Presynaptic dopaminergic compartment determines the susceptibility to L-DOPA–induced dyskinesia in rats

Abstract

Drug-induced dyskinesias in dopamine-denervated animals are known to depend on both pre-and postsynaptic changes of the nigrostriatal circuitry. In lesion models used thus far, changes occur in both of these compartments and, therefore, it has not been possible to dissect the individual contribution of each compartment in the pathophysiology of dyskinesias. Here we silenced the nigrostriatal dopamine neurotransmission without affecting the anatomical integrity of the presynaptic terminals using a short-hairpin RNA-mediated knockdown of tyrosine hydroxylase enzyme (shTH). This treatment resulted in significant reduction (by about 70%) in extracellular dopamine concentration in the striatum as measured by on-line microdialysis. Under these conditions, the animals remained nondyskinetic after chronic L-DOPA treatment, whereas partial intrastriatal 6-hydoxydopamine lesioned rats with comparable reduction in extracellular dopamine levels developed dyskinesias. On the other hand, apomorphine caused moderate to severe dyskinesias in both groups. Importantly, singledose L-DOPA challenge in apomorphine-primed shTH animals failed to activate the already established abnormal postsynaptic responses. Taken together, these data provide direct evidence that the status of the presynaptic, DA releasing compartment is a critical determinant of both the induction and maintenance of L-DOPA-induced dyskinesias.reatment-induced motor complications are a major problem in management of patients suffering from Parkinson's disease (PD) (1). Dyskinesias induced by L-DOPA, in particular, constitute a significant challenge that impacts a higher proportion of the treated patients with treatment duration. Essentially all patients are expected to develop dyskinesias within a decade from onset of treatment (2). The underlying mechanisms of L-DOPA-induced dyskinesias (LIDs) are still not fully understood. Current views suggest that both presynaptic (i.e., production, storage, controlled release, and reuptake of dopamine by nigrostriatal dopaminergic neurons) and postsynaptic (i.e., status of receptors and second messenger signaling pathways in striatal neurons) components are critical in induction and maintenance of dyskinesias (3-5). However, the destruction of the presynaptic dopamine (DA) terminals, typically obtained by administration of a specific neurotoxin in animals, and the plastic changes induced in the postsynaptic striatal neurons occur at the same time. Moreover, synaptic changes secondary to chronic drug treatment further complicate the interpretation of the observations made in studies using animal models of PD (4-6).The aim of this study was to tease apart the contribution of the pre-and postsynaptic compartments in the pathophysiology of LIDs in the parkinsonian brain. The abnormal response of the striatal neurons to DA receptor stimulation following chronic DA depletion could be determined solely by mechanisms intrinsic to the striatal cells or alternatively, the functional activity of the presynaptic compartment could determin...

Putaminal serotonergic innervation

“…Note that there was Correlations between 11 C-DASB/ 18 F-FP-CIT binding potential ratios and UPDRS scores high variability in the 11 C-DASB/ 18 F-FP-CIT ratios in our patients; thus, subsequent plastic changes following or accompanying serotonergic innervation would be needed in this process at presynaptic and/ or postsynaptic levels. 36,37 There is supporting evidence that serotonergic fibers play key roles in initiating cascades of synaptic plasticity in PD animal models with LID. 38 Currently, the precise mechanism of serotonergic fiber innervation and interactions with nondopaminergic modulators as well as dopamine remains largely unknown.…”

Differential Dopamine Receptor Occupancy Underlies L-DOPA-Induced Dyskinesia in a Rat Model of Parkinson's Disease

“…The precise technical description of the setup has been published earlier [26]. Briefly, the outlet of the microdialysis probe was connected to a 14-port external valve that can direct the dialysate into two separate flow paths.…”

Anatomy of graft-induced dyskinesias: Circuit remodeling in the parkinsonian striatum

“…: [65–67]). However, we suggest here that the complexity of pre-synaptic DA release and its involvement with dyskinesias, either LID or GID, has perhaps been underestimated, and that there is an important interplay between pre- and post-synaptic compartments.…”