Bilateral increase in striatal dopamine D2 receptor density in the 6-hydroxydopamine-lesioned rat: a serial in vivo investigation with small animal PET

Abstract

Unilateral destruction of the substantia nigra by local application of 6-hydroxydopamine (6-OHDA) serves as an animal model for Parkinson's disease. In this study, the changes in neostriatal dopamine D(2) receptor density were investigated with a small animal positron emission tomograph (PET) before and after 6-OHDA lesion. PET scans were performed in 14 rats after injection of the D(2) receptor radioligand [(18)F] N-methylbenperidol. After the first scan (day 0), nigrostriatal pathways were lesioned by unilateral injections of 6-OHDA. Further PET scans were performed on days 2 and 14 post-lesion. For both striata, B(max) values were determined from saturation binding curves with non-linear regression analysis. In the striatum ipsilateral to the lesion, B(max) initially amounted to 19.3+/-1. 9 fmol/mg (mean+/-SD) and increased to 19.7+/-2.2 and 29.9+/-5.7 fmol/mg on days 2 and 14 post-lesion, respectively. Contralateral B(max) values increased from 19.2+/-2 fmol/mg prior to the lesion to 21.2+/-2.9 and 28.6+/-5.7 fmol/mg on days 2 and 14, respectively. On day 14, the ipsilateral saturation binding curve differed from the ipsilateral pre-lesion curve (P=0.04; F test). When the contralateral pre-lesion saturation binding curve was compared with the contralateral post-lesion curve on day 14, a P value of 0.08 was obtained. This first serial in vivo imaging study of 6-OHDA-lesioned rats showed a time-dependent increase in striatal D(2) receptor density on both sides, the increase being more pronounced ipsilateral to the lesion. This result implies that compensatory mechanisms in the intact hemisphere contribute to regenerative processes following nigrostriatal dopaminergic denervation. Overall, our findings show the feasibility of repetitive in vivo studies of striatal receptor density with a small animal tomograph. Moreover, the applied in vivo saturation binding technique provides a versatile method for the quantification of time-dependent changes in the concentration of receptor binding sites.

Enhanced function in the good forelimb of hemi-parkinson rats: Compensatory adaptation for contralateral postural instability?

“…The finding of increased levels of extracellular dopamine in striatal dialysates contralateral to 6-OHDA (Robinson and Whishaw, 1988), which until the present study has not had a potential behavioral correlate, coupled with more recent evidence of bilateral upregulation of D2 receptor density following unilateral 6-OHDA lesions (Ferre and Fuxe, 1992;Nikolaus et al, 2003;Waszczak et al, 2006) suggest that the "intact" striatum may have the capacity for increased dopaminergic signaling, possibly via the D2 pathway. Evidence also exists showing an upregulation in post-mortem striatal dopamine content (as measured by HPLC) in striata contralateral to a severe 6-OHDA lesion relative to the striata of sham-operated controls (Warenycia and McKenzie, 1987), though this is not consistently found.…”

Type 1 cannabinoid receptor mapping with [18F]MK-9470 PET in the rat brain after quinolinic acid lesion: a comparison to dopamine receptors and glucose metabolism

“…Reactive compensation of the contralateral hemi- [19,48]. Notably, studies with unilateral intranigral 6-hydroxydopamine (6-OHDA) application to model Parkinson's disease (PD) found similar findings of increased D 2 receptor densities in the contralateral caudate-putamen [49,50]. There is also histologic evidence for interhemispheric projections from the striatum to the motor cortex [51], and upon lesioning, evidence of increased sprouting from intact to damaged hemispheres [52].…”

Development of a simultaneous PET/microdialysis method to identify the optimal dose of 11C-raclopride for small animal imaging

“…This becomes especially interesting in light of a trend that appears to distinguish small animal imaging experiments from their human and non-human primate counterparts, which is the use of a single striatum juxtaposed with the contralateral striatum (see also a series of very thorough experiments performed by Nikolaus et al, 2001Nikolaus et al, , 2003aNikolaus et al, , 2003b. Given the nature of rodent experiments, one striatum is often perturbed while the contralateral striatum is spared as a within animal control (i.e.…”

“…A discussion of artifact produced by partial volume effects in the Concorde tomograph can be found elsewhere . Nevertheless, although the studies by Nikolaus et al (2003a) used a different radiotracer, it appears that contrasting ipsi-and contralateral striata is a useful and valid means of reducing some experimental confounds.…”