Evaluation of (S)-T1 and (S)-T2 ligands targeting α3β4 nAChR as potential nicotine addiction pharmacotherapy.

IF 3.5 3区 医学 Q2 NEUROSCIENCES Psychopharmacology Pub Date : 2024-08-23 DOI:10.1007/s00213-024-06675-w
Saranda Nianpanich, Ratchanee Rodsiri, Ridho Islamie, Patanachai Limpikirati, Thanundorn Thanusuwannasak, Opa Vajragupta, Apinan Kanasuwan, Jiradanai Sarasamkan
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Abstract

Objectives: Substance use disorders (SUDs) represent a significant global health concern, demanding the development of effective pharmacological treatments. To address this, an investigation was conducted to examine the anti-addictive properties of two compounds, (S)-T1 and (S)-T2, which specifically target the α3β4 nicotinic acetylcholine receptor (nAChR).

Methods: The effects of (S)-T1 and (S)-T2 on nicotine-induced conditioned place preference (CPP), locomotor activity and dopamine levels in particular brain regions associated to addiction were investigated and compared in male C57BL/6N mice.

Results: The results demonstrate that neither (S)-T1 nor (S)-T2 induced place conditioning or conditioned place aversion (CPA), suggesting the absence of rewarding or aversive effects. Both compounds significantly attenuated nicotine-induced CPP, with (S)-T1 exhibiting a dose-dependent effect. Furthermore, the co-administration of (S)-T2 (10 mg/kg) with nicotine markedly reduced locomotor activity compared to nicotine treatment alone. Additionally, dopamine analysis revealed that nicotine increased dopamine levels in the nucleus accumbens (NAc) and dorsal striatum, whereas the co-administration of (S)-T1 (1, 3, and 10 mg/kg) and (S)-T2 (10 mg/kg) significantly decreased dopamine levels in these brain regions. No significant effects were observed in the prefrontal cortex (PFC).

Conclusions: These findings suggest that (S)-T1 and (S)-T2 hold promise for treating nicotine addiction by attenuating nicotine-induced CPP and modulating dopamine release in key reward-related brain regions. Further research is needed to gain insights into the underlying mechanisms behind their anti-addictive effects and substantiate their potential for treating nicotine addiction.

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以 α3β4 nAChR 为靶点的 (S)-T1 和 (S)-T2 配体作为潜在尼古丁成瘾药物疗法的评估。
目标:药物使用障碍(SUDs)是全球关注的重大健康问题,需要开发有效的药物治疗方法。为此,我们研究了两种专门针对α3β4烟碱乙酰胆碱受体(nAChR)的化合物(S)-T1和(S)-T2的抗成瘾性:方法:研究并比较了(S)-T1和(S)-T2对尼古丁诱导的条件性位置偏好(CPP)、运动活动和与成瘾有关的特定脑区多巴胺水平的影响:结果表明,(S)-T1和(S)-T2都不能诱导位置条件反射或条件性位置厌恶(CPA),这表明它们不存在奖赏或厌恶效应。这两种化合物都能明显减弱尼古丁诱导的CPP,其中(S)-T1表现出剂量依赖性效应。此外,与单独使用尼古丁相比,(S)-T2(10 毫克/千克)与尼古丁同时使用会明显降低运动活性。此外,多巴胺分析表明,尼古丁增加了伏隔核(NAc)和背侧纹状体中的多巴胺水平,而同时给予(S)-T1(1、3和10毫克/千克)和(S)-T2(10毫克/千克)会显著降低这些脑区的多巴胺水平。结论:这些研究结果表明,(S)-T1和(S)-T2通过减轻尼古丁诱导的CPP和调节关键奖赏相关脑区的多巴胺释放,有望治疗尼古丁成瘾。要深入了解它们的抗成瘾作用背后的机制,并证实它们治疗尼古丁成瘾的潜力,还需要进一步的研究。
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来源期刊
Psychopharmacology
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.
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