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Forensic Toxicology

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Open Access 01-07-2018 | Original Article

Effects of the new generation α-pyrrolidinophenones on spontaneous locomotor activities in mice, and on extracellular dopamine and serotonin levels in the mouse striatum

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

Published in: Forensic Toxicology | Issue 2/2018

Abstract

Purpose

Pyrovalerone derivatives (α-pyrrolidinophenones) form a distinct branch of synthetic cathinones, a popular group of novel psychoactive substances, and exert strong psychostimulatory effects resulting from their high potency to inhibit dopamine (DA) and norepinephrine transporters, with negligible activity at the serotonin (5-HT) transporter. In contrast to the old generation α-pyrrolidinophenones, 3,4-MDPV and α-PVP, there is limited data on the pharmacology and toxicology of the novel analogs. Therefore, the present study assesses the in vivo effects of two new pyrovalerones, PV8 and PV9, along with those of α-PVP, on spontaneous locomotor activities of mice and extracellular DA and 5-HT levels in the mouse striatum.

Methods

Spontaneous locomotor activity was measured using Opto-Varimex Auto-Track. Effects of tested compounds on extracellular levels of DA and 5-HT in the striatum were studied by an in vivo microdialysis technique; their concentrations in dialysate fractions were analyzed by high-performance liquid chromatography with electrochemical detection.

Results

α-PVP, PV8 and PV9 stimulated mice locomotor activity (an effect being blocked by D₁-dopamine receptor antagonist, SCH 23390), and increased extracellular levels of DA and 5-HT in the striatum. Observed effects depend on dose, time and compound under investigation, with α-PVP being more potent than PV8 and PV9. When used at the same dose, the pyrovalerones produced effects significantly weaker than a model, old generation psychostimulant, methamphetamine.

Conclusions

Enhancement of dopaminergic neurotransmission plays a dominant role in the psychomotor stimulation caused by α-PVP, PV8 and PV9. Extending an aliphatic side chain beyond a certain point leads to the decrease in their potency in vivo.

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EMCDDA (2017) European drug report 2017: trends and developments. http://www.emcdda.europa.eu/publications/edr/trends-developments/2017. Accessed 9 Sept 2017

Zawilska JB, Wojcieszak J (2017) α-Pyrrolidinophenones: a new wave of designer cathinones. Forensic Toxicol 35:201–216. https://doi.org/10.1007/s11419-016-0353-6 CrossRef

Uchiyama N, Kikura-Hanajiri R, Kawahara N, Goda Y (2008) Analysis of designer drugs detected in the products purchased in fiscal year 2006. Yakugaku Zasshi 128:1499–1505. https://doi.org/10.1248/yakushi.128.1499 (in Japanese with English abstract) CrossRefPubMed

EMCDDA (2015) EMCDDA-Europol joint report on a new psychoactive substance: 1-phenyl-2-(1-pyrrolidinyl)-1-pentanone (α-PVP) (September 2015). http://www.emcdda.europa.eu/publications/joint-reports/alpha-pvp_en. Accessed 9 Sept 2017

Hasegawa K, Wurita A, Minakata K, Gonmori K, Nozawa H, Yamagishi I, Suzuki O, Watanabe K (2014) Identification and quantitation of a new cathinone designer drug PV9 in an “aroma liquid” product, antemortem whole blood and urine specimens, and a postmortem whole blood specimen in a fatal poisoning case. Forensic Toxicol 32:243–250. https://doi.org/10.1007/s11419-014-0230-0 CrossRef

Uchiyama N, Matsuda S, Kawamura M, Shimokawa Y, Kikura-Hanajiri R, Aritake K, Urade Y, Goda Y (2014) Characterization of four new designer drugs, 5-chloro-NNEI, NNEI indazole analog, α-PHPP and α-POP, with 11 newly distributed designer drugs in illegal products. Forensic Sci Int 243:1–13. https://doi.org/10.1016/j.forsciint.2014.03.013 CrossRefPubMed

