Forebrain Adenosine A_2AReceptors Contribute to l-3,4-Dihydroxyphenylalanine-Induced Dyskinesia in Hemiparkinsonian Mice

Abstract

Adenosine A 2A receptor antagonists provide a promising nondopaminergic approach to the treatment of Parkinson's disease (PD). Initial clinical trials of A 2A antagonists targeted PD patients who had already developed treatment complications known as l -3,4-dihydroxyphenylalanine ( l -DOPA)-induced dyskinesia (LID) in an effort to improve symptoms while reducing existing LID. The goal of this study is to explore the effect of A 2A antagonists and targeted A 2A receptor depletion on the actual development of sensitized responses to l -DOPA in mouse models of LID in PD. Hemiparkinsonian mice (unilaterally lesioned with 6-OHDA) were treated daily for 3 weeks with a low dose of l -DOPA (2 mg/kg) preceded by a low dose of selective A 2A antagonist (KW-6002 [( E )-1,3-diethyl-8-(3,4-dimethoxystyryl)-7-methyl-3,7-dihydro-1 H -purine-2,6-dione] at 0.03 or 0.3 mg/kg, or SCH58261 [5-amino-7-(2-phenylethyl)-2-(2-furyl)-pyrazolo[4,3- e ]-1,2,4-triazolo[1,5- c ]pyrimidine] at 0.03 mg/kg) or vehicle intraperitoneally. In control mice, contralateral rotational responses to daily l -DOPA gradually increased over the initial week before reaching a persistent maximum. Both A 2A antagonists inhibited the development of sensitized contralateral turning, with KW-6002 pretreatment reducing the sensitized rotational responses by up to threefold. The development of abnormal involuntary movements (a measure of LID) as well as rotational responses was attenuated by the postnatal depletion of forebrain A 2A receptors in conditional (Cre/ loxP system) knock-out mice. These pharmacological and genetic data provide evidence that striatal A 2A receptors play an important role in the neuroplasticity underlying behavioral sensitization to l -DOPA, supporting consideration of early adjunctive therapy with an A 2A antagonist to reduce the risk of LID in PD.