USA
[2] Schering Plough Corp, Res Inst, I-20132 Milan, Italy
[3] Inst Cajal, Madrid 20082, Spain
关键词
A(2A) adenosine receptor; L-DOPA; behavioral sensitization; Parkinson's disease; dyskinesia; dynorphin;
D O I
10.1523/JNEUROSCI.22-03-01054.2002
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
To investigate the role of A(2A) adenosine receptors in adaptive responses to chronic intermittent dopamine receptor stimulation, we compared the behavioral sensitization elicited by repeated L-DOPA treatment in hemiparkinsonian wild-type (WT) and A(2A) adenosine receptor knock-out (A(2A) KO) mice. Although the unilateral nigrostriatal lesion produced by intrastriatal injection of 6-hydroxydopamine was indistinguishable between WT and A(2A) KO mice, they developed strikingly different patterns of behavioral sensitization after daily treatment with low doses of L-DOPA for 3 weeks. WT mice initially displayed modest contralateral rotational responses and then developed progressively greater responses that reached a maximum within 1 week and persisted for the duration of the treatment. In contrast, any rotational behavioral sensitization in A(2A) KO mice was transient and completely reversed within 2 weeks. Similarly, the time to reach the peak rotation was progressively shortened in WT mice but remained unchanged in A(2A) KO mice. Furthermore, daily L-DOPA treatment produced gradually sensitized grooming in WT mice but failed to induce any sensitized grooming in A(2A) KO mice. Finally, repeated L-DOPA treatment reversed the 6-OHDA-induced reduction of striatal dynorphin mRNA in WT but not A(2A) KO mice, raising the possibility that the A(2A) receptor may contribute to L-DOPA-induced behavioral sensitization by facilitating adaptations within the dynorphin-expressing striatonigral pathway. Together these results demonstrate that the A(2A) receptor plays a critical role in the development and particularly the persistence of behavioral sensitization to repeated L-DOPA treatment. Furthermore, they raise the possibility that the maladaptive dyskinetic responses to chronic L-DOPA treatment in Parkinson's disease may be attenuated by A(2A) receptor inactivation.
引用
收藏
页码:1054 / 1062
页数:9
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