Induction of depressive-like behavior by intranigral 6-OHDA is directly correlated with deficits in striatal dopamine and hippocampal serotonin

doi:10.1016/j.bbr.2013.10.035

Behavioural Brain Research

Volume 259, 1 February 2014, Pages 70-77

https://doi.org/10.1016/j.bbr.2013.10.035 Get rights and content

Highlights

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The intranigral infusion of 6-OHDA was able to promote a depressive-like behavior.
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6-OHDA-lesioned rats exhibited a reduction in the levels of hippocampal serotonin and striatal dopamine.
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Animals that received 6-OHDA showed a decrease in swimming time and consumption of sucrose.
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There is a correlation between hippocampal serotonin and time swimming and sucrose consumption.
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There is a correlation between striatal dopamine levels and immobility time in the forced swim test.

Abstract

Among the non-motor phenomena of Parkinson's disease (PD) are depressive symptoms, with a prevalence of 40–70%. The reason for this high prevalence is not yet clear. The basal ganglia receives dopamine (DA) inputs from the substantia nigra pars compacta (SNpc), which is known to be impaired in PD patients. The neurotransmitter deficiency hypothesis of PD considers that low serotonin (5-hydroxytryptamine [5-HT]) activity in the brain in PD patients is a risk factor for depression. We investigated whether DA depletion promoted by the neurotoxin 6-hydroxydopamine (6-OHDA) is able to induce depressive-like behavior and neurotransmitter alterations that are similar to those observed in PD. To test this hypothesis, we performed intranigral injections of 6-OHDA in male Wistar rats and conducted motor behavior, depressive-like behavior, histological, and neurochemical tests. After the motor recovery period, 6-OHDA was able to produce anhedonia and behavioral despair 7, 14, and 21 days after neurotoxin infusion. These altered behavioral responses were accompanied by reductions of striatal DA. Additionally, decreases in hippocampal 5-HT content were detected in the 6-OHDA group. Notably, correlations were found between 5-HT and DA levels and swimming, immobility, and sucrose preference. Our results indicate that 6-OHDA produced depressive-like behavior accompanied by striatal DA and hippocampal 5-HT reductions. Moreover, DA and 5-HT levels were strongly correlated with “emotional” impairments, suggesting the important participation of these neurotransmitters in anhedonia and behavioral despair after 6-OHDA-induced nigral lesions.

Introduction

Parkinson's disease (PD) is the second most common neurodegenerative disease among the elderly, second only to Alzheimer's disease [1], [2]. Presently, the major clinical features of PD include the asymmetric onset of bradykinesia, rigidity, resting tremor, and disturbances in balance [3]. In addition to these motor signs of PD, comorbidities also affect these patients, leading to mental, emotional, and social impairment, thus contributing to the reduction of the quality of life of PD patients [4], [5], [6], [7].

Among the non-motor signs of PD are depressive symptoms [5], [8], [9], [10], with a prevalence of 40–70% [8], [9], [11]. The reason for this high prevalence is not yet clear. The basal ganglia receives dopamine (DA) inputs from the substantia nigra pars compacta (SNpc), which is known to be impaired in PD patients. Thus, observations of pathological features in the SNpc in depressed PD patients, though only trending toward significance, appear to be relevant and suggest that the nigrostriatal circuit is involved in PD-related depression [9].

Pathophysiological evidence indicates that serotonin (5-hydroxytryptamine [5-HT]) is altered in patients with PD-associated depression [12]. A 5-HT hypothesis has also been proposed for PD-related depression [13]. This hypothesis posits that 5-HT induces DA release in the basal ganglia, which is downregulated by 5-HT_2C receptors [14]. Decreases in 5-HT content or increases in the inhibitory activity of 5-HT_2C receptors may be associated with a decrease in dopaminergic neurotransmission in PD patients and the subsequent worsening of mood symptoms.

Changes in neural network activity in the basal ganglia may impact serotonergic neurotransmission, thus contributing to the development of depression in PD [15]. Recent studies indicate that animal models of PD are also able to produce comorbid depressive-like behaviors in PD [16], [17], [18], [19]. We previously reported that bilateral injections of 6-hydroxydopamine (6-OHDA) into the SNpc produced depressive-like behavior that was strongly correlated with impairments in striatal DA and 5-HT [20]. The objective of the present study was to investigate the time-dependent relationship between depressive-like behavior and neurochemical (i.e., striatal and hippocampal) and histological changes in a bilateral intranigral model of PD induced by 6-OHDA.

Section snippets

Animals

Male Wistar rats from our breeding colony were used, weighing 280–320 g at the beginning of the experiments. The animals were randomly housed in groups of five in polypropylene cages with wood shavings as bedding and maintained in a temperature-controlled room (22 ± 2 °C) on a 12 h/12 h light/dark cycle (lights on at 7:00 AM). The animals had free access to water and food throughout the experiment. All of the tests were performed weekly (each Tuesday) between 9:00 AM and 11:00 AM.

The studies were

Behavioral tests

In the open-field test (Fig. 1A), the 6-OHDA group exhibited a reduction of distance traveled (p < 0.01) compared with the sham group 1 day after neurotoxin exposure, reflected by significant effects of the column (F_1,62 = 9.361, p = 0.0033) and row (F_3,62 = 4.007, p = 0.0113) factors but no significant interaction (F_3,62 = 1.694, p = 0.1776). Similarly, the speed of locomotion after neurotoxin exposure was reduced in the 6-OHDA group 1 day after neurotoxin exposure compared with the sham group (p < 0.01),

Discussion

The present results showed that the animal model of 6-OHDA-induced PD produced sustained depressive-like behavior associated with striatal and hippocampal DA and 5-HT deficits, respectively. After bilateral 6-OHDA infusion, the animals exhibited marked impairments in swimming and immobility assessed in the FST and a similar pattern of anhedonia reflected by a reduction of sucrose preference. Additionally, a reduction of the neuronal population in the SNpc was consistently observed at all

Conclusions

Although the precise etiology is still unknown, deficits in monoaminergic systems appear to contribute to the onset of depression in PD. Our data showed that rats that received 6-OHDA-induced lesions in the SN exhibited depressive-like behavior from day 7 until day 21 of the study, accompanied by reductions of striatal dopamine and hippocampal serotonin.

Conflict of interest

The authors have no conflict of interest to declare.

Acknowledgments

This work was supported by grants from CNPq and CAPES, who had no further role in the study design; in the collection, analysis, and interpretation of the data; in the writing of the report; and in the decision to submit the paper for publication. CC, RA, and MABFV are recipients of CNPq fellowships. MMSL is a recipient of a Fundação Araucária – Governo do Estado do Paraná fellowship.

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Research reportInduction of depressive-like behavior by intranigral 6-OHDA is directly correlated with deficits in striatal dopamine and hippocampal serotonin

Highlights

Abstract

Introduction

Section snippets

Animals

Behavioral tests

Discussion

Conclusions

Conflict of interest

Acknowledgments

Neuron

J Neurol Sci

Exp Neurol

Parkinsonism Relat Disord

Parkinsonism Relat Disord

J Neurol Sci

Parkinsonism Relat Disord

Neuropharmacology

Neuropharmacology

Neuroscience

Neuroscience

Neurobiol Dis

Prog Neuropsychopharmacol Biol Psychiatry

Eur J Pharmacol

Behav Brain Res

J Neurosci Methods

Exp Neurol

Parkinsonism Relat Disord

Prog Neurobiol

Research report
Induction of depressive-like behavior by intranigral 6-OHDA is directly correlated with deficits in striatal dopamine and hippocampal serotonin