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.

IF 3.5 3区医学 Q2 NEUROSCIENCES Psychopharmacology Pub Date : 2024-12-04 DOI:10.1007/s00213-024-06727-1

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

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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.

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SK609是一种新型多巴胺D3受体激动剂和去甲肾上腺素转运蛋白阻滞剂，被认为具有促进认知的作用，但在概率折现过程中，它不会诱导类似精神兴奋剂的风险选择增加。

理由：精神兴奋剂，如安非他命（AMPH）和哌醋甲酯（MPH），非选择性地提高儿茶酚胺神经递质、多巴胺（DA）和去甲肾上腺素（NE）的细胞外浓度，是用于改善前额叶皮质（PFC）依赖性认知功能障碍的常用药物策略。然而，这种方法可能是有问题的，因为在啮齿动物的风险/回报决策试验中，AMPH已被证明会增加对风险选择的偏好。SK609是一种新型的NE再摄取阻滞剂，可选择性地激活DA D3受体，而不与DA转运体有亲和关系。SK609已被证明可以改善认知能力，而不会增加精神兴奋剂样的自发运动活动，这表明SK609可能有益于神经认知功能，而不会产生精神兴奋剂样的副作用。目的：我们比较了在风险/奖励决策行为的概率贴现任务（PDT）中显示其认知增强特性的剂量范围内的AMPH、MPH和SK609，以评估它们增加风险选择偏好的潜力。方法：大鼠在给予AMPH （0.25-1 mg/kg）、MPH （2-8 mg/kg）和SK609 （4 mg/kg）后，在100%确定的小奖励和概率递减的大奖励（100 - 6.25%）之间进行选择。结果：AMPH和MPH在先前报道的增强认知的剂量下增加风险选择行为，而SK609没有。AMPH和MPH也降低了对无回报风险选择的敏感性。结论：这些数据强调了NE转运蛋白阻断和选择性D3激活的组合在促进认知作用中没有精神兴奋剂样的副作用。缺乏DA转运体阻断和非选择性多巴胺能激活是SK609与传统的促认知精神兴奋剂不同的有益特性。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Psychopharmacology 医学-精神病学

CiteScore

7.10

自引率

5.90%

发文量

257

审稿时长

2-4 weeks

期刊介绍： Official Journal of the European Behavioural Pharmacology Society (EBPS) Psychopharmacology is an international journal that covers the broad topic of elucidating mechanisms by which drugs affect behavior. The scope of the journal encompasses the following fields: Human Psychopharmacology: Experimental This section includes manuscripts describing the effects of drugs on mood, behavior, cognition and physiology in humans. The journal encourages submissions that involve brain imaging, genetics, neuroendocrinology, and developmental topics. Usually manuscripts in this section describe studies conducted under controlled conditions, but occasionally descriptive or observational studies are also considered. Human Psychopharmacology: Clinical and Translational This section comprises studies addressing the broad intersection of drugs and psychiatric illness. This includes not only clinical trials and studies of drug usage and metabolism, drug surveillance, and pharmacoepidemiology, but also work utilizing the entire range of clinically relevant methodologies, including neuroimaging, pharmacogenetics, cognitive science, biomarkers, and others. Work directed toward the translation of preclinical to clinical knowledge is especially encouraged. The key feature of submissions to this section is that they involve a focus on clinical aspects. Preclinical psychopharmacology: Behavioral and Neural This section considers reports on the effects of compounds with defined chemical structures on any aspect of behavior, in particular when correlated with neurochemical effects, in species other than humans. Manuscripts containing neuroscientific techniques in combination with behavior are welcome. We encourage reports of studies that provide insight into the mechanisms of drug action, at the behavioral and molecular levels. Preclinical Psychopharmacology: Translational This section considers manuscripts that enhance the confidence in a central mechanism that could be of therapeutic value for psychiatric or neurological patients, using disease-relevant preclinical models and tests, or that report on preclinical manipulations and challenges that have the potential to be translated to the clinic. Studies aiming at the refinement of preclinical models based upon clinical findings (back-translation) will also be considered. The journal particularly encourages submissions that integrate measures of target tissue exposure, activity on the molecular target and/or modulation of the targeted biochemical pathways. Preclinical Psychopharmacology: Molecular, Genetic and Epigenetic This section focuses on the molecular and cellular actions of neuropharmacological agents / drugs, and the identification / validation of drug targets affecting the CNS in health and disease. We particularly encourage studies that provide insight into the mechanisms of drug action at the molecular level. Manuscripts containing evidence for genetic or epigenetic effects on neurochemistry or behavior are welcome.