Abstract
Background: Lead neurotoxicity is a major health problem known as a risk factor for neurodegenerative diseases, including the manifestation of parkinsonism-like disorder. While lead is known to preferentially accumulate in basal ganglia, the mechanisms underlying behavioral disorders remain unknown. Here, we investigated the neurophysiological and biochemical correlates of motor deficits induced by sub-chronic injections of lead.Methods: Sprague Dawely rats were exposed to sub-chronic injections of lead (10 mg/kg, i.p.) or to a single i.p. injection of 50 mg/kg N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride (DSP-4), a drug known to induce selective depletion of noradrenaline. Rats were submitted to a battery of behavioral tests, including the open field for locomotor activity and rotarod for motor coordination. Electrophysiological recordings were carried out in three major basal ganglia nuclei, the subthalamic nucleus (STN), globus pallidus (GP), and substantia nigra pars reticulata (SNr). At the end of experiments, post-mortem tissue level of the three monoamines (dopamine, noradrenaline, and serotonin) and their metabolites has been determined using HPLC.Results: Lead intoxication significantly impaired exploratory and locomotor activity as well as motor coordination. It resulted in a significant reduction in the level of noradrenaline in the cortex and dopamine and its metabolites, DOPAC, and HVA, in the striatum. The tissue level of serotonin and its metabolite 5-HIAA was not affected in the two structures. Similarly, DSP-4, which induced a selective depletion of noradrenaline, significantly decreased exploratory, and locomotor activity as well as motor coordination. L-DOPA treatment did not improve motor deficits induced by lead and DSP-4 in the two animal groups. Electrophysiological recordings showed that both lead and DSP-4 did not change the firing rate but resulted in a switch from the regular normal firing to irregular and bursty discharge patterns of STN neurons. Neither lead nor DSP-4 treatments changed the firing rate and the pattern of GP and SNr neurons.Conclusions: Our findings provide evidence that lead represents a risk factor for inducing parkinsonism-like deficits. As the motor deficits induced by lead were not improved by L-DOPA, we suggest that the deficits may be due to the depletion of noradrenaline and the parallel disorganization of STN neuronal activity.
Highlights
Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the manifestation of motor symptoms, which are mainly attributed to the loss of dopaminergic neurons in the substantia nigra pars compacta (SNc) (Ehringer and Hornykiewicz, 1960)
It is well established that the degeneration of the monoaminergic systems caused a disorganization of the neuronal activity in the subthalamic nucleus (STN), a basal ganglia structure playing a key role in the pathophysiology of PD
We investigated the effects of sub-chronic low-dose lead intoxication and NA depletion, induced by a systemic administration of the neurotoxin N-(2-chloroethyl)Nethyl-2-bromobenzylamine (DSP-4) (Lapiz et al, 2000; Delaville et al, 2012a,b), on locomotor activity and motor coordination, on the tissue content of the three monoamines and their metabolites, and on the neuronal activity of the three major basal ganglia nuclei, the STN, globus pallidus (GP), and substantia nigra (SNr)
Summary
Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the manifestation of motor symptoms, which are mainly attributed to the loss of dopaminergic neurons in the substantia nigra pars compacta (SNc) (Ehringer and Hornykiewicz, 1960). The regular pattern of the neuronal activity of the STN becomes irregular and bursty in animal models of PD (Bergman et al, 1994; Ni et al, 2001; Belujon et al, 2007; Delaville et al, 2012a) and in PD patients (Hutchison et al, 1998; Benazzouz et al, 2002). Delaville et al (2012a,b) have shown that NA depletion increased the proportion of bursty and irregular neurons in the STN without affecting the neuronal activity of globus pallidus (GP) and the pars reticulata of substantia nigra (SNr). We investigated the neurophysiological and biochemical correlates of motor deficits induced by sub-chronic injections of lead
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