Lead-Induced Atypical Parkinsonism in Rats: Behavioral, Electrophysiological, and Neurochemical Evidence for a Role of Noradrenaline Depletion.

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.

The Suprachiasmatic Nucleus of the Dromedary Camel (Camelus dromedarius): Cytoarchitecture and Neurochemical Anatomy.

In mammals, biological rhythms are driven by a master circadian clock located in the suprachiasmatic nucleus (SCN) of the hypothalamus. Recently, we have demonstrated that in the camel, the daily cycle of environmental temperature is able to entrain the master clock. This raises several questions about the structure and function of the SCN in this species. The current work is the first neuroanatomical investigation of the camel SCN. We carried out a cartography and cytoarchitectural study of the nucleus and then studied its cell types and chemical neuroanatomy. Relevant neuropeptides involved in the circadian system were investigated, including arginine-vasopressin (AVP), vasoactive intestinal polypeptide (VIP), met-enkephalin (Met-Enk), neuropeptide Y (NPY), as well as oxytocin (OT). The neurotransmitter serotonin (5-HT) and the enzymes tyrosine hydroxylase (TH) and aromatic L-amino acid decarboxylase (AADC) were also studied. The camel SCN is a large and elongated nucleus, extending rostrocaudally for 9.55 ± 0.10 mm. Based on histological and immunofluorescence findings, we subdivided the camel SCN into rostral/preoptic (rSCN), middle/main body (mSCN) and caudal/retrochiasmatic (cSCN) divisions. Among mammals, the rSCN is unusual and appears as an assembly of neurons that protrudes from the main mass of the hypothalamus. The mSCN exhibits the triangular shape described in rodents, while the cSCN is located in the retrochiasmatic area. As expected, VIP-immunoreactive (ir) neurons were observed in the ventral part of mSCN. AVP-ir neurons were located in the rSCN and mSCN. Results also showed the presence of OT-ir and TH-ir neurons which seem to be a peculiarity of the camel SCN. OT-ir neurons were either scattered or gathered in one isolated cluster, while TH-ir neurons constituted two defined populations, dorsal parvicellular and ventral magnocellular neurons, respectively. TH colocalized with VIP in some rSCN neurons. Moreover, a high density of Met-Enk-ir, 5-HT-ir and NPY-ir fibers were observed within the SCN. Both the cytoarchitecture and the distribution of neuropeptides are unusual in the camel SCN as compared to other mammals. The presence of OT and TH in the camel SCN suggests their role in the modulation of circadian rhythms and the adaptation to photic and non-photic cues under desert conditions.

Circadian Clock Protein Content and Daily Rhythm of Locomotor Activity Are Altered after Chronic Exposure to Lead in Rat.

Lead exposure has been reported to produce many clinical features, including parkinsonism. However, its consequences on the circadian rhythms are still unknown. Here we aimed to examine the circadian rhythms of locomotor activity following lead intoxication and investigate the mechanisms by which lead may induce alterations of circadian rhythms in rats. Male Wistar rats were injected with lead or sodium acetate (10 mg/kg/day, i.p.) during 4 weeks. Both groups were tested in the "open field" to quantify the exploratory activity and in the rotarod to evaluate motor coordination. Then, animals were submitted to continuous 24 h recordings of locomotor activity under 14/10 Light/dark (14/10 LD) cycle and in complete darkness (DD). At the end of experiments, the clock proteins BMAL1, PER1-2, and CRY1-2 were assayed in the suprachiasmatic nucleus (SCN) using immunohistochemistry. We showed that lead significantly reduced the number of crossing in the open field, impaired motor coordination and altered the daily locomotor activity rhythm. When the LD cycle was advanced by 6 h, both groups adjusted their daily locomotor activity to the new LD cycle with high onset variability in lead-intoxicated rats compared to controls. Lead also led to a decrease in the number of immunoreactive cells (ir-) of BMAL1, PER1, and PER2 without affecting the number of ir-CRY1 and ir-CRY2 cells in the SCN. Our data provide strong evidence that lead intoxication disturbs the rhythm of locomotor activity and alters clock proteins expression in the SCN. They contribute to the understanding of the mechanism by which lead induce circadian rhythms disturbances.

Consequences of manganese intoxication on the circadian rest-activity rhythms in the rat.