Wojcieszak J, Andrzejczak D, Woldan-Tambor A, Zawilska JB (2016) Cytotoxic activity of pyrovalerone derivatives, an emerging group of psychostimulant designer cathinones. Neurotox Res 30:239–250. https://doi.org/10.1007/s12640-016-9640-6 CrossRefPubMed

Kudo K, Usumoto Y, Kikura-Hanajiri R, Sameshima N, Tsuji A, Ikeda N (2015) A fatal case of poisoning related to new cathinone designer drugs, 4-methoxy PV8, PV9, and 4-methoxy PV9, and a dissociative agent, diphenidine. Leg Med 17:421–426. https://doi.org/10.1016/j.legalmed.2015.06.005 CrossRef

Yonemitsu K, Sasao A, Mishima S, Ohtsu Y, Nishitani Y (2016) A fatal poisoning case by intravenous injection of “bath salts” containing acetyl fentanyl and 4-methoxy PV8. Forensic Sci Int 267:e6–e9. https://doi.org/10.1016/j.forsciint.2016.08.025 CrossRefPubMed

10.

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 25:365–376. https://doi.org/10.1016/j.euroneuro.2014.12.012 CrossRefPubMed

11.

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. https://doi.org/10.1111/j.1476-5381.2012.02145.x CrossRefPubMed

12.

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

13.

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 6:1726–1731. https://doi.org/10.1021/acschemneuro.5b00160 CrossRefPubMedPubMedCentral

14.

Chemsarus (2014) https://chemsarus.com/rc-discussions/stimulants/55159-pv9-a-pop-roas/114944. Accessed 9 Sept 2017

15.

Tripsit Factsheet (2017) PV-8. Basic information. http://drugs.tripsit.me/pv-8. Accessed 9 Sept 2017

16.

Hyperreal (2015) alfa-POP; PV-9. https://hyperreal.info/talk/alfa-pop-t44800.html [Website in Polish]. Accessed 9 Sept 2017

17.

PsychonautWiki (2017) A-PVP. https://psychonautwiki.org/wiki/A-PVP. Accessed 9 Sept 2017

18.

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 232:3045–3055. https://doi.org/10.1007/s00213-015-3944-8 CrossRefPubMedPubMedCentral

19.

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

20.

Kaizaki A, Tanaka S, Numazawa S (2014) New recreational drug 1-phenyl-2-(1-pyrrolidinyl)-1-pentanone (alpha-PVP) activates central nervous system via dopaminergic neuron. J Toxicol Sci 39:1–6. https://doi.org/10.2131/jts.39.1 CrossRefPubMed

21.

Marusich J, 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.

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

23.

Gatch MB, Rutledge MA, Forster MJ (2015) Discriminative and locomotor effects of five synthetic cathinones in rats and mice. Psychopharmacology 232:1197–1205. https://doi.org/10.1007/s00213-014-3755-3 CrossRefPubMed

24.

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. https://doi.org/10.1007/s00213-017-4562-4 CrossRefPubMedPubMedCentral

25.

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 31:6605–6615. https://doi.org/10.1523/JNEUROSCI.0576-11.2011 CrossRefPubMedPubMedCentral

26.

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 24:1362–1370. https://doi.org/10.1016/j.euroneuro.2014.04.009 CrossRefPubMed

Title: Effects of the new generation α-pyrrolidinophenones on spontaneous locomotor activities in mice, and on extracellular dopamine and serotonin levels in the mouse striatum
Authors: Jakub Wojcieszak
Dariusz Andrzejczak
Adam Wojtas
Krystyna Gołembiowska
Jolanta B. Zawilska
Publication date: 01-07-2018
Publisher: Springer Japan
Published in: Forensic Toxicology / Issue 2/2018
Print ISSN: 1860-8965
Electronic ISSN: 1860-8973
DOI: https://doi.org/10.1007/s11419-018-0409-x

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Effects of the new generation α-pyrrolidinophenones on spontaneous locomotor activities in mice, and on extracellular dopamine and serotonin levels in the mouse striatum

Abstract

Purpose

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusions

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