Altered adenosine 2A and dopamine D2 receptor availability in the 6-hydroxydopamine-treated rats with and without levodopa-induced dyskinesia

Several lines of evidence imply alterations in adenosine signaling in Parkinson's disease (PD). Here, we investigated cerebral changes in adenosine 2A receptor (A(2A)R) availability in 6-hydroxydopamine (6-OHDA)-lesioned rats with and without levodopa-induced dyskinesia (LID) using positron-emission tomography (PET) with [C-11]preladenant. In parallel dopamine type 2 receptor (D2R) imaging with [C-11]raclopride PET and behavioral tests for motor and cognitive function were performed. Methods: Parametric A(2A)R and D2R binding potential (BPND) images were reconstructed using reference tissue models with midbrain and cerebellum as reference tissue, respectively. All images were anatomically standardized to Paxinos space and analyzed using volume-of-interest (VOI) and voxel-based approaches. The behavioral alternations were assessed with the open field test, Y-maze, novel object recognition test, cylinder test, and abnormal involuntary movement (AIM) score. In total, 28 female Wistar rats were included. Results: On the behavioral level, 6-OHDA-lesioned rats showed asymmetry in forepaw use and deficits in spatial memory and explorative behavior as compared to the sham-operated animals. 15-Days of levodopa (L-DOPA) treatment induced dyskinesia but did not alleviate motor deficits in PD rats. Intranigral 6-OHDA injection significantly increased D2R binding in the lesioned striatum (BPND: 2.69 +/- 0.40 6-OHDA vs. 2.31 +/- 0.18 sham, + 16.6%; p = 0.03), whereas L-DOPA treatment did not affect the D2R binding in the ipsilateral striatum of the PD rats. In addition, intranigral 6-OHDA injection tended to decrease the A(2A)R availability in the lesioned striatum. The decrease became significant when data were normalized to the non-affected side (BPND: 4.32 +/- 0.41 6-OHDA vs. 4.58 +/- 0.89 sham; NS, ratio: 0.94 +/- 0.03 6-OHDA vs. 1.00 +/- 0.02 sham; 6.1%; p = 0.01). L-DOPA treatment significantly increased A(2A)R binding in the affected striatum (BPND: 6.02 +/- 0.91 L-DOPA vs. 4.90 +/- 0.76 saline; + 23.4%; p = 0.02). In PD rats with LID, positive correlations were found between D2R and A(2A)R BPND values in the ipsilateral striatum (r = 0.88, p(peak) = 8.56.10(-4) uncorr), and between AIM score and the D2R BPND in the contralateral striatum (r = 0.98; p(peak) = 9.55.10(-5) uncorr). Conclusion: A(2A)R availability changed in drug-naive and in L-DOPA-treated PD rats. The observed correlations of striatal D2R availability with A(2A)R availability and with AIM score may provide new knowledge on striatal physiology and new possibilities to further unravel the functions of these targets in the pathophysiology of PD.