Objective: To model and assess the differential effects of ventral or dorsal predominant dopaminergic denervation of striatum on development of impulsive compulsive behaviors (ICB) in rats.

Background: In Parkinson’s disease (PD), dopamine replacement therapy related ICB are associated with reduced quality of life. Molecular mechanism and a detailed anatomical basis of these behavioral alterations are still not known. Few studies demonstrated that punding may stem from a dopamine-dependent sensitization to appetitive stimuli within the dorsolateral striatum and DDS from the ventral striatum.

Methods: Bilateral 6-OHDA injection to ventral tegmental area or substansia nigra were performed for development of dorsal (n=21) or vental (n=17) selective dopaminergic denervation. Controls were sham operated (n=20). Conditioned place preference (CPP) paradigm was used to model DDS. In this model, the rewarding properties of low dose apomorphine (0.1mg/kg) was explored. Chronic intermittent injection of apomorphine (1mg/kg) was performed to induce repetitive behaviors that may both model dyskinesia and punding. Behavioral studies were rated by valid scales. The extend of dopaminergic denervation is mapped with tyrosine hydroxylase immunohistochemistry staining.

Results: All the dopamine denervated rats received chronic apomorphine injection developed dyskinetic behaviors. The severity of dyskinesia increased day by day and they were very strongly and positively correlated with mean lesion volume (r=849, p<0.001). Low dose apomorphine injection induced CPP in rats with parkinsonism but conditioned place avoidance in controls. The conditioning score was strongly and positively correlated with mean ventral lesion volume (r=0.642, p<0.001). Interestingly, stereotypic behaviors were attenuated in rats with dorsal predominat dopaminergic denervation.

Conclusions: In this study we show that development of DDS in PD may be related to the severity of ventral striatal dopaminergic denervation. On the other hand, we found that stereotypies were decreased in rats with dorsal predominant dopaminergic depletion. We think that the insufficiency of classical stereotypy scales in evolution of the rich repetitive behavioral repertoire in subjects with dopamine depleted striatum may accounted on this finding.

References: 1.            Canales, J.J. and A.M. Graybiel, A measure of striatal function predicts motor stereotypy. Nat Neurosci, 2000. 3(4): p. 377-83.

2.            Ouachikh, O., et al., Differential behavioral reinforcement effects of dopamine receptor agonists in the rat with bilateral lesion of the posterior ventral tegmental area. Behav Brain Res, 2013. 252: p. 24-31.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/differential-effects-of-ventral-or-dorsal-predominant-dopaminerjic-denervation-of-striatum-on-development-of-dopamine-dysregulation-syndrome-and-punding-in-a-rat-model-of-parkinsonism/