Manganese (Mn) intoxication is associated with neurological dysfunctions collectively known as Parkinsonism or Manganism. Like in Parkinson's disease, Manganism is associated with motor disturbances, together with non-motor symptoms including cognitive and neuropsychiatric deficits. Although sleep dysfunctions are commonly reported among workers exposed to Mn, their underlying pathophysiology remains unknown. In this study, we investigated the rest-activity rhythms in rats treated daily with MnCl2 (10mg/kg, i.p) for 5weeks. Locomotor activity was assessed under a light-dark (LD) cycle, constant darkness (DD) and during adjustment to 6h shifts of the LD cycle. In LD conditions, Mn-treated rats exhibited a more fragmented and less stable rest-activity rhythm in addition to a reduction in the total 24-h amount of locomotor activity as well as in the activity confined to the active dark phase of the LD. Consequently, a significant decrease in the amplitude of the rest-activity rhythm was observed. These disturbances were displayed during and after Mn treatment. Furthermore, after the 6-h phase advance of the LD cycle, Mn-treated rats failed to re-adjust accurately their behavioral activity to the new shifted LD cycle. Upon release from LD into DD, Mn-treated rats expressed a normal and stable free-running period of their rest-activity rhythm (23.92±0.07h in Mn group vs. 24.01±0.04h in control rats). However, their rest-activity rhythm remained highly fragmented and less stable. Our results provide the first evidence that chronic Mn intoxication leads to impairment of rest-activity rhythms in addition to the motor and non-motor disturbances reported in Manganism.

Manganese neurotoxicity: behavioral disorders associated with dysfunctions in the basal ganglia and neurochemical transmission.

Manganese (Mn) is an essential element required for many physiological functions. While it is essential at physiological levels, excessive accumulation of Mn in the brain causes severe dysfunctions in the central nervous system known as manganism. Manganism is an extrapyramidal disorder characterized by motor disturbances associated with neuropsychiatric and cognitive disabilities similar to Parkinsonism. As the primary brain regions targeted by Mn are the basal ganglia, known to be involved in the pathophysiology of extrapyramidal disorders, this review will examine the impact of Mn exposure on the basal ganglia circuitry and neurotransmitters in relation to motor and non-motor disorders. The collected data from recent available studies in humans and experimental animal models provide new information about the mechanisms by which Mn affects behavior, neurotransmitters, and basal ganglia function observed in manganism. The effects of the alterations of metals on basal ganglia and neurochemical functioning are critical to develop effective modalities not only for the treatment of vulnerable populations (e.g., Mn-exposed workers) but also for understanding the etiology of neurodegenerative diseases where brain metal imbalances are involved, such as Parkinson's disease. We examine the impact of manganese (Mn) exposure on the basal ganglia circuitry and neurotransmitters in relation with motor and non-motor disorders. The collected data from available studies show that when accumulated in the globus pallidus, Mn influences the subthalamic (STN) and substantia nigra (SN) neurons, which are at the origin of changes in the thalamus and the cortex.

Monoamine content during the reproductive cycle of Perna perna depends on site of origin on the Atlantic Coast of Morocco.

Bivalve molluscs such as Perna perna display temporal cycles of reproduction that result from the complex interplay between endogenous and exogenous signals. The monoamines serotonin, dopamine and noradrenaline represent possible endocrine and neuronal links between these signals allowing the molluscs to modulate reproductive functions in conjunction with environmental constraints. Here, we report a disruption of the reproductive cycle of mussels collected from two of three sites along the Moroccan atlantic coast soiled by industrial or domestic waste. Using high pressure liquid chromatography, we show that the temporal pattern of monoamine content in the gonads, pedal and cerebroid ganglia varied throughout the reproductive cycle (resting, developing, maturing, egg-laying) of mussels from the unpolluted site. Marked modification of monoamine tissue content was found between sites, notably in noradrenaline content of the gonads. Discriminant statistics revealed a specific impact of mussel location on the temporal variations of noradrenaline and serotonin levels in gonads and cerebroid ganglia. Correlation analyses showed profound and temporal changes in the monoamine content between organs and ganglia, at the two sites where the reproduction was disrupted. We suggest that environmental constraints lead to profound changes of monoaminergic systems, which thereby compromises the entry of mussels into their reproductive cycle.

Manganese-induced atypical parkinsonism is associated with altered Basal Ganglia activity and changes in tissue levels of monoamines in the rat.

Manganese neurotoxicity is associated with motor and cognitive disturbances known as Manganism. However, the mechanisms underlying these deficits remain unknown. Here we investigated the effects of manganese intoxication on motor and non-motor parkinsonian-like deficits such as locomotor activity, motor coordination, anxiety and "depressive-like" behaviors. Then, we studied the impact of this intoxication on the neuronal activity, the globus pallidus (GP) and subthalamic nucleus (STN). At the end of experiments, post-mortem tissue level of the three monoamines (dopamine, norepinephrine and serotonin) has been determined. The experiments were carried out in adult Sprague-Dawley rats, daily treated with MnCl2 (10 mg/kg/, i.p.) for 5 weeks. We show that manganese progressively reduced locomotor activity as well as motor coordination in parallel with the manifestation of anxiety and "depressive-like" behaviors. Electrophysiological results show that, while majority of GP and STN neurons discharged regularly in controls, manganese increased the number of GP and STN neurons discharging irregularly and/or with bursts. Biochemical results show that manganese significantly decreased tissue levels of norepinephrine and serotonin with increased metabolism of dopamine in the striatum. Our data provide evidence that manganese intoxication is associated with impaired neurotransmission of monoaminergic systems, which is at the origin of changes in basal ganglia neuronal activity and the manifestation of motor and non-motor deficits similar to those observed in atypical Parkinsonism.

