In Vivo Occupancy of Dopamine D₃ Receptors by Antagonists Produces Neurochemical and Behavioral Effects of Potential Relevance to Attention-Deficit–Hyperactivity Disorder

Abstract

Consistent with these findings, the D 3 receptor antagonists enhanced the acquisition of learning of rats either alone or in the presence of the norepinephrine uptake blocker reboxetine as with the attention-deficit-hyperactivity disorder (ADHD) drug methylphenidate. Like reboxetine, the D 3 receptor antagonists also prevented deficits induced by scopolamine in object recognition memory of rats. Mice in which the dopamine transporter (DAT) has been deleted exhibit hyperactivity that is normalized by compounds that are effective in the treatment of ADHD. Both D 3 receptor antagonists decreased the hyperactivity of DAT 2/2 mice without affecting the activity of wild type controls. The present findings indicate that dopamine D 3 receptor antagonists engender cognition-enhancing and hyperactivity-dampening effects. Thus, D 3 receptor blockade could be considered as a novel treatment approach for cognitive deficits and hyperactivity syndromes, including those observed in ADHD.

What is the role of the D3 receptor in addiction? A mini review of PET studies with [11C]-(+)-PHNO

“…In this regard, the selective D 3 receptor antagonist SB-277011-A has been shown to increase extracellular levels of acetylcholine (Barth et al, 2013) and monoamines (Lacroix et al, 2003) in cortical areas implicated in addiction (anterior cingulate, medial prefrontal cortex) and to reverse cognitive deficits (Loiseau and Millan, 2009), and a recent human study combining positron emission tomography (PET) with resting state functional connectivity demonstrated a link between midbrain D 3 availability and cortical networks implicated in cognitive control (Cole et al, 2012).…”

Juvenile methylphenidate reduces prefrontal cortex plasticity via D3 receptor and BDNF in adulthood

“…The most commonly prescribed stimulant is methylphenidate (MPH). MPH predominantly affects the dopamine and noradrenergic systems, with recent evidence showing a role of the dopamine D3 receptor (D3R) in ADHD-associated behaviors in animals (Andersen et al, 2008; Barth et al, 2013). For example, D3R antagonists reduce hyperactivity and facilitate object recognition in DAT knockout mice, which have been used to model an ADHD phenotype.…”

Dopamine’s Actions in Primate Prefrontal Cortex: Challenges for Treating Cognitive Disorders

“…S33138 improved working memory and attentional set-shifting performance when given systemically to monkeys with cognitive deficits arising from low-dose MPTP, which causes mild DA depletion (Millan et al, 2010). Thus, D3R antagonists are being considered as therapeutics for both attention-deficit hyperactivity disorder (ADHD) and schizophrenia (Barth et al, 2013;Gross et al, 2013). Dissection of D2R versus D3R actions within the primate PFC will be an important challenge for future studies and may be aided by the development of D3R negative allosteric modulators.…”