Reinforcing effects of fentanyl analogs found in illicit drug markets.

IF 3.5 3区 医学 Q2 NEUROSCIENCES Psychopharmacology Pub Date : 2024-11-01 Epub Date: 2024-07-05 DOI:10.1007/s00213-024-06641-6
Alexander D Maitland, Shelby A McGriff, Grant C Glatfelter, Charles W Schindler, Michael H Baumann
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Abstract

Rationale: The potent synthetic opioid fentanyl, and its analogs, continue to drive opioid-related overdoses. Although the pharmacology of fentanyl is well characterized, there is little information about the reinforcing effects of clandestine fentanyl analogs (FAs).

Objectives: Here, we compared the effects of fentanyl and the FAs acetylfentanyl, butyrylfentanyl, and cyclopropylfentanyl on drug self-administration in male and female rats. These FAs feature chemical modifications at the carbonyl moiety of the fentanyl scaffold.

Methods: Sprague-Dawley rats fitted with intravenous jugular catheters were placed in chambers containing two nose poke holes. Active nose poke responses resulted in drug delivery (0.2 mL) over 2 s on a fixed-ratio 1 schedule, followed by a 20 s timeout. Acquisition doses were 0.01 mg/kg/inj for fentanyl and cyclopropylfentanyl, and 0.03 mg/kg/inj for acetylfentanyl and butyrylfentanyl. After 10 days of acquisition, dose-effect testing was carried out, followed by 10 days of saline extinction.

Results: Self-administration of fentanyl and FAs was acquired by both male and female rats, with no sex differences in acquisition rate. Fentanyl and FAs showed partial inverted-U dose-effect functions; cyclopropylfentanyl and fentanyl had similar potency, while acetylfentanyl and butyrylfentanyl were less potent. Maximal response rates were similar across drugs, with fentanyl and cyclopropylfentanyl showing maximum responding at 0.001 mg/kg/inj, acetylfentanyl at 0.01 mg/kg/inj, and butyrylfentanyl at 0.003 mg/kg/inj. No sex differences were detected for drug potency, efficacy, or rates of extinction.

Conclusions: Our work provides new evidence that FAs display significant abuse liability in male and female rats, which suggests the potential for compulsive use in humans.

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非法毒品市场上发现的芬太尼类似物的强化作用。
理由:强效合成阿片类药物芬太尼及其类似物继续导致与阿片类药物相关的吸毒过量。尽管芬太尼的药理学特征已被充分描述,但有关秘密芬太尼类似物(FAs)的强化作用的信息却很少:在此,我们比较了芬太尼与乙酰芬太尼、丁酰芬太尼和环丙基芬太尼类似物对雄性和雌性大鼠药物自我给药的影响。这些FA的特点是芬太尼支架的羰基发生了化学修饰:方法:将装有静脉颈静脉导管的 Sprague-Dawley 大鼠放入含有两个戳鼻孔的小室中。按固定比例 1 计划,主动戳鼻反应导致在 2 秒内给药(0.2 毫升),然后是 20 秒的超时。芬太尼和环丙芬太尼的采集剂量为 0.01 mg/kg/inj,乙酰芬太尼和丁酰芬太尼的采集剂量为 0.03 mg/kg/inj。习得10天后,进行剂量效应测试,然后进行为期10天的生理盐水消退测试:结果:雌雄大鼠均能获得芬太尼和FAs的自我给药,获得率没有性别差异。芬太尼和FAs呈现部分倒U型剂量效应函数;环丙基芬太尼和芬太尼的药效相似,而乙酰芬太尼和丁酰芬太尼的药效较弱。不同药物的最大反应率相似,芬太尼和环丙芬太尼的最大反应率为 0.001 毫克/千克/小鼠,乙酰芬太尼为 0.01 毫克/千克/小鼠,丁酰芬太尼为 0.003 毫克/千克/小鼠。在药力、药效或熄灭率方面未发现性别差异:我们的研究工作提供了新的证据,证明FAs在雄性和雌性大鼠体内都有明显的滥用倾向,这表明FAs有可能被人类强迫使用。
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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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