Attention-deficit hyperactivity disorder (ADHD) is a clinically heterogeneous disorder characterized by core features of impulsivity, hyperactivity, and attention deficits. ADHD is estimated to affect 8-12% of school-aged children worldwide. ADHD is a complex disorder with significant genetic contributions. However, no single gene has been linked to a significant percentage of cases, suggesting that environmental factors or gene-environment interactions may contribute to the etiology or clinical manifestation of ADHD. Dopamine transporter (DAT) polymorphisms and elevated expression of the DAT have been observed in ADHD patients, suggesting alterations in DAT levels may contribute to ADHD. Since environmental factors, such as pesticides, have been shown to alter DAT expression, we have hypothesized that in utero pesticide exposure may contribute to the incidence or severity of ADHD. Recent data from this laboratory have demonstrated that the offspring of mice exposed to low levels of the pyrethroid pesticide deltamethrin during development exhibit similar symptoms as observed in children with ADHD, including elevated DAT levels, hyperactivity, a paradoxical calming response to psychostimulants, behavioral deficits, and a male gender-preference of these effects. Importantly, the doses that elicited these effects were at or below the no observable adverse effect level (NOAEL) established by the EPA for deltamethrin. This is particularly notable because the NOAEL used by the EPA when making regulatory decisions on pesticides. Because there has been documented exposure of pregnant women to pyrethroids and pyrethroid use has increased dramatically in the last decade, it may be prudent to evaluate pesticide exposure as a potential risk factor for ADHD. Furthermore, these mice represent a novel animal model to test therapies for ADHD and provide insight into the basic mechanisms underlying this disorder. Here, the investigators propose three Specific Aims to investigate mechanisms underlying the effects of deltamethrin on the dopamine system and characterize the behavioral effects of developmental deltamethrin expsoure. The investigators will then use this information to exploit this novel model to identify molecular targets for therapeutic intervention in ADHD.
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