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Adenosine A_2A and dopamine receptor interactions in basal ganglia of dopamine denervated rats

From the Department of Toxicology and Center of Excellence for Neurobiology of Dependence (Drs. Carta, Pinna, and Morelli) and CNR, Institute of Neurogenetic and Neuropharmacology (Drs. Pinna and Morelli), University of Cagliari, Italy.

Address correspondence and reprint requests to Dr. Micaela Morelli, Department of Toxicology, Via Ospedale 72, 09124 Cagliari, Italy; e-mail: morelli{at}unica.it

In the unilateral 6-hydroxydopamine-lesioned rat model of Parkinson’s disease, blockade of A_2A receptors facilitates L-dopa-induced turning behavior by antagonism of A_2A transmission, which is increased after dopamine depletion. After long-term intermittent administration of doses that produced the same effect on turning behavior, SCH 58261 (5 mg/kg) + L-dopa (3 mg/kg) induced a stable turning behavior, whereas L-dopa (6 mg/kg) alone induced a sensitized turning behavior. Behavioral studies were correlated to changes in dynorphin and enkephalin mRNAs in the striatum and in glutamic acid decarboxylase 67 (GAD67) mRNA in the striatum, globus pallidus, and substantia nigra. The expression of dynorphin and, to a lesser extent, enkephalin mRNAs was increased in the lesioned striatum of rats that received long-term L-dopa treatment but not in rats that received long-term SCH 58261 + L-dopa treatment. Similarly, GAD67 mRNA was increased in the striatum and globus pallidus by long-term L-dopa administration but not by long-term SCH 58261 + L-dopa administration. GAD67 mRNA was strongly reduced in the lesioned substantia nigra after long-term L-dopa treatment, whereas the reduction of GAD67 mRNA was less marked after SCH 58261 + L-dopa treatment. By increasing L-dopa turning behavior, A_2A receptor antagonism allows the utilization of doses of L-dopa that do not produce sensitization of turning behavior, an effect correlated with the dyskinetic potential of dopamine agonist drugs. Moreover, the combination of SCH 58261 + L-dopa produces little or no change in the striatal, pallidal, and nigral expression of markers correlated with dopamine agonist dyskinetic potential.

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