Methylphenidate alleviates cognitive dysfunction caused by early manganese exposure: Role of catecholaminergic
Stephane A Beaudin1, Shanna Howard1, Nicholas Santiago1
1Department of Microbiology and Environmental Toxicology, University of California, Santa Cruz, CA, USA.
Abstract:
Environmental manganese (Mn) exposure is associated with impaired attention and psychomotor functioning, as well as impulsivity/hyperactivity in children and adolescents. We have shown previously that developmental Mn exposure can cause these same dysfunctions in a rat model. Methylphenidate (MPH) lessens impairments in attention, impulse control, and psychomotor function in children, but it is unknown whether MPH ameliorates these dysfunctions when induced by developmental Mn exposure. Here, we sought to (1) determine whether oral MPH treatment ameliorates the lasting attention and sensorimotor impairments caused by developmental Mn exposure, and (2) elucidate the mechanism(s) of Mn neurotoxicity and MPH effectiveness. Rats were given 50 mg Mn/kg/d orally over PND 1-21 and assessed as adults in a series of attention, impulse control and sensorimotor tasks during oral MPH treatment (0, 0.5, 1.5, or 3.0 mg/kg/d). Subsequently, selective catecholaminergic receptor antagonists were administered to gain insight into the mechanism(s) of action of Mn and MPH. Developmental Mn exposure caused persistent attention and sensorimotor impairments. MPH treatment at 0.5 mg/kg/d completely ameliorated the Mn attentional dysfunction, whereas the sensorimotor deficits were ameliorated by the 3.0 mg/kg/d MPH dose. Notably, the MPH benefit on attention was only apparent after prolonged treatment, while MPH efficacy for the sensorimotor deficits emerged early in treatment. Selectively antagonizing D1, D2, or α2A receptors had no effect on the Mn-induced attentional dysfunction or MPH efficacy in this domain. However, antagonism of D2R attenuated the Mn sensorimotor deficits, whereas the efficacy of MPH to ameliorate those deficits was diminished by D1R antagonism. These findings demonstrate that MPH is effective in alleviating the lasting attentional and sensorimotor dysfunction caused by developmental Mn exposure, and they clarify the mechanisms underlying developmental Mn neurotoxicity and MPH efficacy. Given that the cause of attention and psychomotor deficits in children is often unknown, these findings have implications for the treatment of environmentally induced attentional and psychomotor dysfunction in children more broadly.
Insights
Methylphenidate (MPH) effectively treats attention and sensorimotor deficits caused by developmental manganese (Mn) exposure in rats. MPH shows dose-dependent efficacy, highlighting its potential for treating environmentally induced neurodevelopmental disorders.
Area of Science:
- Neuroscience
- Environmental Health
- Pharmacology
Background:
- Environmental manganese (Mn) exposure is linked to attention and psychomotor deficits in children.
- Developmental Mn exposure induces similar dysfunctions in a rat model.
- Methylphenidate (MPH) improves attention and psychomotor function in children, but its efficacy against Mn-induced deficits is unknown.
Purpose of the Study:
- To determine if oral MPH treatment ameliorates lasting attention and sensorimotor impairments from developmental Mn exposure.
- To elucidate the mechanisms of Mn neurotoxicity and MPH effectiveness in this context.
Main Methods:
- Rats received oral Mn (50 mg/kg/d) during postnatal days 1-21.
- Adult rats were assessed in attention, impulse control, and sensorimotor tasks during MPH treatment (0-3.0 mg/kg/d).
- Catecholaminergic receptor antagonists were used to explore mechanisms of Mn neurotoxicity and MPH action.
Main Results:
- Developmental Mn exposure caused persistent attention and sensorimotor impairments.
- MPH (0.5 mg/kg/d) fully ameliorated attentional deficits; higher doses (3.0 mg/kg/d) improved sensorimotor deficits.
- D2 receptor antagonism reduced Mn sensorimotor deficits, while D1 receptor antagonism diminished MPH's efficacy for these deficits.
Conclusions:
- MPH effectively alleviates lasting attention and sensorimotor dysfunction induced by developmental Mn exposure.
- Findings clarify mechanisms of Mn neurotoxicity and MPH efficacy, involving specific catecholaminergic pathways.
- Results have implications for treating environmentally induced neurodevelopmental disorders in children.
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