Abstract
Here, we report the association between depressive behavior (anhedonia) and astroglial expression of 5-hydroxytryptamine receptor 2B (5-HT2B) in an animal model of Parkinson’s disease, induced by bilateral injection of 6-hydroxydopamine (6-OHDA) into the striatum. Expression of the 5-HT2B receptor at the mRNA and protein level was decreased in the brain tissue of 6-OHDA-treated animals with anhedonia. Expression of the 5-HT2B receptor was corrected by four weeks treatment with either l-3,4-dihydroxyphenylalanine (l-dopa) or fluoxetine. Simultaneously, treatment with l-dopa abolished 6-OHDA effects on both depressive behavior and motor activity. In contrast, fluoxetine corrected 6-OHDA-induced depression but did not affect 6-OHDA-induced motor deficiency. In addition, 6-OHDA downregulated gene expression of the 5-HT2B receptor in astrocytes in purified cell culture and this downregulation was corrected by both l-dopa and fluoxetine. Our findings suggest that 6-OHDA-induced depressive behavior may be related to the downregulation of gene expression of the 5-HT2B receptor but 6-OHDA-induced motor deficiency reflects, arguably, dopamine depletion. Previously, we demonstrated that fluoxetine regulates gene expression in astrocytes by 5-HT2B receptor-mediated transactivation of epidermal growth factor receptor (EGFR). However, the underlying mechanism of l-dopa action remains unclear. The present work indicates that the decrease of gene expression of the astroglial 5-HT2B receptor may contribute to development of depressive behavior in Parkinson’s disease.
Highlights
Parkinson’s disease (PD) is characterized by a progressive degeneration of dopaminergic midbrain neurons in the substantia nigra pars compacta (SNpc) [1] and becomes clinically manifest when more than 50% of SNpc neurons are lost
We found that expression of 5-hydroxytryptamine receptor 2B (5-HT2B) receptors as well as other signaling molecules is suppressed in astrocytes but not in neurons in the cerebral cortex of anhedonic animals, which experienced chronic mild stress (CMS) [11,12]
We reported that the decrease of gene expression of astrocytic 5-HT2B receptor parallels the development of depressive behavior in the MPTP mouse model of PD, while fluoxetine ameliorates both the decrease in 5-HT2B receptor expression and anhedonia [13]
Summary
Parkinson’s disease (PD) is characterized by a progressive degeneration of dopaminergic midbrain neurons in the substantia nigra pars compacta (SNpc) [1] and becomes clinically manifest when more than 50% of SNpc neurons are lost. In addition to motor symptoms, which include resting tremor, slowness of movement, rigidity, and postural instability, the non-motor symptoms, such as cognitive deficits and behavioral abnormalities, have been recognized as integral part of the clinical presentation of PD [2]. Depression is the frequent psychiatric signature of the PD and it is one of the most significant factors affecting the quality of life of patients [3]. Neuroglia 2018, 1 system is affected in PD patients and in some animal models [4], while 5-hydroxytryptamine (5-HT). It is generally acknowledged that the morbid changes associated with depression include profound remodeling of neuroglia, and the contribution of astrocytes to the pathogenesis of various neuropsychiatric disorders is well appreciated [8,9]
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