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Forensic Toxicology

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Open Access 01-07-2020 | Original Article

Comparative neuropharmacological studies on three pyrrolidine-containing synthetic cathinones

Authors: Jakub Wojcieszak, Dariusz Andrzejczak, Adam Wojtas, Krystyna Gołembiowska, Jolanta B. Zawilska

Published in: Forensic Toxicology | Issue 2/2020

Abstract

Purpose

3,4-Methylenedioxypyrovalerone (3,4-MDPV) is a prevalent member of α-pyrrolidinophenones, a group of new psychoactive substances, known for its strong psychostimulant effect resulting from potent stimulation of dopamine (DA) circuitry in the brain. As 3,4-MDPV and its derivatives are successively being scheduled, each year novel analogs appear on the market. This study aimed at examination and direct comparison of psychostimulant properties of structural isomer of 3,4-MDPV, namely 2,3-MDPV along with a model α-pyrrolidinophenone, pyrovalerone.

Methods

Open field spontaneous locomotor activity of mice was assessed as a measure of psychostimulant potency. To evaluate the in vivo pharmacological properties of the drugs, extracellular levels of DA and serotonin (5-HT) in the mouse striatum were measured using an in vivo microdialysis technique followed by high-performance liquid chromatography with electrochemical detection. Involvement of dopaminergic system in the behavioral effects of the tested α-pyrrolidinophenones was examined by pre-treatment with a selective D₁-DA receptor antagonist, SCH 23390, before measurement of locomotor activity in response to the drugs.

Results

3,4-MDPV, 2,3-MDPV and pyrovalerone produced time- and dose-dependent stimulation of locomotor activity, with 3,4-MDPV being more potent than the other two compounds. Observed locomotor stimulation was mediated by elevated DA-ergic neurotransmission, as all compounds caused a significant increase of extracellular DA levels in the striatum, with 3,4-MDPV being the most potent, and psychostimulant effects were abolished by SCH 23390. Interestingly, the tested pyrovalerones caused in vivo elevation of extracellular 5-HT levels, which contrasted with their in vitro pharmacologic properties.

Conclusions

Pyrovalerone, 2,3-MDPV and 3,4-MDPV produced psychostimulant effects mediated by stimulation of dopaminergic neurotransmission. Additionally, all tested compounds elevated extracellular levels of 5-HT in vivo.

EMCDDA (2019) European drug report 2019: trends and developments. https://www.emcdda.europa.eu/system/files/publications/11364/20191724_TDAT19001ENN_PDF.pdf. Accessed 27 Aug 2019.

Rickli A, Hoener MC, Liechti ME (2015) Monoamine transporter and receptor interaction profiles of novel psychoactive substances: Para-halogenated amphetamines and pyrovalerone cathinones. Eur Neuropsychopharmacol 25(3):365–376. https://doi.org/10.1016/j.euroneuro.2014.12.012 CrossRefPubMed

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(2):458–470. https://doi.org/10.1111/j.1476-5381.2012.02145.x CrossRefPubMed

Zawilska JB, Wojcieszak J (2013) Designer cathinones—an emerging class of novel recreational drugs. Forensic Sci Int 231(1–3):42–53. https://doi.org/10.1016/j.forsciint.2013.04.015 CrossRefPubMed

Karila L, Lafaye G, Scocard A, Cottencin O, Benyamina A (2018) MDPV and α-PVP use in humans: the twisted sisters. Neuropharmacology 134(Pt A):65–72. https://doi.org/10.1016/j.neuropharm.2017.10.007 CrossRefPubMed

Baumann MH, Partilla JS, Lehner KR, Thorndike EB, Hoffman AF, Holy M, Rothman RB, Goldberg SR, Lupica CR, Sitte HH, Brandt SD, Tella SR, Cozzi NV, Schindler CW (2013) Powerful cocaine-like actions of 3,4-methylenedioxypyrovalerone (MDPV), a principal constituent of psychoactive 'bath salts' products. Neuropsychopharmacology 38(4):552–562. https://doi.org/10.1038/npp.2012.204 CrossRefPubMed

Cameron KN, Kolanos R, Solis E Jr, Glennon RA, De Felice LJ (2013) Bath salts components mephedrone and methylenedioxypyrovalerone (MDPV) act synergistically at the human dopamine transporter. Br J Pharmacol 168(7):1750–1757. https://doi.org/10.1111/bph.12061 CrossRefPubMedPubMedCentral

