Ventral striatal dopaminergic loss drives dopamine dysregulation syndrome-like behaviors in an experimental model of parkinsonism

Abstract

Objectives: This study aimed to establish an animal model to investigate the pathophysiology of these behaviors and to explore the role of ventral versus dorsal distribution of dopaminergic denervation. Materials and methods: This experimental study was conducted with 70 male Sprague-Dawley rats (mean weight: 358±43 g). A low dose of 6-hydroxydopamine (6-OHDA) or 0.9% saline was bilaterally injected into either the ventral tegmental area or the substantia nigra. Additionally, a control group of intact rats was included. The rewarding properties of apomorphine were assessed using the conditioned place preference paradigm. Stereotypical and dyskinetic behaviors were induced by daily high-dose apomorphine treatment and evaluated using two behavioral scales. At the end of the experiments, the extent of dopaminergic denervation was confirmed by tyrosine hydroxylase immunohistochemical staining. Results: All rats with dopaminergic lesions developed dyskinetic behaviors following apomorphine administration. The severity of these behaviors increased progressively and was strongly correlated with the mean lesion volume (r=0.849, p<0.001). Low-dose apomorphine induced conditioned place preference in parkinsonian rats but conditioned place avoidance in control animals. The conditioning score was higher in the ventral-dominant denervation group and moderately correlated with the mean ventral lesion volume (r=0.642, p=0.001). Conclusion: These findings suggest that the rewarding effects of dopamine replacement therapy are associated with the sensitization of the ventral striatum due to dopaminergic denervation. © 2025 Elsevier B.V., All rights reserved.