Oral methylphenidate alleviates the fine motor dysfunction caused by chronic postnatal manganese exposure in adult rats

• Published in: Toxicological sciences 2015-04, Vol.144 (2), p.318-327
• Main Authors: Beaudin, Stéphane A, Strupp, Barbara J, Lasley, Stephen M, Fornal, Casimir A, Mandal, Shyamali, Smith, Donald R
• Format: Article
• Language: English
• Subjects: Administration, Oral; Animals; Central Nervous System Stimulants - administration & dosage; Central Nervous System Stimulants - pharmacology; Male; Manganese - administration & dosage; Manganese - toxicity; Methylphenidate - administration & dosage; Methylphenidate - pharmacology; Motor Activity - drug effects; Rats; Rats, Long-Evans; Treatment of Manganese Impairment by Methylphenidate
• ISSN: 1096-6080; 1096-0929
• DOI: 10.1093/toxsci/kfv007

Developmental manganese (Mn) exposure is associated with motor dysfunction in children and animal models, but little is known about the underlying neurochemical mechanisms or the potential for amelioration by pharmacotherapy. We investigated whether methylphenidate (MPH) alleviates fine motor dysfunction due to chronic postnatal Mn exposure, and whether Mn exposure impairs brain extracellular dopamine (DA) and norepinephrine (NE) in the prefrontal cortex (PFC) and striatum in adult animals. Rats were orally exposed to 0 or 50 mg Mn/kg/day from postnatal day 1 until the end of the study (PND 145). The staircase test was used to assess skilled forelimb function. Oral MPH (2.5 mg/kg/day) was administered daily 1 h before staircase testing for 16 days. DA and NE levels were measured by dual probe microdialysis. Results show that Mn exposure impaired reaching and grasping skills and the evoked release of DA and NE in the PFC and striatum of adult rats. Importantly, oral MPH treatment fully alleviated the fine motor deficits in the Mn-exposed animals, but did not affect forelimb skills of control rats not exposed to Mn. These results suggest that catecholaminergic hypofunctioning in the PFC and striatum may underlie the Mn-induced fine motor dysfunction, and that oral MPH pharmacotherapy is an effective treatment approach for alleviating this dysfunction in adult animals. The therapeutic potential of MPH for the treatment of motor dysfunction in Mn-exposed children and adults appears promising pending further characterization of MPH efficacy in other functional areas (eg, attention) believed to be affected by developmental Mn exposure.