l-Dopa and Fluoxetine Upregulate Astroglial 5-HT2B Receptors and Ameliorate Depression in Parkinson’s Disease Mice

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.

Structure, Function, and Pharmaceutical Ligands of 5-Hydroxytryptamine 2B Receptor

“…Increasing evidence has suggested that astroglial 5-HT 2B R is involved in depression [96]. In both 1-methyl-4phenyl-1,2,3,6-tetrahydropyridine-induced and 6-hydroxydopamine-induced Parkinson's disease mouse models [97,98], the decrease of astroglial 5-HT 2B R expression paralleled the development of depressive behavior. Treatment with fluoxetine corrected both the decrease of astroglial 5-HT 2B R expression and depressive behavior.…”

Neuroglia: Realising their true potential

“…Reactive astrogliosis represents a complex remodelling of astrocytes, accompanied by changes in gene expression and functional changes; astrogliosis is a genuinely defensive and evolutionarily conserved response, the inhibition of which, as a rule, exacerbates neuropathological development and jeopardises post lesion regeneration (Burda and Sofroniew, 2014). Hence, astrocytes are therapeutic targets for promoting neuroprotection, for example, in stroke and Parkinson’s disease (Song et al, 2018; Vermehren et al, 2018). The astroglial component of neuropathology is highly variable and is often disease specific.…”