Destruction of Dopaminergic Neurons in the Midbrain by 6-Hydroxydopamine Decreases Hippocampal Cell Proliferation in Rats: Reversal by Fluoxetine

Katsuaki Suzuki,Hideo Matsuzaki,Keiko Iwata,Tomoyasu Wakuda,Norio Mori,Kyoko Okada,Kenji Hashimoto,Yasuhide Iwata,Shiro Suda,Taro Takahashi,Yosuke Kameno,Chie Shinmura

doi:10.1371/journal.pone.0009260

Abstract

BackgroundNon-motor symptoms (e.g., depression, anxiety, and cognitive deficits) in patients with Parkinson disease (PD) precede the onset of the motor symptoms. Although these symptoms do not respond to pharmacological dopamine replacement therapy, their precise pathological mechanisms are currently unclear. The present study was undertaken to examine whether the unilateral 6-hydroxydopamine (6-OHDA) lesion to the substantia nigra pars compacta (SNc), which represents a model of long-term dopaminergic neurotoxicity, could affect cell proliferation in the adult rat brain. Furthermore, we examined the effects of the selective serotonin reuptake inhibitor (SSRI) fluoxetine and the selective noradrenaline reuptake inhibitor maprotiline on the reduction in cell proliferation in the subgranular zone (SGZ) by the unilateral 6-OHDA lesion.Methodology/Principal FindingsA single unilateral injection of 6-OHDA into the rat SNc resulted in an almost complete loss of tyrosine hydroxylase (TH) immunoreactivity in the striatum and SNc, as well as in reductions of TH-positive cells and fibers in the ventral tegmental area (VTA). On the other hand, an injection of vehicle alone showed no overt change in TH immunoreactivity. A unilateral 6-OHDA lesion to SNc significantly decreased cell proliferation in the SGZ ipsilateral to the 6-OHDA lesion, but not in the contralateral SGZ or the subventricular zone (SVZ), of rats. Furthermore, subchronic (14 days) administration of fluoxetine (5 mg/kg/day), but not maprotiline significantly attenuated the reduction in cell proliferation in the SGZ by unilateral 6-OHDA lesion.Conclusions/SignificanceThe present study suggests that cell proliferation in the SGZ of the dentate gyrus might be, in part, under dopaminergic control by SNc and VTA, and that subchronic administration of fluoxetine reversed the reduction in cell proliferation in the SGZ by 6-OHDA. Therefore, SSRIs such as fluoxetine might be potential therapeutic drugs for non-motor symptoms as well as motor symptoms in patients with PD, which might be associated with the reduction in cell proliferation in the SGZ.

Highlights

Parkinson’s disease (PD) is a chronic and progressive neurodegenerative disease with multiple motor and non-motor features that contribute to the impairment of health-related quality of life (QOL)
A single unilateral injection of 6-OHDA into the midbrain resulted in an almost complete loss of tyrosine hydroxylase (TH) immunoreactivity in the striatum (Fig. 2B) and substantia nigra pars compacta (SNc) (Fig. 2D, F), and in reductions in the number of TH-positive cells and fibers in the ventral tegmental area (VTA) (Fig. 2H), while an injection of vehicle alone showed no overt change in TH immunoreactivity (Fig. 2A, C, E and G)
Using BrdU immunohistochemistry, we examined the effect of the loss of dopaminergic projection on cell proliferation in the subventricular zone (SVZ) of the lateral ventricle and the subgranular zone (SGZ) of the dentate gyrus of the hippocampus

Summary

Introduction

Parkinson’s disease (PD) is a chronic and progressive neurodegenerative disease with multiple motor and non-motor features that contribute to the impairment of health-related quality of life (QOL). Non-motor symptoms, including depression and anxiety, occur after the onset of motor symptoms and may develop many years, even decades, before the onset of PD, suggesting these neuropsychiatric symptoms are risk factors for the development of PD [11,12,13]. These data suggest the need for earlier evaluation and treatment of non-motor symptoms (e.g., depression, anxiety, and cognitive deficits) in PD, which potentially could improve health-related QOL and patient productivity while reducing morbidity and minimizing direct and indirect healthcare costs [11]. We examined the effects of the selective serotonin reuptake inhibitor (SSRI) fluoxetine and the selective noradrenaline reuptake inhibitor maprotiline on the reduction in cell proliferation in the subgranular zone (SGZ) by the unilateral 6-OHDA lesion

Methods

Results

Conclusion