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Relative reinforcing effects of dibutylone, ethylone, and N-ethylpentylone: self-administration and behavioral economics analysis in rats

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Abstract

Rationale

Following the emergence of methylone as one of the most popular synthetic cathinones, this group of novel psychoactive substance with names ending in “-lone,” such as dibutylone, ethylone, and N-ethylpentylone, appeared on the recreational drug market. The pharmacological mechanisms of dibutylone, ethylone, and N-ethylpentylone are well understood; however, to date, the reinforcing effects of dibutylone, ethylone, and N-ethylpentylone are still unclear.

Objectives

This study aimed to examine the self-administration of dibutylone, ethylone, and N-ethylpentylone relative to methamphetamine (METH) and to quantify their relative reinforcing effectiveness using behavioral economic analysis.

Methods

Male Sprague–Dawley rats were trained to self-administer METH (0.05 mg/kg) under a fixed-ratio 1 (FR1) schedule. Following the training, dose substitution was used to generate full dose–response curves for METH and the three synthetic cathinones. According to the first doses on the descending limb of the dose–response curves, rats were trained to self-administer METH (0.05 mg/kg), dibutylone (0.1 mg·kg−1·infusion−1), ethylone (0.4 mg·kg−1·infusion−1), or N-ethylpentylone (0.1 mg·kg−1·infusion−1) under an FR1 schedule, and a behavioral economic evaluation of their reinforcing effectiveness was then performed.

Results

Dibutylone, ethylone, and N-ethylpentylone functioned as reinforcers, and the inverted U-shaped dose–response curves were obtained. The rank order of reinforcing potency in this procedure was METH > N-ethylpentylone ≈ dibutylone > ethylone. In the economic analysis, the comparisons of the essential value (EV) transformed from demand elasticity (α) indicated that the rank order of efficacy as reinforcers was METH (EV = 7.93) ≈ dibutylone (EV = 7.81) > N-ethylpentylone (EV = 5.21) ≈ ethylone (EV = 4.19).

Conclusions

These findings demonstrated that dibutylone, ethylone, and N-ethylpentylone function as reinforcers and have addictive potential, suggesting that the modification of α-alkyl and N-alkyl side chains may affect their reinforcing efficacy.

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References

  • Bauer CT, Banks ML, Blough BE, Negus SS (2013) Use of intracranial self-stimulation to evaluate abuse-related and abuse-limiting effects of monoamine releasers in rats. Br J Pharmacol 168:850–862

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • China Food and Drug Administration (2015) Announcement on printing and distributing the measures for the control of non pharmaceutical narcotic drugs and psychotropic substances (in Chinese). https://www.mps.gov.cn/n6557558/c5102861/content.html. Accessed 10 Sept 2020

  • China Food and Drug Administration (2018) Announcement on the listing of 32 substances such as 4-chloroethylcasinone in the supplementary catalogue of non pharmaceutical narcotic drugs and psychotropic substances (in Chinese). https://www.mps.gov.cn/n6557558/c6219874/content.html. Accessed 10 Sep 2020

  • Costa JL, Cunha KF, Lanaro R, Cunha RL, Walther D, Baumann MH (2019) Analytical quantification, intoxication case series, and pharmacological mechanism of action for N-ethylnorpentylone (N-ethylpentylone or ephylone). Drug Test Anal 11:461–471

    Article  CAS  PubMed  Google Scholar 

  • DEA (2011) Schedules of controlled substances: temporary placement of three synthetic cathinones in Schedule I. Final Order. Fed Regist 76:65371–65375

    Google Scholar 

  • DEA (2013) Establishment of drug codes for 26 substances. Final rule. Fed Regist 78:664–666

    Google Scholar 

  • DEA (2014) National Forensic Laboratory Identification System 2014 Annual Report. https://www.deadiversion.usdoj.gov/nflis/NFLIS2014AR.pdf. Accessed 10 Sept 2020

  • DEA (2016) National forensic laboratory identification system 2016 annual report. https://www.nflis.deadiversion.usdoj.gov/DesktopModules/ReportDownloads/Reports/NFLIS2016AR.pdf. Accessed 10 Sept 2020

  • DEA (2018) Schedules of controlled substances: temporary placement of n-ethylpentylone in schedule I. Fed Regist 83:444474–444478

