Journal article
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 (Berlin, Germany)
04 Dec 2024
PMID: 39630237
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
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.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.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.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.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).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).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.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.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.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.
Metrics
3 Record Views
Details
- Title
- 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
- Creators
- Christopher P Knapp - Rowan UniversityBrooke Fallon - Rowan UniversitySandhya Kortagere - Drexel UniversityBarry D Waterhouse - Rowan UniversityStan B Floresco - University of British ColumbiaRachel L Navarra - Rowan University
- Publication Details
- Psychopharmacology (Berlin, Germany)
- Publisher
- SPRINGER
- Number of pages
- 11
- Grant note
- New Jersey Commission on Brain Injury Research
Figure 1 schematic was created using BioRender.com (accessed on 09/03/2024).
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Microbiology and Immunology; [Retired Faculty]
- Web of Science ID
- WOS:001370395400001
- Scopus ID
- 2-s2.0-85211455627
- Other Identifier
- 991021985204404721
UN Sustainable Development Goals (SDGs)
This publication has contributed to the advancement of the following goals:
InCites Highlights
Data related to this publication, from InCites Benchmarking & Analytics tool:
- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Neurosciences
- Pharmacology & Pharmacy
- Psychiatry