# Psychostimulants, Attention Deficit and Basal Ganglia Disorders

> **NIH NIH R21** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2022 · $191,979

## Abstract

Attention-deficit/hyperactivity disorder (ADHD) is characterized largely by an ongoing pattern of three primary
behavioral characteristics: hyperactivity, impulsivity and inattention. This disorder involves dysregulation of
dopaminergic (DAergic) pathways. Thus, DAergic psychostimulants (i.e., amphetamine (AMPH) and
methylphenidate (MPD)) are prescribed as treatment.
It is established, both preclinically and in humans, that high-dose AMPH/methamphetamine (METH) exposure
causes persistent DAergic deficits. This is of interest for several reasons, including findings that DAergic deficits
are hallmarks of Parkinson’s disease (PD). Not surprisingly, others and we have reported that individuals with
evidence of AMPH/METH abuse are more likely to develop basal ganglia degenerative disorders, including PD.
Given that dysregulation of DAergic systems contribute to both ADHD and PD, and that both are impacted by
stimulants, our group investigated: 1) the association between ADHD and disorders of the basal ganglia and
cerebellum (BG&C), including PD; and 2) if treatment of ADHD with stimulants might impact the development of
BG&C disorders. We reported in a retrospective cohort study that individuals with ADHD had an approximately
2-fold increased risk of developing BG&C disorders (including PD), compared with non-ADHD-affected persons.
Importantly, in ADHD patients that were prescribed stimulants (i.e., AMPH-salts and MPD), the risk of these
disorders between ages 21 – 49 y was especially pronounced, at approximately 8-fold. This population-based
study raises highly clinically-relevant questions: 1) why are individuals displaying attention deficits more likely to
develop BG&C disorders; and 2) why does stimulant therapy increase the likelihood of developing BG&C
disorders in individuals displaying attention deficits?
A preclinical model of DAergic deficits in subjects with attention deficits is needed to mechanistically address the
questions posed above. Thus, we propose studies in rats that display the core behavioral features and cognitive
deficits observed in ADHD: specifically, spontaneously hypertensive rats (SHRs). We will test the vulnerability
of SHRs to DAergic deficits using two neurotoxins that induce neurochemical and/or behavioral deficits modeling
those in PD; that is, 6-hydroxydopamine (6-OHDA) and METH. The focus on METH is particularly significant,
given the prevalence of METH abuse per se, and in combination with other drugs of abuse. We hypothesize
that adolescent SHRs will be more susceptible to DAergic damage caused by METH and 6-OHDA than similarly
treated controls (Aim 1). In addition, we posit that chronic MPD treatment will enhance the neurotoxic potential
of METH and 6-OHDA in SHRs (Aim 2). The second hypothesis will be tested in rats that receive MPD: a)
throughout adolescence; or b) throughout adolescence and into young adulthood. These hypotheses will be
tested in both male and female rats, and provide models to investigate bo...

## Key facts

- **NIH application ID:** 10441781
- **Project number:** 1R21DA055980-01
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** ANNETTE FLECKENSTEIN
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $191,979
- **Award type:** 1
- **Project period:** 2022-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10441781

## Citation

> US National Institutes of Health, RePORTER application 10441781, Psychostimulants, Attention Deficit and Basal Ganglia Disorders (1R21DA055980-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10441781. Licensed CC0.

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