    Google Scholar 

  • Eshleman AJ, Nagarajan S, Wolfrum KM, Reed JF, Swanson TL, Nilsen A, Janowsky A (2019) Structure-activity relationships of bath salt components: substituted cathinones and benzofurans at biogenic amine transporters. Psychopharmacology 236:939–952

    Article  CAS  PubMed  Google Scholar 

  • Eshleman AJ, Wolfrum KM, Hatfield MG, Johnson RA, Murphy KV, Janowsky A (2013) Substituted methcathinones differ in transporter and receptor interactions. Biochem Pharmacol 85:1803–1815

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Eshleman AJ, Wolfrum KM, Reed JF, Kim SO, Swanson T, Johnson RA, Janowsky A (2017) Structure-activity relationships of substituted cathinones, with transporter binding, uptake, and release. J Pharmacol Exp Ther 360:33–47

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • European Monitoring Center for Drugs and Drug Addiction (2010) EMCDDA- Europol 2010 Annual Report on the implementation of Council Decision 2005/387/JHA [R]. October, 2010. https://www.emcdda.europa.eu/news/2010/annualReport2010PowerPoint_en. Accessed 10 Sept 2020

  • Gannon BM, Baumann MH, Walther D, Jimenez-Morigosa C, Sulima A, Rice KC, Collins GT (2018a) The abuse-related effects of pyrrolidine-containing cathinones are related to their potency and selectivity to inhibit the dopamine transporter. Neuropsychopharmacology 43:2399–2407

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gannon BM, Galindo KI, Mesmin MP, Rice KC, Collins GT (2018b) Reinforcing effects of binary mixtures of common bath salt constituents: studies with 3,4-methylenedioxypyrovalerone (MDPV), 3,4-methylenedioxymethcathinone (methylone), and caffeine in rats. Neuropsychopharmacology 43:761–769

    Article  CAS  PubMed  Google Scholar 

  • Gannon BM, Galindo KI, Mesmin MP, Sulima A, Rice KC, Collins GT (2018c) Relative reinforcing effects of second-generation synthetic cathinones: acquisition of self-administration and fixed ratio dose-response curves in rats. Neuropharmacology 134:28–35

    Article  CAS  PubMed  Google Scholar 

  • Gatch MB, Dolan SB, Forster MJ (2017) Locomotor activity and discriminative stimulus effects of a novel series of synthetic cathinone analogs in mice and rats. Psychopharmacology 234:1237–1245

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gatch MB, Dolan SB, Forster MJ (2019) Locomotor activity and discriminative stimulus effects of five novel synthetic cathinone analogs in mice and rats. Drug Alcohol Depend 199:50–58

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gatch MB, Taylor CM, Forster MJ (2013) Locomotor stimulant and discriminative stimulus effects of ‘bath salt’ cathinones. Behav Pharmacol 24:437–447

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hursh SR, Silberberg A (2008) Economic demand and essential value. Psychol Rev 115:186–198

    Article  PubMed  Google Scholar 

  • Hursh SR, Galuska CM, Winger G, Woods JH (2005) The economics of drug abuse: a quantitative assessment of drug demand. Mol Interv 5:20–28

    Article  PubMed  Google Scholar 

  • Huskinson SL, Naylor JE, Rowlett JK, Freeman KB (2014) Predicting abuse potential of stimulants and other dopaminergic drugs: overview and recommendations. Neuropharmacology 87:66–80

    Article  CAS  PubMed  Google Scholar 

  • Huskinson SL, Naylor JE, Townsend EA, Rowlett JK, Blough BE, Freeman KB (2017) Self-administration and behavioral economics of second-generation synthetic cathinones in male rats. Psychopharmacology 234:589–598

    Article  CAS  PubMed  Google Scholar 

  • Ikeji C, Sittambalam CD, Camire LM, Weisman DS (2018) Fatal intoxication with N-ethylpentylone: a case report. J Community Hosp Intern Med Perspect 8:307–310

    Article  PubMed  PubMed Central  Google Scholar 

  • Lai M, Chen W, Zhu H, Zhou X, Liu H, Zhang F, Zhou W (2013) Low dose risperidone attenuates cue-induced but not heroin-induced reinstatement of heroin seeking in an animal model of relapse. Int J Neuropsychopharmacol 16:1569–1575

