Persistent Behavioral Sensitization to Chronic L-DOPA Requires A2A Adenosine Receptors

• Published in: The Journal of neuroscience Vol. 22; no. 3; pp. 1054 - 1062
• Main Authors: Fredduzzi, Silva, Moratalla, Rosario, Monopoli, Angela, Cuellar, Beatriz, Xu, Kui, Ongini, Ennio, Impagnatiello, Francesco, Schwarzschild, Michael A, Chen, Jiang-Fan
• Format: Journal Article
• Language: English
• Published: United States Soc Neuroscience 01.02.2002; Society for Neuroscience
• Subjects: 3,4-Dihydroxyphenylacetic Acid - metabolism; Adaptation, Physiological - physiology; Animals; Autoradiography; Behavior, Animal - drug effects; Corpus Striatum - chemistry; Corpus Striatum - drug effects; Corpus Striatum - metabolism; Corpus Striatum - pathology; Dopamine - metabolism; Dopamine Plasma Membrane Transport Proteins; Drug Administration Schedule; Dynorphins - genetics; Dynorphins - metabolism; Female; Levodopa - administration & dosage; Male; Membrane Glycoproteins; Membrane Transport Proteins - metabolism; Mice; Mice, Knockout; Motor Activity - drug effects; Nerve Tissue Proteins; Oxidopamine; Parkinson Disease, Secondary - chemically induced; Parkinson Disease, Secondary - metabolism; Parkinson Disease, Secondary - pathology; Receptor, Adenosine A2A; Receptors, Purinergic P1 - deficiency; Receptors, Purinergic P1 - genetics; Receptors, Purinergic P1 - metabolism; RNA, Messenger - metabolism; Substantia Nigra - drug effects; Substantia Nigra - metabolism; Substantia Nigra - pathology
• ISSN: 0270-6474; 1529-2401; 1529-2401
• DOI: 10.1523/jneurosci.22-03-01054.2002

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.