# Mechanisms and therapies for the neurobehavioral deficits from early Mn exposure

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA SANTA CRUZ · 2021 · $551,255

## Abstract

Project Summary
 Studies in children/adolescents have linked developmental environmental manganese (Mn) exposure to
inattention, impulsivity, hyperactivity, oppositional behaviors, and fine motor deficits, though these studies are
limited by their cross-sectional designs and limited control of confounding that make it impossible to demonstrate
that Mn causes these deficits. Our recent studies have shown that developmental Mn exposure causes lasting
deficits in attention, impulse control, and fine motor function, providing the first causal evidence supporting the
human studies. Our initial studies of the potential benefits of chronic oral methylphenidate (Ritalin) treatment
revealed that the one dose studied alleviated the Mn-induced impulse control and fine motor dysfunctions, but
impaired attentional performance in the Mn animals. We propose to build upon these findings to elucidate the
neural mechanisms underlying the lasting attentional, impulse control, and fine motor dysfunction caused by
developmental Mn exposure, and test potential therapeutic interventions (methylphenidate, guanfacine), in our
established rodent model of childhood Mn exposure. Our testable hypotheses are 1) Oral MPH and/or
guanfacine treatment will alleviate the lasting fine motor, attention and impulse control deficits caused by
developmental Mn exposure; and 2) These lasting deficits caused by Mn exposure are due to changes levels of
catecholaminergic system proteins in the pre-frontal cortex - striatal pathway. We will test these hypotheses via
the following aims: Aim 1 will (i) Identify a clinically-relevant therapeutic regimen of MPH for the Mn deficits in
attention, impulse control, and fine motor function by determining the dose-response relationship with MPH in
male and female control vs Mn animals, and (ii) Determine involvement of DA D1, D2, and α2A adrenoreceptors
in the Mn deficits and in the therapeutic efficacy of MPH, using administration of selective receptor antagonists
during behavioral testing. Aim 2 will use PET neuroimaging and quantitative immunohistochemistry to further
elucidate changes in catecholaminergic system proteins implicated in the attention/impulse control/fine motor
Mn deficits, and the association of these measures with the attention/impulse control/fine motor outcomes. Aim
3 will test the hypotheses that guanfacine alleviates the attention/impulse control deficits produced by Mn. These
studies will be the first to identify potentially efficacious therapies for the treatment/prevention of attentional and
co-morbid fine motor deficits due to developmental Mn exposure, and to elucidate their neural mechanisms.

## Key facts

- **NIH application ID:** 10250387
- **Project number:** 5R01ES028369-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA SANTA CRUZ
- **Principal Investigator:** DONALD R SMITH
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $551,255
- **Award type:** 5
- **Project period:** 2018-09-30 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10250387

## Citation

> US National Institutes of Health, RePORTER application 10250387, Mechanisms and therapies for the neurobehavioral deficits from early Mn exposure (5R01ES028369-04). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10250387. Licensed CC0.

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