Although supersensitivity 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 Accordingly, the D 2 /D 3 receptor agonists exert an antiparkinsonian effect with a reduced propensity to elicit dyskinesia when administered de novo in PD patients. 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 12 ; and that an altered subcellular 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 primate (NHP) brain bank constituted to study the pathophysiology of LID, 16 we determined changes affecting D 1 and D 2 DA receptors within the striatum of four experimental groups: normal, parkinsonian, parkinsonian chronically treated with L-dopa without exhibiting 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 pivFrom the

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Striatal GABAergic microcircuits modulate cortical responses and movement execution in part by controlling the activity of medium spiny neurons (MSNs). How this is altered by chronic dopamine depletion, such as in Parkinson's disease, is not presently understood. We now report that, in dopamine-depleted slices of the striatum, MSNs generate giant spontaneous postsynaptic GABAergic currents (single or in bursts at 60 Hz) interspersed with silent episodes, rather than the continuous, low-frequency GABAergic drive (5 Hz) observed in control MSNs. This shift was observed in one-half of the MSN population, including both "D 1 -negative" and "D 1 -positive" MSNs. Single GABA and NMDA channel recordings revealed that the resting membrane potential and reversal potential of GABA were similar in control and dopamine-depleted MSNs, and depolarizing, but not excitatory, actions of GABA were observed. Glutamatergic and cholinergic antagonists did not block the GABAergic oscillations, suggesting that they were generated by GABAergic neurons. In support of this, cell-attached recordings revealed that a subpopulation of intrastriatal GABAergic interneurons generated bursts of spikes in dopamine-deprived conditions. This subpopulation included low-threshold spike interneurons but not fast-spiking interneurons, cholinergic interneurons, or MSNs. Therefore, a population of local GABAergic interneurons shifts from tonic to oscillatory mode when dopamine deprived and gives rise to spontaneous repetitive giant GABAergic currents in one-half the MSNs. We suggest that this may in turn alter integration of cortical signals by MSNs.

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The classic view of anatomofunctional organization of the basal ganglia is that striatopallidal neurons of the "indirect" pathway express D 2 dopamine receptors and corelease enkephalin with GABA, whereas striatopallidal neurons of the "direct" pathway bear D 1 dopamine receptors and corelease dynorphin and substance P with GABA. Although many studies have investigated the pathophysiology of the basal ganglia after dopamine denervation and subsequent chronic levodopa (L-dopa) treatment, none has ever considered the possibility of plastic changes leading to profound reorganization and/or biochemical phenotype modifications of medium spiny neurons. Therefore, we studied the phenotype of striatal neurons in four groups of nonhuman primates, including the following: normal, parkinsonian, parkinsonian chronically treated with L-dopa without exhibiting dyskinesia, and parkinsonian chronically treated with L-dopa exhibiting overt dyskinesia. To identify striatal cells projecting to external (indirect) or internal (direct) segments of the globus pallidus, the retrograde tracer cholera toxin subunit B (CTb) was injected stereotaxically into the terminal areas. Using immunohistochemistry techniques, brain sections were double labeled for CTb and dopamine receptors, opioid peptides, or the substance P receptor (NK1). We also used HPLC-RIA to assess opioid levels throughout structures of the basal ganglia. Our results suggest that medium spiny neurons retain their phenotype because no variations were observed in any experimental condition. Therefore, it appears unlikely that dyskinesia is related to a phenotype modification of the striatal neurons. However, this study supports the concept of axonal collateralization of striatofugal cells that project to both globus pallidus pars externa and globus pallidus pars interna. Striatofugal pathways are not as segregated in the primate as previously considered.

Background Involuntary movements, or dyskinesia, represent a debilitating complication of dopamine replacement therapy for Parkinson disease (PD). The transcription factor ΔFosB accumulates in the denervated striatum and dimerizes primarily with JunD upon repeated L-DOPA administration. Previous studies in rodents have shown that striatal ΔFosB levels accurately predict dyskinesia severity, and indicate that this transcription factor may play a causal role in dyskinesia sensitization process. Methods We asked whether the correlation previously established in rodents extends to the best non-human primate model of PD, the MPTP-lesioned macaque. We used Western Blotting and quantitative PCR to compare ΔFosB protein and mRNA levels across 2 subpopulations of macaques with differential dyskinesia severity. Second, we tested the causal implication of ΔFosB in this primate model. Serotype 2 Adeno-Associated Vectors (AAV2) were used to overexpress, within the motor striatum, either ΔFosB, or ΔJunD, a truncated variant of JunD lacking a transactivation domain, and therefore acting as a dominant negative inhibitor of ΔFosB. Results A linear relationship was observed between endogenous striatal levels of ΔFosB and the severity of Dyskinesia in Parkinsonian macaques treated with L-DOPA. Viral overexpression of ΔFosB did not alter dyskinesia severity in animals previously rendered dyskinetic, whereas the overexpression of ΔJunD dramatically dropped the severity of this side effect of L-DOPA, without altering the antiparkinsonian activity of the treatment. Conclusion These results establish a mechanism of dyskinesia induction and maintenance by L-DOPA and validate a strategy, with strong translational potential, to de-prime the L-DOPA-treated brain

The extent of nigrostriatal denervation is presumed to play a role in the genesis of levodopa-induced dyskinesia. Yet some parkinsonian patients who have been treated over a long period do not develop dyskinesia, raising the possibility that the pattern of denervation is as important as the extent of lesioning as a risk factor. Here we study the extent and pattern of nigrostriatal denervation in a homogeneous population of parkinsonian macaque monkeys chronically treated with levodopa. Based on the characteristics of the lesioning, non-dyskinetic animals could not be differentiated from those with dyskinesia. Indeed, the number of tyrosine-hydroxylase (TH)-immunopositive neurons in the substantia nigra pars compacta, striatal dopamine transporter (DAT) binding and TH immunostaining, as well as the overall TH striatal content measured by Western blotting were identical. Moreover, the patterns of lesioning assessed by a detailed analysis of the TH- and DAT-immunopositive striatal fibers were comparable in all functional quadrants and at all rostro-caudal levels considered. These data indicate that neither the extent nor the pattern of nigrostriatal lesioning are sufficient to explain the occurrence of levodopa-induced dyskinesia.