    Article  CAS  PubMed  Google Scholar 

  • Lai M, Zhu H, Sun A, Zhuang D, Fu D, Chen W, Zhang HT, Zhou W (2014) The phosphodiesterase-4 inhibitor rolipram attenuates heroin-seeking behavior induced by cues or heroin priming in rats. Int J Neuropsychopharmacol 17:1397–1407

    Article  CAS  PubMed  Google Scholar 

  • Lee D, Chronister CW, Hoyer J, Goldberger BA (2015) Ethylone-related deaths: toxicological findings. J Anal Toxicol 39:567–571

    Article  CAS  PubMed  Google Scholar 

  • Li J, Lin Z, Tao X, Huang Z, Zhang Y, Zheng S, Wang H, Rao Y (2019) Effects of N-ethylpentylone on locomotor activity and anxiety-like behavior in rats. Behav Pharmacol 30:500–505

    Article  CAS  PubMed  Google Scholar 

  • Lile JA, Ross JT, Nader MA (2005) A comparison of the reinforcing efficacy of 3,4-methylenedioxymethamphetamine (MDMA, “ecstasy”) with cocaine in rhesus monkeys. Drug Alcohol Depend 78:135–140

    Article  CAS  PubMed  Google Scholar 

  • Lile JA, Wang Z, Woolverton WL, France JE, Gregg TC, Davies HM, Nader MA (2003) The reinforcing efficacy of psychostimulants in rhesus monkeys: the role of pharmacokinetics and pharmacodynamics. J Pharmacol Exp Ther 307:356–366

    Article  CAS  PubMed  Google Scholar 

  • Maguire DR, Minervini V, Dodda V, France CP (2020) Impact of order of fixed-ratio presentation on demand for self-administered remifentanil in male rats. Behav Pharmacol 31:216–220

    Article  CAS  PubMed  Google Scholar 

  • McIntyre IM, Hamm CE, Sherrard JL, Gary RD, Burton CG, Mena O (2015) Acute 3,4-methylenedioxy-N-ethylcathinone (ethylone) intoxication and related fatality: a case report with postmortem concentrations. J Anal Toxicol 39:225–228

    Article  CAS  PubMed  Google Scholar 

  • National Forensic Laboratory Information System (2016) Synthetic cannabinoids and synthetic cathinones reported in NFLIS, 2013–2015. https://www.deadiversion.usdoj.gov/nflis/SR-SynthCannabinoidCathinone.pdf#search=ethylpentylon. Accessed 10 Sept 2020

  • NDEWS (2018) Emerging threat report. https://ndews.umd.edu/resources/dea‐emerging‐threatreports. Accessed 10 Sept 2020

  • Negus SS, Banks ML (2017) Decoding the structure of abuse potential for new psychoactive substances: structure-activity relationships for abuse-related effects of 4-substituted methcathinone analogs. Curr Top Behav Neurosci 32:119–131

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Negus SS, Schrode K, Stevenson GW (2008) Micro/kappa opioid interactions in rhesus monkeys: implications for analgesia and abuse liability. Exp Clin Psychopharmacol 16:386–399

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • NRC (2011) Guide for the Care and Use of Laboratory Animals, 8th edn. National Academies Press, Washington DC

    Google Scholar 

  • Pieprzyca E, Skowronek R, Nižnanský Ľ, Czekaj P (2020) Synthetic cathinones – from natural plant stimulant to new drug of abuse. Eur J Pharmacol 875:173012

    Article  CAS  PubMed  Google Scholar 

  • Russell MJ, Bogun B (2011) New, “party pill” components in New Zealand: the synthesis and analysis of some beta-ketone analogues of 3,4-methylenedioxymethamphetamine (MDMA) including betak-DMBDB (beta-ketone-N, N-dimethyl-1-(1,3-benzodioxol-5-yl)-2-butanamine). Forensic Sci Int 210:174–181

    Article  CAS  PubMed  Google Scholar 

  • Simmler LD, Buser TA, Donzelli M, Schramm Y, Dieu LH, Huwyler J, Chaboz S, Hoener MC, Liechti ME (2013) Pharmacological characterization of designer cathinones in vitro. Br J Pharmacol 168:458–470

