Oral guanfacine treatment ameliorates the ADHD-like symptoms caused by developmental manganese exposure

Epidemiological studies have linked developmental manganese (Mn) exposure to increased risk of ADHD and related symptoms in children and adolescents. Rodent model studies have 1) confirmed causality by demonstrating that developmental Mn exposure can cause lasting ADHD-like symptoms, 2) revealed that these symptoms (in Mn-exposed animals) are accompanied by a hypofunctioning catecholaminergic system in fronto-cortical-striatal brain areas, and 3) demonstrated that methylphenidate is efficacious in ameliorating these ADHD-like symptoms in Mn-exposed animals. However, stimulant medications such as methylphenidate do not lessen symptoms in 25-30 % of children and adolescents diagnosed with ADHD, indicating the need for alternative ADHD medications. Guanfacine, a specific noradrenergic α_2A receptor agonist, has proven to be an effective non-stimulant ADHD medication, although it is unknown whether this drug is effective in treating the ADHD-like symptoms produced by developmental Mn exposure. The present study was designed to test this hypothesis. Additionally, due to the pharmacological specificity of guanfacine, its use may provide mechanistic insight into the role of noradrenergic dysfunction as a contributor to the Mn-induced impairments. Male Long-Evans neonatal rats were orally dosed with vehicle or Mn (50 mg Mn/kg/d) from postnatal day 1-21, and orally treated with guanfacine (0, 0.1, or 0.3 mg/kg/d) during behavioral testing as adults. The results revealed that developmental Mn exposure produced lasting impairments in impulse control, attention, and sensorimotor function, and that oral guanfacine was efficacious in ameliorating the Mn-induced impairments in all three functional domains, although the treatment duration needed for efficacy varied by functional domain. In addition, in control (unexposed) animals, there was little or no effect of guanfacine on any functional domain. There was also little effect of the drug in the Mn-exposed animals under trial conditions where Mn deficits did not emerge. These findings 1) demonstrate the efficacy of oral guanfacine to ameliorate the lasting ADHD-like symptoms caused by developmental Mn exposure, and 2) provide additional support for the hypothesis that hypofunctioning of the noradrenergic system contributes to these lasting Mn deficits. Collectively, these findings suggest that individuals with environmentally-induced ADHD, such as that induced by developmental Mn exposure, may benefit from oral guanfacine treatment.