Interpreting DTBZ binding data in rodent: Inherent variability and compensation

Abstract

[11C]-dihydrotetrabenazine (DTBZ) Positron Emission Tomography was used to evaluate the vesicular monoamine transporter type 2 as an index of dopaminergic function in the striatum of adult Sprague-Dawley rats obtained from two different animal sources (Charles River Laboratories [CR] or UBC's Animal Care Centre [ACC]) and later submitted to two different unilateral lesions of the nigro-striatal pathway. The results showed a significant difference in the striatal binding potential (BP(ND)) at baseline (before lesioning) between the CR and ACC groups providing evidence that the origin of the animals, possibly due to differences in early environmental factors or breeding conditions associated with different animal vendors plays a role in the development of the adult dopaminergic system. Further, in both animal models, an increase in DTBZ BP(ND) was observed, after unilateral intervention, in the striatum contralateral to the lesion, likely reflecting compensatory effects. Based on these findings, we conclude that in unilateral models, the unlesioned side/hemisphere may not be an appropriate control and that care should be taken to control for the origin of the animals in any given study, especially in longitudinal and replication studies.

Early synaptic dysfunction induced by α-synuclein in a rat model of Parkinson’s disease

“…Indeed, unilateral 6-OHDA lesions have been shown to induce a compensatory bilateral increase in dopamine release 62 . Moreover, bilaterally increased VMAT2 PET binding, as seen here, has been previously shown in the 6-OHDA and the lactacystin unilateral PD models 63 . In the ASYN rats reported here, only contralateral intact SNc neurons were efficiently able to increase VMAT2, since the pathological accumulation of ASYN in the ipsilateral SNc neurons may inadequately support dopaminergic neurotransmission and therefore compensatory mechanisms may fail.…”

Nigrostriatal proteasome inhibition impairs dopamine neurotransmission and motor function in minipigs

“…As lactacystin is an irreversible inhibitor, it would also be interesting to test its effect over a longer time period than the 4 weeks in this study, in a longitudinal design to investigate if the impairments are sustained or lead to even further progression or recovery. However, a recent study suggests that lactacystin induces a stable lesion in rodents during an 8 week period (Mejias et al, 2016) and thus our timeline was likely sufficient for a preliminary study. To the left, α-syn staining is shown in the saline-injected minipig# 1, and to the right, in a lactacystin (Lac)-injected minipig #2.…”

Selecting the Best Animal Model of Parkinson’s Disease for Your Research Purpose: Insight from in vivo PET Imaging Studies

“…A major disadvantage is the invasive surgery which promotes a neuroinflammatory response independently of 6-OHDA effects. Some researchers use the contralateral side of the 6-OHDA model as a ‘control’, however due to possible compensatory responses observed in this model and intra-hemispheric connections complicating the matter, this may not be ideal, and an injection of saline in additional animals may provide a more appropriate control [ 102 ]. Furthermore, the model is limited by a lack of α-syn pathology, which is a hallmark of PD.…”