Sarah L Withey, Harshawardhan U Deshpande, Lei Cao, Jack Bergman, Stephen J Kohut
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引用次数: 0
Abstract
Naltrexone, an opioid antagonist that blocks the reinforcing properties of opioid agonists, is often prescribed to preclude relapse to opioid use disorder (OUD) following detoxification. However, few laboratory studies have directly investigated the ability of naltrexone to alter relapse-inducing effects of opioid agonists, including their priming strength in reinstatement studies and their impact in brain regions known to be involved in drug-induced reinforcement in MRI studies. Here we directly address this issue by investigating the effects of continuous exposure to naltrexone on 1) fentanyl-induced reinstatement of drug-seeking behavior, 2) fentanyl-induced patterns of blood oxygenation level dependent (BOLD) activation in the nucleus accumbens (NAcc), and 3) fentanyl-induced changes in NAcc functional connectivity (FC) in awake non-human primates that are engaged in ongoing opioid self-administration studies. We found that naltrexone antagonizes the priming strength of fentanyl as shown by a rightward shift in its reinstatement dose-effect curve and that naltrexone surmountably antagonizes the BOLD response induced by fentanyl. However, while naltrexone also countered fentanyl's effects on NAcc FC, the effects were not surmounted by a higher dose of fentanyl. Together, these data suggest that, in contrast to naltrexone's modulation of fentanyl's effects on behavior and BOLD responses, their interactive effects on FC between multiple brain regions do not reflect their receptor-mediated activity. Additionally, we demonstrated opposing effects in the absence and presence of naltrexone on NAcc FC at baseline (i.e., in the absence of any fentanyl prime) suggesting that naltrexone alters FC at baseline, even though naltrexone appears behaviorally silent in the absence of an agonist prime. Together these data provide additional insight into ways in which naltrexone interacts with opioid agonists, both behaviorally and in the brain. Further understanding the effects of opioid agonists on patterns of FC could help elucidate our understanding of the neural processes that contribute to the initiation of and relapse to opioid-seeking behavior in OUD.
纳曲酮是一种阿片类拮抗剂,可阻断阿片类激动剂的强化作用,通常用于防止戒毒后阿片类药物使用障碍(OUD)的复发。然而,很少有实验室研究直接探讨纳曲酮改变阿片类激动剂复发诱导效应的能力,包括其在复吸研究中的诱导强度,以及在核磁共振成像研究中对已知参与药物诱导强化的大脑区域的影响。在这里,我们通过研究持续暴露于纳曲酮对以下方面的影响来直接解决这个问题:1)芬太尼诱导的觅药行为恢复;2)芬太尼诱导的伏隔核(NAcc)血氧水平依赖性(BOLD)激活模式;3)芬太尼诱导的NAcc功能连接性(FC)变化。我们发现,纳曲酮可拮抗芬太尼的诱导强度,这表现在芬太尼的恢复剂量效应曲线向右移动,而且纳曲酮可克服芬太尼诱导的BOLD反应。然而,虽然纳曲酮也能抵消芬太尼对 NAcc FC 的影响,但更大剂量的芬太尼并不能克服这种影响。这些数据共同表明,与纳曲酮调节芬太尼对行为和 BOLD 反应的影响相反,它们对多个脑区 FC 的交互影响并不反映其受体介导的活动。此外,我们还证明了纳曲酮的缺失和存在对基线(即没有芬太尼刺激)NAcc FC 的影响是相反的,这表明纳曲酮会改变基线的 FC,尽管在没有激动剂刺激的情况下纳曲酮在行为上似乎是沉默的。综合这些数据,我们可以进一步了解纳曲酮与阿片类激动剂在行为和大脑中的相互作用方式。进一步了解阿片类受体激动剂对FC模式的影响有助于阐明我们对导致OUD中阿片寻求行为的开始和复发的神经过程的理解。
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.