Horsley RR, Lhotkova E, Hajkova K, Feriancikova B, Himl M, Kucharr M, Páleníček T (2018) Behavioural, pharmacokinetic, metabolic, and hyperthermic profile of 3,4-methylenedioxypyrovalerone (MDPV) in the Wistar rat. Front Psychiatry 9:144. https://doi.org/10.3389/fpsyt.2018.00144 CrossRefPubMedPubMedCentral

Schindler CW, Thorndike EB, Goldberg SR, Lehner KR, Cozzi NV, Brandt SD, Baumann MH (2016) Reinforcing and neurochemical effects of the “bath salts” constituents 3,4-methylenedioxypyrovalerone (MDPV) and 3,4-methylenedioxy-N-methylcathinone (methylone) in male rats. Psychopharmacology 233(10):1981–1990. https://doi.org/10.1007/s00213-015-4057-0 CrossRefPubMed

10.

Aarde SM, Creehan KM, Vandewater SA, Dickerson TJ, Taffe MA (2015) In vivo potency and efficacy of the novel cathinone α-pyrrolidinopentiophenone and 3,4-methylenedioxypyrovalerone: self-administration and locomotor stimulation in male rats. Psychopharmacology 232(16):3045–3055. https://doi.org/10.1007/s00213-015-3944-8 CrossRefPubMedPubMedCentral

11.

Aarde SM, Huang PK, Creehan KM, Dickerson TJ, Taffe MA (2013) The novel recreational drug 3,4-methylenedioxypyrovalerone (MDPV) is a potent psychomotor stimulant: self-administration and locomotor activity in rats. Neuropharmacology 71:130–140. https://doi.org/10.1016/j.neuropharm.2013.04.003 CrossRefPubMedPubMedCentral

12.

Allen SA, Tran LH, Oakes HV, Brown RW, Pond BB (2019) Dopaminergic effects of major bath salt constituents 3,4-methylenedioxypyrovalerone (MDPV), mephedrone, and methylone are enhanced following co-exposure. Neurotox Res 36(1):132–143. https://doi.org/10.1007/s12640-019-00020-2 CrossRefPubMed

13.

Anizan S, Concheiro M, Lehner KR, Bukhari MO, Suzuki M, Rice KC, Baumann MH, Huestis MA (2016) Linear pharmacokinetics of 3,4-methylenedioxypyrovalerone (MDPV) and its metabolites in the rat: relationship to pharmacodynamic effects. Addict Biol 21(2):339–347. https://doi.org/10.1111/adb.12201 CrossRefPubMed

14.

Atehortua-Martinez LA, Masniere C, Campolongo P, Chasseigneaux S, Callebert J, Zwergel C, Mai A, Laplanche JL, Chen H, Etheve-Quelquejeu M, Mégarbane B, Benturquia N (2019) Acute and chronic neurobehavioral effects of the designer drug and bath salt constituent 3,4-methylenedioxypyrovalerone in the rat. J Psychopharmacol 33(3):392–405. https://doi.org/10.1177/0269881118822151 CrossRefPubMed

15.

Berquist MD 2nd, Traxler HK, Mahler AM, Baker LE (2016) Sensitization to the locomotor stimulant effects of "bath salt" constituents, 4-methylmethcathinone (4-MMC) and 3,4-methylenedioxypyrovalerone (MDPV), in male Sprague-Dawley rats. Drug Alcohol Depend 164:128–134. https://doi.org/10.1016/j.drugalcdep.2016.05.001 CrossRefPubMedPubMedCentral

16.

Fantegrossi WE, Gannon BM, Zimmerman SM, Rice KC (2013) In vivo effects of abused 'bath salt' constituent 3,4-methylenedioxypyrovalerone (MDPV) in mice: drug discrimination, thermoregulation, and locomotor activity. Neuropsychopharmacology 38(4):563–573. https://doi.org/10.1038/npp.2012.233 CrossRefPubMed

17.

Gatch MB, Taylor CM, Forster MJ (2013) Locomotor stimulant and discriminative stimulus effects of 'bath salt' cathinones. Behav Pharmacol 24(5–6):437–447. https://doi.org/10.1097/FBP.0b013e328364166d CrossRefPubMedPubMedCentral

18.

Giannotti G, Canazza I, Caffino L, Bilel S, Ossato A, Fumagalli F, Marti M (2017) The cathinones MDPV and α-PVP elicit different behavioral and molecular effects following acute exposure. Neurotox Res 32(4):594–602. https://doi.org/10.1007/s12640-017-9769-y CrossRefPubMed

19.

