Increased D 1 Dopamine Receptor Signaling in Levodopa-Induced Dyskinesia Incarnation Aubert, PhD, 1 Ce ´line Guigoni, PhD, 2 Kerstin Håkansson, PhD, 3 Qin Li, BsC, 4 Sandra Dovero, 2 Nicole Barthe, MD, PhD, 5 Bernard H. Bioulac, MD, PhD, 2 Christian E. Gross, PhD, 2 Gilberto Fisone, PhD, 3 Bertrand Bloch, MD, PhD, 1 and Erwan Bezard, PhD 2 Involuntary movements, or dyskinesia, represent a debilitating complication of levodopa therapy for Parkinson’s disease. Although changes affecting D 1 and D 2 dopamine receptors have been studied in association with this condition, no causal relationship has yet been established. Taking advantage of a monkey brain bank constituted to study levodopa- induced dyskinesia, we report changes affecting D 1 and D 2 dopamine receptors within the striatum of normal, parkin- sonian, nondyskinetic levodopa-treated parkinsonian, and dyskinetic levodopa-treated parkinsonian animals. Whereas D 1 receptor expression itself is not related to dyskinesia, D 1 sensitivity per D 1 receptor measured by D 1 agonist-induced [ 35 S]GTPS binding is linearly related to dyskinesia. Moreover, the striata of dyskinetic animals show higher levels of cyclin-dependent kinase 5 (Cdk5) and of the dopamine- and cAMP-regulated phosphoprotein of 32kDa (DARPP-32). Our data suggest that levodopa-induced dyskinesia results from increased dopamine D 1 receptor–mediated transmission at the level of the direct pathway. Ann Neurol 2005;57:17–26 Long-term L-3,4-dihydroxyphenylalanine (L-dopa) treat- ment of Parkinson’s disease (PD) 1–3 induces adverse fluctuations in motor response and involuntary move- ments, known as L-dopa–induced dyskinesia (LID) (for a review, see Bezard and colleagues 4 ). Denervation-induced supersensitivity of dopamine (DA) receptors (D 1 -like and D 2 -like) has been widely suggested as the most plausible mechanism of LID. Indeed, striatal D 2 receptor–binding sites are in- creased in postmortem tissue of untreated parkinso- nian patients and in animal models. 5,6 Although su- persensitivity of D 2 receptors is expected when parkinsonism is first apparent, the first L-dopa dose administered does not generally induce dyskinesia, but dyskinesia develops gradually over time. 7 Accord- ingly, the D 2 /D 3 receptor agonists exert an antipar- kinsonian effect with a reduced propensity to elicit dyskinesia when administered de novo in PD pa- tients. 8 There is some evidence that D 1 messenger RNA (mRNA) levels are increased after dopaminergic treatment of the DA-depleted striatum in animal models of LID 9 ; that downstream signal transduction cascades is abnormal in LID, 10,11 including increased phosphorylation of cAMP-regulated phosphoprotein of 32kDa (DARPP-32) 12 ; and that an altered subcel- lular localization of D 1 receptors is involved in LID. 13 Moreover, a DA D 1 receptor agonist with proven antiparkinsonian action 14 induced LID similar to that induced by L-dopa in PD patients, 15 further suggesting that D 1 supersensitivity plays a key role in LID occurrence. Together, these observations call for a reassessment of the changes affecting D 1 and D 2 DA receptors in LID. In this study, taking advantage of a nonhuman pri- mate (NHP) brain bank constituted to study the pathophysiology of LID, 16 we determined changes af- fecting D 1 and D 2 DA receptors within the striatum of four experimental groups: normal, parkinsonian, par- kinsonian chronically treated with L-dopa without ex- hibiting dyskinesia, and parkinsonian chronically treated with L-dopa that shows overt dyskinesia. We show that LIDs are linked to a modification of both D 1 receptor expression and sensitivity of the D 1 - signaling cascade, reinforcing the hypothesis of the piv- From the 1 Centre National de la Recherche Scientifique Unite Mixte de Recherche 5541 and 2 Basal Gang Centre National de la Recherche Scientifique UMR 5543, Bordeaux Cedex, France; 3 Karolinska Institutet, Department of Neuroscience, Stockholm, Sweden; 4 Lab Animal Research Center, China Agricultural Univer- sity, Beijing, China; and 5 Institut National de la Sante et de la Re- cherche Me ´dicale U443, Universite ´ Victor Segalen-Bordeaux 2, Bor- deaux Cedex, France. Received Jun 3, 2004, and in revised form Aug 19. Accepted for publication Aug 24, 2004. Published online Oct 27, 2004, in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/ana.20296 Address correspondence to Dr Bezard, Laboratoire de Physiologie et Physiopathologie de la Signalisation Cellulaire, Centre National de la Recherche Scientifique Unite Mixte de Recherche 5543, Univer- site ´ Victor Segalen, 146 rue Le ´o Saignat, 33076 Bordeaux Cedex, France. E-mail: erwan.bezard@umr5543.u-bordeaux2.fr © 2004 American Neurological Association 17 Published by Wiley-Liss, Inc., through Wiley Subscription Services