Methylphenidate alleviates cognitive dysfunction from early Mn exposure: Role of catecholaminergic receptors

Abstract

BACKGROUND: Environmental manganese (Mn) exposure is associated with impair-ments in attention and psychomotor function as well as impulsivity/hyperactivity in children and adolescents. We have shown previously that developmental Mn exposure can cause these same areas of dysfunction in a rat model. Although treatment with methylphenidate (MPH) is well documented to lessen impairments in attention, im-pulse control, and sensorimotor function in children, it is unknown whether this treat-ment is effective in improving these areas of dysfunction induced by developmental Mn exposure. OBJECTIVES: Determine if oral MPH therapy ameliorates the lasting attention and sensorimotor impairments caused by developmental Mn exposure and elucidate the underlying mechanisms of Mn neurotoxicity and MPH effectiveness, if observed. 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 chronic oral MPH treatment (0, 0.5, 1.5, or 3.0 mg/kg/d), followed by continued behavioral testing in the presence of selective catecholaminergic receptor antagonists (SCH 23390, raclopride, and BRL 44408 s.c.) and MPH treatment, using a quasi-Latin-Square design. RESULTS: Developmental Mn exposure caused persistent attention and sensorimotor impairments in adult rats. MPH therapy at 0.5 mg/kg/d completely ameliorated the Mn-induced attentional dysfunction; notably this benefit was not seen following acute ad-ministration, but was apparent after prolonged (i.e., >8 days) treatment. The Mn-induced sensorimotor dysfunction was also ameliorated by MPH treatment but only at the 3 mg/kg/d MPH dose. Furthermore, selectively antagonizing D1, D2, or α2A recep-tors had no effect on the Mn-induced attentional deficits, or MPH efficacy to ameliorate those deficits. However, antagonism of D2R attenuated the sensorimotor deficits pro-duced by Mn, whereas the efficacy of MPH to ameliorate those sensorimotor deficits was diminished by D1R antagonism. CONCLUSIONS: These findings demonstrate that MPH treatment is effective in treat-ing the lasting attention and sensorimotor deficits caused by developmental Mn expo-sure, and they clarify the mechanisms underlying developmental Mn neurotoxicity and MPH efficacy. Given that the cause of attention and co-morbid psychomotor deficits in children is often unknown, these findings may have implications for the treatment of environmentally-induced attentional and psychomotor dysfunction in children more broadly.

Maternal choline supplementation lessens the behavioral dysfunction produced by developmental manganese exposure in a rodent model of ADHD

“…The catecholaminergic system in the prefrontal cortex/anterior cingulate cortex has been well-established as critical to executive functioning, including attention, emotion regulation, error monitoring, and behavioral inhibition [107][108][109][110][111][112][113] , and thus Mn-induced alterations to this system may well underlie the ADHD-like behavioral phenotype of the Mn exposed animals. This inference is further supported by studies from our group showing that oral methylphenidate (a catecholamine reuptake inhibitor) ameliorates the Mn behavioral deficits in attention and sensorimotor function 19,21,114 . Notably, our group has also demonstrated that developmental Mn exposure causes lasting alterations in DNA methylation and expression of genes related to DNA methylation, neuronal development and catecholaminergic neuronal systems in our rat model 115 , and other studies have also shown that Mn exposure can lead to altered DNA methylation [116][117][118][119] .…”