Harvey EL, Burroughs RL, Baker LE (2017) Effects of D1 and D2 receptor antagonists on the discriminative stimulus effects of methylendioxypyrovalerone and mephedrone in male Sprague-Dawley rats trained to discriminate d-amphetamine. Behav Pharmacol 28(7):586–589. https://doi.org/10.1097/FBP.0000000000000328 CrossRefPubMedPubMedCentral

20.

Kohler RJ, Perrine SA, Baker LE (2018) Repeated exposure to 3,4-methylenedioxypyrovalerone and cocaine produces locomotor sensitization with minimal effects on brain monoamines. Neuropharmacology 134(Pt A):22–27. https://doi.org/10.1016/j.neuropharm.2017.10.019 CrossRefPubMed

21.

Marusich JA, Antonazzo KR, Wiley JL, Blough BE, Partilla JS, Baumann MH (2014) Pharmacology of novel synthetic stimulants structurally related to the "bath salts" constituent 3,4-methylenedioxypyrovalerone (MDPV). Neuropharmacology 87:206–213. https://doi.org/10.1016/j.neuropharm.2014.02.016 CrossRefPubMedPubMedCentral

22.

Marusich JA, Grant KR, Blough BE, Wiley JL (2012) Effects of synthetic cathinones contained in "bath salts" on motor behavior and a functional observational battery in mice. Neurotoxicology 33(5):1305–1313. https://doi.org/10.1016/j.neuro.2012.08.003 CrossRefPubMedPubMedCentral

23.

Nguyen JD, Aarde SM, Cole M, Vandewater SA, Grant Y, Taffe MA (2016) Locomotor stimulant and rewarding effects of inhaling methamphetamine, MDPV, and mephedrone via electronic cigarette-type technology. Neuropsychopharmacology 41(11):2759–2771. https://doi.org/10.1038/npp.2016.88 CrossRefPubMedPubMedCentral

24.

Oliver CF, Simmons SJ, Nayak SU, Smith GR, Reitz AB, Rawls SM (2018) Chemokines and 'bath salts': CXCR4 receptor antagonist reduces rewarding and locomotor-stimulant effects of the designer cathinone MDPV in rats. Drug Alcohol Depend 186:75–79. https://doi.org/10.1016/j.drugalcdep.2018.01.013 CrossRefPubMedPubMedCentral

25.

Gannon BM, Russell LN, Modi MS, Rice KC, Fantegrossi WE (2017) Effects of orally self-administered bath salt constituent 3,4-methylenedioxypyrovalerone (MDPV) in mice. Drug Alcohol Depend 179:408–415. https://doi.org/10.1016/j.drugalcdep.2017.06.031 CrossRefPubMedPubMedCentral

26.

Bonano JS, Glennon RA, De Felice LJ, Banks ML, Negus SS (2014) Abuse-related and abuse-limiting effects of methcathinone and the synthetic "bath salts" cathinone analogs methylenedioxypyrovalerone (MDPV), methylone and mephedrone on intracranial self-stimulation in rats. Psychopharmacology 231(1):199–207. https://doi.org/10.1007/s00213-013-3223-5 CrossRefPubMed

27.

Lisek R, Xu W, Yuvasheva E, Chiu YT, Reitz AB, Liu-Chen LY, Rawls SM (2012) Mephedrone ('bath salt') elicits conditioned place preference and dopamine-sensitive motor activation. Drug Alcohol Depend 126(1–2):257–262. https://doi.org/10.1016/j.drugalcdep.2012.04.021 CrossRefPubMedPubMedCentral

28.

Duart-Castells L, López-Arnau R, Buenrostro-Jáuregui M, Muñoz-Villegas P, Valverde O, Camarasa J, Pubill D, Escubedo E (2019) Neuroadaptive changes and behavioral effects after a sensitization regime of MDPV. Neuropharmacology 144:271–281. https://doi.org/10.1016/j.neuropharm.2018.10.005 CrossRefPubMed

29.

López-Arnau R, Duart-Castells L, Aster B, Camarasa J, Escubedo E, Pubill D (2019) Effects of MDPV on dopamine transporter regulation in male rats. Comparison with cocaine. Psychopharmacology 236(3):925–938. https://doi.org/10.1007/s00213-018-5052-z CrossRefPubMed

30.

