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Selective activation of Dopamine D3 receptors and norepinephrine transporter blockade enhances sustained attention
Journal article   Open access   Peer reviewed

Selective activation of Dopamine D3 receptors and norepinephrine transporter blockade enhances sustained attention

Courtney A. Marshall, Zachary D. Brodnik, Ole V. Mortensen, Maarten E.A. Reith, Jed S. Shumsky, Barry D. Waterhouse, Rodrigo A. España and Sandhya Kortagere
Neuropharmacology, v 148, pp 178-188
Apr 2019
DOI: https://doi.org/10.1016/j.neuropharm.2019.01.003
PMID: 30633928
Featured in Collection :   UN Sustainable Development Goals @ Drexel
url
https://europepmc.org/articles/pmc6424628View
Accepted (AM)Open Access (License Unspecified),  Open

Abstract

Catecholamine Dopamine D3R agonist Dopamine transporter Executive function Locomotor activity Methylphenidate Microdialysis Norepinephrine transporter inhibitor Sustained attention
Catecholamine transmitters dopamine (DA) and norepinephrine (NE) regulate prefrontal cortical (PFC) circuit activity and PFC-mediated executive functions. Accordingly, pharmacological agents that influence catecholamine neurotransmission exert prominent effects on cognition. Many such agents are used clinically to treat attention disorders. For example, methylphenidate blocks DA and NE reuptake and is the leading choice for attention deficit hyperactivity disorder (ADHD) treatment. Recently, we have designed SK609 – a selective small molecule agonist of the DA D3 receptor (D3R). In this study, we further characterized SK609's ability to selectively inhibit the reuptake of NE by NE transporters (NET). Our results indicate SK609 selectively inhibits NET with a Ki value of ∼500 nM and behaves as a NET substrate. Systemic dosing of SK609 (4 mg/kg; i.p.) in naïve rats produced a 300% and 160% increase in NE and DA, respectively, in the PFC as measured by microdialysis. Based on these neurochemical results, SK609 was tested in a PFC-dependent, visually-guided sustained attention task in rats. SK609 improved performance in a dose-dependent manner with a classical inverted-U dose response function with a peak effect at 4 mg/kg. SK609's peak effect was blocked by a pre-treatment with either the D2/D3R antagonist raclopride (0.05 mg/kg; i.p) or the alpha-1 adrenergic receptor antagonist prazosin (0.25 mg/kg; i.p), confirming a role for both DA and NE in promoting sustained attention. Additionally, SK609 improved sustained attention more prominently among low-performing animals. Doses of SK609 (2, 4, and 8 mg/kg) associated with cognitive enhancement did not produce an increase in spontaneous locomotor activity, suggesting a lack of side effects mediated by DA transporter (DAT) activity. These results demonstrate that the novel catecholaminergic modulator SK609 has the potential to treat sustained attention deficits without affecting DAT activity, distinguishing it from amphetamines and methylphenidate. •SK609 specifically improved sustained attention performance in low performing rats.•SK609's produced an inverted-U shaped dose response similar to methylphenidate.•SK609's peak dose increased the levels of DA by 160% and NE by 300% in the PFC suggesting a role in sustained attention.

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15 citations in Web of Science
18 citations in Scopus

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Collaboration types
Domestic collaboration
Web of Science research areas
Neurosciences
Pharmacology & Pharmacy
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