Investigation of Behavioral Dysfunctions Induced by Monoamine Depletions in a Mouse Model of Parkinson's Disease.

Yong Li,Lingling Jiao,Hong Jiang,Shuaishuai Han,Xixun Du,Qian Jiao,Mingxia Bi

doi:10.3389/fncel.2018.00241

Abstract

Parkinson's disease (PD) is characterized not only by typical motor symptoms, but also by nonmotor symptoms in the early stages. In addition to the loss of dopaminergic (DAergic) neurons, progressive degenerations of noradrenergic (NA) and serotonergic (5-HT) neurons were also observed. However, the respective effects and interactions of these monoamine depletions on certain nonmotor symptoms are still largely unknown. In the present study, we performed selective depletions of NA, 5-HT and DA in mice by intraperitioneal injection of N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride (DSP-4), 4-chloro-L-phenylalanine (pCPA) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), respectively. DSP-4 led to a 34% decrease in the number of NAergic neurons in the locus coeruleus, and MPTP led to a 30% decrease in the number of DAergic neurons in the substantia nigra. Although there was no obvious change in the number of 5-HTergic neurons in the dorsal raphe nucleus after pCPA treatment, the levels of 5-HT and its metabolite in the frontal cortex and hippocampus were reduced, respectively. Locomotor activity deficit was induced by DA depletion and a decrease in traveled distance was potentiated by additional NA depletion. Despair-associated depressive-like behavior could be observed in every group. Anxiety states emerged only from the combined depletion of two or three monoamines. However, combined depletion of the three monoamines dramatically induced anhedonia, and it could also aggravate the depressive-like and anxiety behavior. Furthermore, NA depletion significantly reduced spatial learning and memory ability, which was not enhanced by additional 5-HT or DA depletion. Our data highlighted the interactive role of NA, 5-HT and DA in the motor, emotional and cognitive deficits, providing new insight into the complex orchestration of impaired monoaminergic systems that related to the pathology of PD.

Highlights

Parkinson’s disease (PD) is a common neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra (SN) and depletion of dopamine (DA) in the striatum
Significantly decreased NA and MHPG levels in the frontal cortex and hippocampus were observed in DSP-4/pCPA, DSP4/MPTP and DSP-4/pCPA/MPTP groups [two-way analysis of variance (ANOVA), F(3, 76) = 40.50 and F(3, 72) = 35.49, p < 0.001, respectively]; these decreased values were similar to that in DSP-4 group, suggesting that pCPA and/or MPTP injections did not modify by themselves tissue content of NA and its metabolite in DSP-4-injected mice
PCPA injection significantly decreased by 53% tissue level of 5-HT [one-way ANOVA, F(7, 72) = 35.74, p < 0.001, Table 2] and by 73% tissue level of 5-Hydroxyindoleacetic acid (5-HIAA) [F(7, 72) = 27.31, p < 0.001] in the frontal cortex, and decreased by 57% of 5-HT [F(7, 69) = 38.32, p < 0.001] and by 76% of 5-HIAA [F(7, 69) = 45.64, p < 0.001] in the hippocampus compared to saline-treated animals

Summary

Introduction

Parkinson’s disease (PD) is a common neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra (SN) and depletion of dopamine (DA) in the striatum. Increasing evidence implicated that other monoaminergic systems such as noradrenergic (NA) and serotonergic (5-HT) are affected in the process of PD (Fornai et al, 2007; Kish et al, 2008) The degeneration of these neurons has been shown to play essential roles in the emergence of various clinical symptoms (Delaville et al, 2012). The following studies have reported that the pathology in regions adjacent to the medulla oblongata including the locus ceruleus (LC), a principal site of NA neurons, and the dorsal raphe nuclei (DRN), a main site of 5-HT neurons, occur at stage 1 or 2, whereas the SN neuronal loss occurs at stage 3 or 4 and induces a striking motor symptom (Braak et al, 2004; Burke et al, 2008). The loss extent of 5-HT neurons in the DRN is under debate, 5HT concentrations in the putamen and caudate nucleus of dorsal striatum are highly reduced by 51–66% in PD patients (Kish, 2003; Kish et al, 2008)

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Discussion

Conclusion