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bioRxiv · 10.1101/2024.06.05.597571

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

Knapp, C. P.·Fallon, B.·Kortagere, S.·Waterhouse, B. D.·Floresco, S. B.·Navarra, R. L.
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Abstract

RationalePsychostimulants, 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. ObjectivesWe 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. MethodsRats 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). ResultsAMPH 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. ConclusionsThese 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.

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Knapp, C. P., Fallon, B., Kortagere, S., Waterhouse, B. D., Floresco, S. B., Navarra, R. L.. 2024-06-08. SK609, a novel dopamine D3 receptor agonist and norepinephrine transporter blocker with pro-cognitive actions, does not induce psychostimulant-like increases in risky choice during probabilistic discounting. https://doi.org/10.1101/2024.06.05.597571

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