López-Arnau R, Luján MA, Duart-Castells L, Pubill D, Camarasa J, Valverde O, Escubedo E (2017) Exposure of adolescent mice to 3,4-methylenedioxypyrovalerone increases the psychostimulant, rewarding and reinforcing effects of cocaine in adulthood. Br J Pharmacol 174(10):1161–1173. https://doi.org/10.1111/bph.13771 CrossRefPubMedPubMedCentral

31.

Gannon BM, Williamson A, Suzuki M, Rice KC, Fantegrossi WE (2016) Stereoselective effects of abused "Bath Salt" constituent 3,4-methylenedioxypyrovalerone in mice: Drug discrimination, locomotor activity, and thermoregulation. J Pharmacol Exp Ther 356(3):615–623. https://doi.org/10.1124/jpet.115.229500 CrossRefPubMedPubMedCentral

32.

Kolanos R, Partilla JS, Baumann MH, Hutsell BA, Banks ML, Negus SS, Glennon RA (2015) Stereoselective actions of methylenedioxypyrovalerone (MDPV) to inhibit dopamine and norepinephrine transporters and facilitate intracranial self-stimulation in rats. ACS Chem Neurosci 6(5):771–777. https://doi.org/10.1021/acschemneuro.5b00006 CrossRefPubMed

33.

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. https://doi.org/10.1124/jpet.116.236349 CrossRefPubMedPubMedCentral

34.

Gatch MB, Dolan SB, Forster MJ (2015) Comparative behavioral pharmacology of three pyrrolidine-containing synthetic cathinone derivatives. J Pharmacol Exp Ther 354(2):103–110. https://doi.org/10.1124/jpet.115.223586 CrossRefPubMedPubMedCentral

35.

Kolanos R, Sakloth F, Jain AD, Partilla JS, Baumann MH, Glennon RA (2015) Structural modification of the designer stimulant α-pyrrolidinovalerophenone (α-PVP) influences potency at dopamine transporters. ACS Chem Neurosci 6(10):1726–1731. https://doi.org/10.1021/acschemneuro.5b00160 CrossRefPubMed

36.

Wojcieszak J, Andrzejczak D, Wojtas A, Gołembiowska K, Zawilska JB (2018) Effects of the new generation α-pyrrolidinophenones on spontaneous locomotor activities in mice, and on extracellular dopamine and serotonin levels in the mouse striatum. Forensic Toxicol 36(2):334–350. https://doi.org/10.1007/s11419-018-0409-x CrossRefPubMedPubMedCentral

37.

Paxinos G, Franklin K (2008) The mouse brain in stereotaxic coordinates, 3rd edn. Academic, Cambridge

38.

Larsen MB, Sonders MS, Mortensen OV, Larson GA, Zahniser NR, Amara SG (2011) Dopamine transport by the serotonin transporter: a mechanistically distinct mode of substrate translocation. J Neurosci 31(17):6605–6615. https://doi.org/10.1523/JNEUROSCI.0576-11.2011 CrossRefPubMedPubMedCentral

39.

Matsumoto T, Maeno Y, Kato H, Seko-Nakamura Y, Monma-Ohtaki J, Ishiba A, Nagao M, Aoki Y (2014) 5-hydroxytryptamine- and dopamine-releasing effects of ring-substituted amphetamines on rat brain: a comparative study using in vivo microdialysis. Eur Neuropsychopharmacol 24(8):1362–1370. https://doi.org/10.1016/j.euroneuro.2014.04.009 CrossRefPubMed

40.

Wojcieszak J, Andrzejczak D, Wojtas A, Gołembiowska K, Zawilska JB (2019) Methcathinone and 3-fluoromethcathinone stimulate spontaneous horizontal locomotor activity in mice and elevate extracellular dopamine and serotonin levels in the mouse striatum. Neurotox Res 35(3):594–605. https://doi.org/10.1007/s12640-018-9973-4 CrossRefPubMed

Title: Comparative neuropharmacological studies on three pyrrolidine-containing synthetic cathinones
Authors: Jakub Wojcieszak
Dariusz Andrzejczak
Adam Wojtas
Krystyna Gołembiowska
Jolanta B. Zawilska
Publication date: 01-07-2020
Publisher: Springer Singapore
Published in: Forensic Toxicology / Issue 2/2020
Print ISSN: 1860-8965
Electronic ISSN: 1860-8973
DOI: https://doi.org/10.1007/s11419-020-00523-0

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Comparative neuropharmacological studies on three pyrrolidine-containing synthetic cathinones

Abstract

Purpose

Methods

Results

Conclusions

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusions

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