Neurobehavioral effects of acute and chronic lead exposure in a desert rodent Meriones shawi: Involvement of serotonin and dopamine

https://doi.org/10.1016/j.jchemneu.2019.101689Get rights and content

Highlights

  • Lead (Pb) is a risk factor for motor and mood disorders.

  • Pb-exposure alters serotonergic and dopaminergic systems.

  • Pb affects locomotor behavior.

  • Pb induced evident anxiogenic-like effects.

Abstract

Lead (Pb) is a non physiological metal that has been implicated in toxic processes affecting several organs and biological systems, including the central nervous system. Several studies have focused on changes in lead-associated neurobehavioral and neurochemical alterations that occur due to Pb exposure. The present study evaluates the effects of acute and chronic Pb acetate exposure on serotoninergic and dopaminergic systems within the dorsal raphe nucleus, regarding motor activity and anxiety behaviours. Experiments were carried out on adult male Meriones shawi exposed to acute lead acetate intoxication (25 mg/kg b.w., 3 i.p. injections) or to a chronic lead exposure (0,5%) in drinking water from intrauterine age to adult age. Immunohistochemical staining demonstrated that both acute and chronic lead exposure increased anti-serotonin (anti-5HT) and tyrosine hydroxylase (anti-TH) immuno-reactivities in the dorsal raphe nucleus. In parallel, our results demonstrated that a long term Pb-exposure, but not an acute lead intoxication, induced behavioural alterations including, hyperactivity (open field test), and anxiogenic like-effects. Such neurobehavioral impairments induced by Pb-exposure in Meriones shawi may be related to dopaminergic and serotoninergic injuries identified in the dorsal raphe nucleus.

Introduction

Lead (Pb) is a highly neurotoxic agent that causes functional and structural abnormalities in the brain (Lidsky and Schneider, 2003; Mason et al., 2014; Toscano and Guilarte, 2005). Various adverse effects of Pb exposure on human health especially on the nervous system have been recognized (Assi et al., 2016; Oszlánczi et al., 2011; White et al., 2007). The neurological and behavioral alterations induced by Pb have been identified in children, adults, non-human primates (Rocha and Trujillo, 2019), and various animal models (Benammi et al., 2017; Cobbina et al., 2015). In brain, Pb affects glial cells (Rocha and Trujillo, 2019) by delaying the differentiation of glial progenitors and causes hypomyelination and demyelination (Coria et al., 1984). Pb interferes with galactolipid metabolic enzymes, which disrupts the developmental maturation of oligodendrocytes. In neurons, Pb affects neurotransmitters in the serotonergic system (Graham et al., 2011; Sprowles et al., 2018). This alteration disturbs certain specific behaviours including aggression and feeding (Best et al., 2010; Rocha and Trujillo, 2019). Lead exposure induces cognitive injuries, such as memory impairment (Wang et al., 2013), and disturbed spatial cognitive flexibility (Alber and Strupp, 1996). Locomotor effects are also described, comprising augmented rearing during spatial memory and reduced exploratory behavior in mice (Flores-Montoya and Sobin, 2015; Leasure et al., 2008). Similarly, a reduction in exploratory behavior and motor coordination are observed in Pb-exposed rats (Sabbar et al., 2012). Such motor injuries were accompanied by noradrenaline diminution whereas dopamine levels stay unaffected within the striatum (Sabbar et al., 2012).

The serotonin (5-hydroxytryptamine, 5-HT) and dopamine (DA) neurotransmitters are two examples of several biogenic amines widely distributed within the CNS that play an important role in a wide variety of cognitive and behavioural functions (Jacobs and Azmitia, 1992​; Nieoullon, 2002; Shohamy and Adcock, 2010; Wise, 2004). The vast majority of 5-HT-containing cell bodies are located in the brainstem on, or near, the midline, especially in the raphe nuclei (Andrade and Haj-Dahmane, 2013). Among the brainstem raphe nuclei, the highest concentration of 5-HT-containing cell bodies was found in the dorsal raphe nucleus (DRN) (Abrams et al., 2004; Li et al., 2016), which is the origin of major ascending 5-HT pathways to the forebrain. It has been implicated in a wide variety of physiological functions, such as nociception, feeding, aggression, anxiety, motor control, and control of behavioural states (Abbaoui et al., 2016; Abbaoui and Gamrani, 2018, 2019; Abdellatif et al., 2017; Benammi et al., 2014a; Coccaro, 1989; John Mann, 2013; Müller and Homberg, 2015).

Catecholamines are thought to regulate motor activity in rodents, as well (Hynes and Berkowitz, 1983; Misra et al., 2009). Moreover, alterations in the functioning of catecholamines neurotransmitters have been suggested to play a role in toxic effects of Pb on the central nervous system (Sauerhoff and Arthur Michaelson, 1973). Pb induced brain dysfunction has been proposed to involve over activation of biogenic amine systems mainly at high Pb levels (Sauerhoff and Arthur Michaelson, 1973). Most studies, using rather high Pb doses were conducted on whole brains and measured the endogenous levels of catecholamines, norepinephrine or dopamine, amino acid precursor and tyrosine.

Thus, it was important to study the effect of acute and chronic Pb exposure on the serotonin and dopamine systems, particularly in the dorsal raphe nucleus that contains the major part of serotonin and dopamine cells in part and the relationship between these neurotransmitters and behaviour, especially, locomotor performance and anxiety state.

Section snippets

Animals

In this study, we used male meriones, weighing 80–100 g. Animals were requested, approved and delivered by the central animal-care facilities of Cadi Ayyad University, Marrakech (UCAM), Morocco. All meriones were retained at constant temperature (25◦C) on a 12-h dark–light cycle. All animals had ad libitum access to water and food. All Meriones treatments were completed with respect to the UCAM guidelines. All procedures were in accordance to February 1, 2013 European decree, related to the

Dark/light box test

Animals subjected chronically to lead exposure showed a significant (p < 0,05) (F = 7,625) enhancement of the time spent in the dark box in comparison with the control group (Fig. 1). However, in acutely Pb-exposed Meriones a small increase of the time spent in the dark chamber was seen without being statistically significant (Fig. 1).

Open field test

The chronic administration of lead acetate induced a significant increase (p < 0,05) (F = 6,426) in locomotor activity during a 20 min trial period compared to

Discussion

Our results show that Pb-exposure, especially chronic intoxication, altered Meriones behaviour. We observed an enhancement of locomotor activity and increased anxiety-related behaviours. The 5-HT and TH immunolabeling showed significant augmentation of both neuronal systems in the dorsal raphe nucleus of Pb-exposed animals in comparison to controls, especially in the dorsal raphe nucleus caudal part (DRC) and dorsal part (DRD) that have been involved as important components of stress and

Conclusion

The Pb doses and behavioural protocols are highly variable and have led to different results in the literature. In general, several works seem to be agreement that exposure to Pb damaged locomotor activity both in experimental animal models and in humans (Rocha and Trujillo, 2019). The study herein demonstrated an evident neurotoxic effect of Pb leading to serotonergic and dopaminergic injuries. Such effects disturbed anxiety state and locomotor performance in the semi desert rodent Meriones

Declaration of Competing Interest

The authors declare that there are no conflicts of interest.

Acknowledgements

We acknowledge Dr. Reem Abdelwahab Elsaadany and Dr. Abdalrhman Mostafa Mokhtar from Mansoura University, Egypt, for English revision.

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