Abnormal Motor Function and the Expression of Striatal Dopamine D2 Receptors in Manganese-Treated Mice

Abstract

Manganese (Mn) exists in a number of physical and chemical forms in the environment, and is an essential trace metal, necessary for normal cellular functioning. 1) In the brain, Mn is a cofactor for some metalloprotein enzymes, including Mn-superoxide dismutase and glutamine synthetase.2,3) Although Mn is an essential element, excessive exposure to Mn can be toxic to the brain. Mn overload may lead to a neurological disorder similar to Parkinson's disease, called "manganism". 4,5) However, unlike Parkinson's disease, in which neurodegeneration occurs primarily in the substantia nigra pars compacta, Mn intoxication in human and animal models results in prominent neuronal loss and gliosis in the globus pallidus and striatum.6) The symptoms associated with Mn toxicity are neuropsychiatric and behavioral deficits, including poor motor coordination. 7)Although the mechanisms underlying Mn neurotoxicity remain unclear, research on the neurobiological consequences of Mn toxicity has largely focused on dopamine metabolism and associated behavioral alterations. Mn may alter the biochemical pathway involving brain dopamine systems in children with attention deficit hyperactivity disorder, 8) and alters dopamine levels in both neonatal and older rats. 9) These observations suggest that Mn may exert its neurotoxic effect(s), at least in part, by disturbing dopaminergic neurotransmission.The neurotransmitter dopamine plays important roles in many brain functions, including locomotor activity, cognition, emotion, positive reinforcement, food intake, and endocrine regulation.10) Dopamine biosynthesis is regulated by tyrosine hydroxylase (TH), a rate-limiting enzyme in the synthesis of catecholamine. Moreover, dopamine affects neurons through dopamine receptors (DR) of two categories (D1-like and D2-like), according to pharmacological and biochemical properties. The D1-like subtype includes the D1 and D5 receptors, while the D2-like subtype consists of the D2, D3, and D4 receptors.11) The D1-like receptors interact with Gproteins that stimulate adenylate cyclase activity, while D2-like receptors inhibit adenylate cyclase activity.12) Most studies that have examined the effects of Mn neurotoxicity and dopamine receptors have focused on the D2 receptor, which is implicated in many of the behavioral alterations observed in subjects exposed to Mn. 13)We investigated whether acute exposure to Mn may change motor activity and the expression of TH and the dopamine D2-like receptors D2 (DRD2), D3 (DRD3), and D4 (DRD4) at the mRNA and protein level in the striatum of the mouse brain. MATERIALS AND METHODS Animals and TreatmentExperiments were approved by the Institutional Animal Care and Use Committee of Keimyung University, Korea. Experiments were conducted according to the NIH guidelines for the care and use of laboratory animals. Animals were housed in an Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC)-accredited facility, with free access to food and water.C57BL/6 mice (nϭ24, 8-week-old males, weighin...

Mapping of functional brain activity in freely behaving rats during voluntary running using manganese-enhanced MRI: Implication for longitudinal studies

“…Various symptoms of manganese toxicity are routinely tested in animals (Burton and Guilarte, 2009;Calabresi et al, 2001;Gwiazda et al, 2007;Newland, 1999;Olanow et al, 1996;Shukakidze et al, 2003). In particular, the effect of manganese on motor function has been reliably reproduced in different animals and experimental paradigms; this effect is apparent across a wide range of doses, different routes of administration and chemical species of manganese (Calabresi et al, 2001;Dodd et al, 2005;Mohammad and Faris, 2006;Nam and Kim, 2008;Newland and Weiss, 1992;Normandin et al, 2004). Manganese treatment typically results in decreased motor activity or disturbances in motor coordination, although a manganese-induced hyperactivity has also been reported (Calabresi et al, 2001;Eriksson et al, 1987).…”

“…Although the mechanisms underlying manganese neurotoxicity remain unclear, experimental evidence exists that manganese may affect dopaminergic and cholinergic neuromodulatory systems, which may lead to various cognitive and neurological disorders including motor dysfunction (Calabresi et al, 2001;Eriksson et al, 1987;Nam and Kim, 2008;Newland and Weiss, 1992;Olanow et al, 1996). Taking this into account, a successful application of MEMRI technique for longitudinal studies, particularly involving behaving animals, critically depends on the manganese administration regimen that does not or minimally compromise homeostatic capacity, while achieving MRI-detectable cumulative concentration of Mn 2+ in the brain.…”

“…In general, various forms of locomotor activity are used as an indicator of manganese toxicity (Calabresi et al, 2001;Gwiazda et al, 2007;Nam and Kim, 2008;Newland and Weiss, 1992). In the present study, we demonstrated a significant decrease in rat running activity after a single systemic injection of all tested doses of MnCl 2 (16-80 mg/kg) using the voluntary wheel running model.…”

Behavioral, electrophysiological and histopathological consequences of systemic manganese administration in MEMRI

“…The choice accuracy in the task was not affected by any Mn 2+ dose. However, the response latency was increased in Mn-treated rats receiving the highest concentration, likely reflecting the Mn-induced motor disturbances described in toxicology studies [22][23][24][25]. Adverse acute side effects of Mn 2+ on animal general well-being (e.g., drowsiness) may also contributed to the impaired motor performance on the T-maze.…”

Short-term manganese inhalation decreases brain dopamine transporter levels without disrupting motor skills in rats

“…Many studies using animals have also demonstrated a positive relationship between Mn deposition in the brain and subsequent neurochemical and behavioral changes. For example, Normandin et al demonstrated that Mn was deposited in the brain of the rats following exposure to 3 mg Mn/m 3 via inhalation (Normandin et al, 2004;Tapin et al, 2006) and exposure through drinking water (Nachtman et al, 1986) and both intra-striatal (Inoue et al, 1975) and intraperitoneal (Nam and Kim, 2008) injections of Mn all resulted in behavioral changes in rats. Intranasal instillation of Mn in mice and rats also alters behavioral organization and impairs neurochemical homeostasis (Kim et al, 2012;Kim, 2015a, 2015b).…”