Physiological and pharmacological properties of 5-methoxytryptophol.

5-methoxytryptophol (5-ML) is a pineal indoleamine derived from serotonin shown to be biologically active in a number of species. This indolamine exhibits a circadian pattern synchronized with the day-night cycle with significant increases during daylight, already recognized in vertebrates. The multiplicity of physiological and endocrine functions of 5-ML is remarkable; it is involved in circadian rhythms, reproduction and sexual processes. Furthermore, a number of pharmacological benefits of 5-ML have been reported, including immunomodulatory, antitumor and antioxidative activities. However, the molecular mechanisms of these pharmacological effects remain unclear. The purpose of this article is to provide an overview on the general properties and physiological functions of 5-ML. An attempt has been made to fully document all studies performed using 5-ML. In addition, this article aims to gain insight into the current state of knowledge regarding pharmacological and therapeutic effects of this indoleamine.

Phase and period responses of the jerboa Jaculus orientalis to short light pulses.

The phase and period responses to short light pulses were studied in the jerboa, a seasonal, hibernating, nocturnal rodent from the Atlas region in Morocco. The jerboa, which is a saltatory species, showed precise activity onsets and offsets under a light-dark (LD) cycle using infrared captors to record locomotor activity. When released into constant darkness (DD), the majority of animals showed a circadian period (tau) < 24 h (mean tau = 23.89 +/- 0.13 h) and a lengthening of the activity span, alpha. Animals were subsequently exposed to up to eight 15-min light pulses, each separated by at least 2 wks, for up to 160 days in DD. During this span, most individuals maintained robust circadian rhythmicity, with clearly defined activity onsets and offsets, similar levels of total activity, duration of alpha, and percent activity occurring during the subjective night. The phase response curve (PRC) is typical of other nocturnal rodents, with light eliciting delays during late subjective day and early subjective night (CT8-CT19) and advances during late subjective night to early subjective day (CT19-CT2). A dead zone, when light had no effect on phase, is observed during mid-subjective day (CT3-CT8). A few individuals showed large (> 9 h) Type 0 phase resetting near the singularity region (CT19) that resulted in a complete phase reversal, but otherwise displayed normal phase-shifting responses at other CT times. The tau response curve showed a decrease in period from early to late subjective night with increases at other times, but these changes were small (maximum < 9 min) and highly variable. There was a distinct tendency for animals that had an initial short tau in DD to conserve a short tau during the series of light pulses and, inversely, for animals with long tau to conserve a long tau. This suggests possible constraints on the plasticity of variation of tau in relation to the endogenous period of the animal.

Testosterone-dependent and -independent mechanisms involved in the photoperiodic control of neuropeptide levels in the brain of the jerboa (Jaculus orientalis).

Vasoactive intestinal peptide (VIP) and neuropeptide Y (NPY) content in the suprachiasmatic nucleus have been shown to exhibit seasonal changes with an increase in late summer, the period of sexual quiescence in the jerboa (Jaculus orientalis). In this study, VIP content in the SCN and NPY and enkephaline (ENK) content in the geniculo-suprachiasmatic system have been assayed in wild-caught male jerboas (Jaculus orientalis) in order to determine whether these neuropeptides are controlled directly by photoperiod changes or indirectly by short photoperiod induced changes in circulating sex hormones levels. In agreement with previous studies seasonal variations occur in the VIP and NPY content in the SCN. Variations also occur in NPY content in the IGL with an increase in the period of sexual quiescence. In contrast, no seasonal changes are observed in Enk content in the IGL or the SCN. In short photoperiod conditions increases are observed in both VIP and NPY content in the SCN as well as NPY content in the IGL. Castration during the period of sexual activity (spring) or under long photoperiod which drastically reduces testosterone, also induced an increase in the levels of these neuropeptides. Testosterone implants which reproduce the sex hormonal status of the sexual activity period failed to prevent the short photoperiod-induced increase of VIP and NPY in the SCN and of NPY in the IGL. These results clearly show that the photoperiod modulates VIP and NPY in the geniculo-suprachiasmatic system both by testosterone-linked and testosterone-independent mechanisms.