Psychostimulants, Attention Deficit and Basal Ganglia Disorders

注意缺陷/多动障碍（ADHD）的主要特征是三个主要的持续模式

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 both mechanisms underlying DAergic degeneration and strategies for treatment.