SK609, a novel dopamine D3 receptor agonist and norepinephrine transporter blocker with putative pro-cognitive actions, does not induce psychostimulant-like increases in risky choice during probabilistic discounting

Christopher P Knapp; Brooke Fallon; Sandhya Kortagere; Barry D Waterhouse; Stan B Floresco; Rachel L Navarra

doi:10.1007/s00213-024-06727-1

SK609, a novel dopamine D3 receptor agonist and norepinephrine transporter blocker with putative pro-cognitive actions, does not induce psychostimulant-like increases in risky choice during probabilistic discounting

Psychopharmacology (Berl). 2024 Dec 4. doi: 10.1007/s00213-024-06727-1. Online ahead of print.

Authors

Christopher P Knapp¹, Brooke Fallon¹, Sandhya Kortagere², Barry D Waterhouse¹, Stan B Floresco³, Rachel L Navarra⁴

Affiliations

¹ Department of Cell Biology and Neuroscience, Rowan-Virtua School of Translational Biomedical Engineering and Sciences, School of Osteopathic Medicine, Suite 2200, Stratford, NJ, 08084, USA.
² Department of Microbiology and Immunology, Drexel University, 2900 W. Queen Lane, Philadelphia, PA, 19129, USA.
³ Department of Psychology and Djavad Mowafaghian Centre for Brain Health, University of British Columbia, 2136 West Mall, Vancouver, BC, V6T 1Z4, Canada.
⁴ Department of Cell Biology and Neuroscience, Rowan-Virtua School of Translational Biomedical Engineering and Sciences, School of Osteopathic Medicine, Suite 2200, Stratford, NJ, 08084, USA. navarra@rowan.edu.

PMID: 39630237
DOI: 10.1007/s00213-024-06727-1

Abstract

Rationale: Psychostimulants, such as amphetamine (AMPH) and methylphenidate (MPH), non-selectively elevate extracellular concentrations of the catecholamine neurotransmitters, dopamine (DA) and norepinephrine (NE), and are common pharmacological strategies used to improve prefrontal cortex (PFC)-dependent cognitive dysfunction. However, this approach can be problematic given AMPH has been shown to increase preference for risky choices in a rodent assay of risk/reward decision making. SK609 is a novel NE reuptake blocker that selectively activates DA D3 receptors without affinity for the DA transporter. SK609 has been shown to improve cognitive performance without increasing psychostimulant-like spontaneous locomotor activity, suggesting SK609 may benefit neurocognitive function without psychostimulant-like side effect liability.

Objectives: We compared AMPH, MPH, and SK609 within dose ranges that display their cognitive enhancing properties in a probabilistic discounting task (PDT) of risk/reward decision making behavior to assess their potential to increase risky choice preference.

Methods: Rats chose between small/certain rewards delivered with 100% certainty and large/risky rewards delivered with descending probabilities across a session (100 - 6.25%) following administration of AMPH (0.25-1 mg/kg), MPH (2-8 mg/kg), and SK609 (4 mg/kg).

Results: AMPH and MPH increased risky choice behavior at doses previously reported to enhance cognition, whereas SK609 did not. AMPH and MPH also reduced sensitivity to non-rewarded risky choices.

Conclusions: These data highlight the combination of NE transporter blockade and selective D3 activation in pro-cognitive action without psychostimulant-like side effect liability. The absence of DA transporter blockade and non-selective dopaminergic activation are beneficial properties of SK609 that differentiates it from the traditional pro-cognitive psychostimulants.

Keywords: Amphetamine; Decision making; Dopamine D3 receptor; Methylphenidate; Norepinephrine transporter.

Abstract

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