    Article  CAS  PubMed  Google Scholar 

  • Soares J, Costa VM, Bastos ML, Carvalho F, Capela JP (2021) An update review on synthetic cathinones. Arch Toxicol 95:2895–2940

    Article  CAS  PubMed  Google Scholar 

  • Thirakul P, Hair LS, Bergen KL, Pearson JM (2017) Clinical Presentation, Autopsy results and toxicology findings in an acute N-ethylpentylone fatality. J Anal Toxicol 41:342–346

    CAS  PubMed  Google Scholar 

  • Thomsen M, Hall FS, Uhl GR, Caine SB (2009) Dramatically decreased cocaine self-administration in dopamine but not serotonin transporter knock-out mice. J Neurosci 29:1087–1092

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • UNODS (2018) Analysis of drug markets: opiates, cocaine, cannabis, synthetic drugs. World Drug Report 2018. https://www.unodc.org/pdf/opioids-crisis/WDR18_Booklet_3_DRUG_MARKETS.PDF. Accessed 10 Sept 2020

  • Wang Z, Woolverton WL (2007) Estimating the relative reinforcing strength of (+/-)-3,4-methylenedioxymethamphetamine (MDMA) and its isomers in rhesus monkeys: comparison to (+)-methamphetamine. Psychopharmacology 189:483–488

    Article  CAS  PubMed  Google Scholar 

  • Wilcox KM, Rowlett JK, Paul IA, Ordway GA, Woolverton WL (2000) On the relationship between the dopamine transporter and the reinforcing effects of local anesthetics in rhesus monkeys: practical and theoretical concerns. Psychopharmacology 153:139–147

    Article  CAS  PubMed  Google Scholar 

  • Xu P, Lai M, Fu D, Liu H, Wang Y, Shen H, Zhou W (2021) Reinforcing and discriminative-stimulus effects of two pyrrolidine-containing synthetic cathinone derivatives in rats. Pharmacol Biochem Behav 203:173128

    Article  CAS  PubMed  Google Scholar 

  • Zanettini C, Wilkinson DS, Katz JL (2018) Behavioral economic analysis of the effects of N-substituted benztropine analogs on cocaine self-administration in rats. Psychopharmacology 235:47–58

    Article  CAS  PubMed  Google Scholar 

  • Zhou W, Liu H, Zhang F, Tang S, Zhu H, Lai M, Kalivas PW (2007) Role of acetylcholine transmission in nucleus accumbens and ventral tegmental area in heroin-seeking induced by conditioned cues. Neuroscience 144:1209–1218

    Article  CAS  PubMed  Google Scholar 

  • Zhou W, Zhang F, Tang S, Liu H, Gu J, Yang G (2005) The dissociation of heroin-seeking patterns induced by contextual, discriminative, or discrete conditioned cues in a model of relapse to heroin in rats. Psychopharmacology 181:197–206

    Article  CAS  PubMed  Google Scholar 

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Funding

This research was supported by the Ningbo public welfare research project (202002N3169), the Open Project of Key Laboratory of Drug Monitoring and Control, the Ministry of Public Security (2021-KLDMC-03), and the National Natural Science Foundation of China (82071499).

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Authors and Affiliations

  1. Zhejiang Provincial Key Laboratory of Addiction, Ningbo Kangning Hospital, School of Medicine, Ningbo University, Zhejiang Province, Ningbo, 315201, People’s Republic of China

    Miaojun Lai, Dan Fu, Zeming Xu, Han Du, Huifen Liu & Wenhua Zhou

  2. Key Laboratory of Drug Monitoring and Control, Drug Intelligence and Forensic Center, Ministry of Public Security, Beijing, 100093, People’s Republic of China

    Youmei Wang & Peng Xu

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  1. Miaojun Lai
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  2. Dan Fu
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  7. Peng Xu
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Correspondence to Peng Xu or Wenhua Zhou.

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All procedures followed the National Institutes of Health Guide for the Care and Use of Laboratory Animals.

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Lai, M., Fu, D., Xu, Z. et al. Relative reinforcing effects of dibutylone, ethylone, and N-ethylpentylone: self-administration and behavioral economics analysis in rats. Psychopharmacology 239, 2875–2884 (2022). https://doi.org/10.1007/s00213-022-06173-x

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