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

Abstract 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 [ 11 C]preladenant. In parallel dopamine type 2 receptor (D 2 R) imaging with [ 11 C]raclopride PET and behavioral tests for motor and cognitive function were performed. Methods Parametric A 2A R and D 2 R binding potential ( BP ND ) 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 D 2 R binding in the lesioned striatum ( BP ND : 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 D 2 R 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 ( BP ND : 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 ( BP ND : 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 D 2 R and A 2A R BP ND values in the ipsilateral striatum (r = 0.88, p peak = 8.56.10 −4 uncorr), and between AIM score and the D 2 R BP ND 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 D 2 R 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.