ABSTRACT
Studies in children have reported associations between elevated manganese (Mn) exposure and ADHD-related symptoms of inattention, impulsivity/hyperactivity, and psychomotor impairment. Maternal choline supplementation (MCS) during pregnancy/lactation may hold promise as a protective strategy because it has been shown to lessen cognitive dysfunction caused by numerous early insults. Our objectives were to determine whether (1) developmental Mn exposure alters behavioral reactivity/emotion regulation, in addition to impairing learning, attention, impulse control, and sensorimotor function, and (2) MCS protects against these Mn-induced impairments. Pregnant Long-Evans rats were given standard diet, or a diet supplemented with additional choline throughout gestation and lactation (GD 3 - PND 21). Male offspring were exposed orally to 0 or 50 mg Mn/kg/day over PND 1-21. In adulthood, animals were tested in a series of learning, attention, impulse control, and sensorimotor tasks. Mn exposure caused lasting dysfunction in attention, reactivity to errors and reward omission, learning, and sensorimotor function, recapitulating the constellation of symptoms seen in ADHD children. MCS lessened Mn-induced attentional dysfunction and partially normalized reactivity to committing an error or not receiving an expected reward but provided no protection against Mn-induced learning or sensorimotor dysfunction. In the absence of Mn exposure, MCS produces lasting offspring benefits in learning, attention, and reactivity to errors. To conclude, developmental Mn exposure produces a constellation of deficits consistent with ADHD symptomology, and MCS offered some protection against the adverse Mn effects, adding to the evidence that maternal choline supplementation is neuroprotective for offspring and improves offspring cognitive functioning.
Subject(s)
Attention Deficit Disorder with Hyperactivity , Manganese , Humans , Animals , Rats , Female , Pregnancy , Child , Male , Manganese/toxicity , Rodentia , Attention Deficit Disorder with Hyperactivity/chemically induced , Attention Deficit Disorder with Hyperactivity/prevention & control , Rats, Long-Evans , Dietary Supplements , CholineABSTRACT
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.
Subject(s)
Attention Deficit Disorder with Hyperactivity , Central Nervous System Stimulants , Cognitive Dysfunction , Methylphenidate , Humans , Child , Adolescent , Rats , Animals , Methylphenidate/pharmacology , Methylphenidate/therapeutic use , Manganese/toxicity , Attention , Attention Deficit Disorder with Hyperactivity/chemically induced , Attention Deficit Disorder with Hyperactivity/drug therapy , Attention Deficit Disorder with Hyperactivity/psychology , Cognitive Dysfunction/drug therapy , Central Nervous System Stimulants/pharmacologyABSTRACT
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 sensorimotor 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 attention 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.
ABSTRACT
Studies in children have reported associations between elevated manganese (Mn) exposure and ADHD-related symptoms of inattention, impulsivity/hyperactivity, and psychomotor impairment. Maternal choline supplementation (MCS) during pregnancy/lactation may hold promise as a protective strategy because it has been shown to lessen cognitive dysfunction caused by numerous early insults. Our objectives were to determine whether (1) developmental Mn exposure alters behavioral reactivity/emotion regulation, in addition to impairing learning, attention, impulse control, and sensorimotor function, and (2) MCS protects against these Mn-induced impairments. Pregnant Long-Evans rats were given standard diet, or a diet supplemented with additional choline throughout gestation and lactation (G3 - PND 21). Male offspring were exposed orally to 0 or 50 mg Mn/kg/day over PND 1-21. In adulthood, animals were tested in a series of learning, attention, impulse control, and sensorimotor tasks. Mn exposure caused lasting dysfunction in attention, reactivity to errors and reward omission, learning, and sensorimotor function, recapitulating the constellation of symptoms seen in ADHD children. MCS lessened Mn-induced attentional dysfunction and partially normalized reactivity to committing an error or not receiving an expected reward but provided no protection against Mn-induced learning or sensorimotor dysfunction. In the absence of Mn exposure, MCS produces lasting offspring benefits in learning, attention, and reactivity to errors. To conclude, developmental Mn exposure produces a constellation of deficits consistent with ADHD symptomology, and MCS offered some protection against the adverse Mn effects, adding to the evidence that maternal choline supplementation is neuroprotective for offspring and improves offspring cognitive functioning. Highlights: Developmental Mn exposure causes lasting dysfunction consistent with ADHD symptomology.Maternal choline supplementation (MCS) protects against Mn-induced deficits in attention and behavioral reactivity.MCS in control animals produces lasting benefits to offspring in learning, attention, and error reactivity.These data support efforts to increase choline intake during pregnancy, particularly for individuals at risk of neurotoxicant exposure.
