Dysregulation of Dopaminergic Regulatory Factors TH, Nurr1, and Pitx3 in the Ventral Tegmental Area Associated with Neuronal Injury Induced by Chronic Morphine Dependence.

Weibo Shi,Yaxing Zhang,Songjun Wang,Guozhong Zhang,Guoting Zhao,Yingmin Li,Bin Cong,Chunling Ma

doi:10.3390/ijms20020250

Weibo Shi, Yaxing Zhang + Show 6 more

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https://doi.org/10.3390/ijms20020250

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Abstract

The ventral tegmental area (VTA), a critical portion of the mesencephalic dopamine system, is thought to be involved in the development and maintenance of addiction. It has been proposed that the dopaminergic regulatory factors TH, Nurr1, and Pitx3 are crucial for determining the survival and maintenance of dopaminergic neurons. Thus, the present study investigated whether abnormalities in these dopaminergic regulatory factors in the VTA were associated with neuronal injury induced by chronic morphine dependence. Rat models with different durations of morphine dependence were established. Thionine staining was used to observe morphological changes in the VTA neurons. Immunohistochemistry and western blot were used to observe changes in the expression of the dopaminergic regulatory proteins TH, Nurr1, and Pitx3. Thionine staining revealed that prolonged morphine dependence resulted in dopaminergic neurons with edema, a lack of Nissl bodies, and pyknosis. Immunohistochemistry showed that the number of TH+, Nurr1+, and Pitx3+ cells, and the number of TH+ cells expressing Nurr1 or Pitx3, significantly decreased in the VTA after a long period of morphine dependence. Western blot results were consistent with the immunohistochemistry findings. Chronic morphine exposure resulted in abnormalities in dopaminergic regulatory factors and pathological changes in dopaminergic neurons in the VTA. These results suggest that dysregulation of dopaminergic regulatory factors in the VTA are associated with neuronal injury induced by chronic morphine dependence.

Highlights

Morphine is a common analgesic drug that is highly efficient and is highly addictive
The ventral tegmental area (VTA), a critical part of the mesencephalic dopamine system, participates in almost all of the rewarding effects of drug dependence and is thought to be the key brain region involved in the development and maintenance of addiction [3,4]
The mesencephalic dopamine system is the key brain region involved in the development and maintenance of addiction [3,4]

Summary

Introduction

Morphine is a common analgesic drug that is highly efficient and is highly addictive. The ventral tegmental area (VTA), a critical part of the mesencephalic dopamine system, participates in almost all of the rewarding effects of drug dependence and is thought to be the key brain region involved in the development and maintenance of addiction [3,4]. Nurr is an orphan member of the nuclear receptor superfamily of transcription factors and is critical for the differentiation, migration, maturity, and survival of dopaminergic neurons in the mesencephalon [13,14], as well as being partially involved with non-dopaminergic neurons [15,16,17]. The gene encoding Pitx is expressed exclusively in mesencephalic dopaminergic neurons and activates the transcription of genes directly involved in the survival and maintenance of these neurons It remains unclear what effects TH, Nurr, and Pitx have on dopaminergic neurons relating to morphine dependence. The findings of the present study provide evidence of the mechanisms of nerve injury induced by chronic morphine dependence

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