Skip to main content

In vivo potency and efficacy of the novel cathinone α-pyrrolidinopentiophenone and 3,4-methylenedioxypyrovalerone: self-administration and locomotor stimulation in male rats

Psychopharmacology volume 232, pages 3045–3055 (2015)Cite this article

Abstract

Rationale

Numerous substituted cathinone drugs have appeared in recreational use. This variety is often a response to legal actions; the scheduling of 3,4-methylenedioxypyrovalerone (MDPV; “bath salts”) in the USA was followed by the appearance of the closely related drug α-pyrrolidinopentiophenone (alpha-PVP; “flakka”).

Objectives

This study aimed to directly compare the efficacy and potency of alpha-PVP with that of MDPV.

Methods

Groups of male Wistar rats were trained in the intravenous self-administration (IVSA) alpha-PVP or MDPV under a fixed-ratio 1 schedule of reinforcement. An additional group was examined for locomotor and body temperature responses to noncontingent administration of MDVP or alpha-PVP (1.0, 5.6, and 10.0 mg/kg, i.p.).

Results

Acquisition of alpha-PVP (0.1 mg/kg/infusion) IVSA resulted in low, yet consistent drug intake and excellent discrimination for the drug-paired lever. Dose substitution (0.05–0.25 mg/kg/infusion) under a fixed-ratio 1 schedule confirmed potency was similar to MDPV in prior studies. In direct comparison to MDPV (0.05 mg/kg/infusion), rats trained on alpha-PVP (0.05 mg/kg/infusion) responded for more infusions but demonstrated similar drug-lever discrimination by the end of acquisition. However, the dose–response (0.018–0.56 mg/kg/infusion) functions of these drugs under a progressive-ratio schedule of reinforcement reflected identical efficacy and potency. Peak locomotor responses to MDPV or alpha-PVP were observed after the 1.0 mg/kg, i.p. dose and lasted ∼2 h. Modest body temperature decreases were of similar magnitude (∼0.75 °C) for each compound.

Conclusions

The potency and efficacy of MDPV and alpha-PVP were very similar across multiple assays, predicting that the abuse liability of alpha-PVP will be significant and similar to that of MDPV.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

USD 39.95

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

References

  • Aarde SM, Angrish D, Barlow DJ, Wright MJ Jr, Vandewater SA, Creehan KM, Houseknecht KL, Dickerson TJ, Taffe MA (2013a) Mephedrone (4-methylmethcathinone) supports intravenous self-administration in Sprague–Dawley and Wistar rats. Addict Biol 18:786–799

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Aarde SM, Huang PK, Creehan KM, Dickerson TJ, Taffe MA (2013b) The novel recreational drug 3,4-methylenedioxypyrovalerone (MDPV) is a potent psychomotor stimulant: self-administration and locomotor activity in rats. Neuropharmacology 71:130–140

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Aarde SM, Huang PK, Dickerson TJ, Taffe MA (2015) Binge-like acquisition of 3,4-methylenedioxypyrovalerone (MDPV) self-administration and wheel activity in rats. Psychopharmacology (Berl). doi:10.1007/s00213-014-3819-4

  • Baumann MH, Ayestas MA Jr, Partilla JS, Sink JR, Shulgin AT, Daley PF, Brandt SD, Rothman RB, Ruoho AE, Cozzi NV (2012) The designer methcathinone analogs, mephedrone and methylone, are substrates for monoamine transporters in brain tissue. Neuropsychopharmacology 37:1192–1203

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • 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 38:552–562

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Borek HA, Holstege CP (2012) Hyperthermia and multiorgan failure after abuse of “Bath Salts” containing 3,4-methylenedioxypyrovalerone. Ann Emerg Med 60:103–105

  • Brown PL, Bae D, Kiyatkin EA (2007) Relationships between locomotor activation and alterations in brain temperature during selective blockade and stimulation of dopamine transmission. Neuroscience 145:335–343

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Colussi-Mas J, Wise RJ, Howard A, Schenk S (2010) Drug seeking in response to a priming injection of MDMA in rats: relationship to initial sensitivity to self-administered MDMA and dorsal striatal dopamine. Int J Neuropsychopharmacol 13:1315–1327

  • Cox B, Lee TF (1979) Evidence for an endogenous dopamine-mediated hypothermia in the rat. Br J Pharmacol 67:605–610

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Crean RD, Davis SA, Von Huben SN, Lay CC, Katner SN, Taffe MA (2006) Effects of (+/−)3,4-methylenedioxymethamphetamine, (+/−)3,4-methylenedioxyamphetamine and methamphetamine on temperature and activity in rhesus macaques. Neuroscience 142:515–525

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Crean RD, Davis SA, Taffe MA (2007) Oral administration of (+/−)3,4-methylenedioxymethamphetamine and (+)methamphetamine alters temperature and activity in rhesus macaques. Pharmacol Biochem Behav 87:11–19

  • Creehan KM, Vandewater SA, Taffe MA (2015) Intravenous self-administration of mephedrone, methylone and MDMA in female rats. Neuropharmacology 92:90–97

    Article  CAS  PubMed  Google Scholar 

  • Dalley JW, Laane K, Theobald DE, Pena Y, Bruce CC, Huszar AC, Wojcieszek M, Everitt BJ, Robbins TW (2007) Enduring deficits in sustained visual attention during withdrawal of intravenous methylenedioxymethamphetamine self-administration in rats: results from a comparative study with d-amphetamine and methamphetamine. Neuropsychopharmacology 32:1195–1206

    Article  CAS  PubMed  Google Scholar 

  • De La Garza R II, Fabrizio KR, Gupta A (2007) Relevance of rodent models of intravenous MDMA self-administration to human MDMA consumption patterns. Psychopharmacology (Berl) 189:425–434

    Article  CAS  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 

  • Drug Enforcement Administration DJ (2014) Schedules of controlled substances: temporary placement of 10 synthetic cathinones into Schedule I. Final order. Fed Regist 79:12938–12943

    Google Scholar 

  • 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 38:563–573

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Feduccia AA, Kongovi N, Duvauchelle CL (2010) Heat increases MDMA-enhanced NAcc 5-HT and body temperature, but not MDMA self-administration. Eur Neuropsychopharmacol 20:884–894

  • Froberg BA, Levine M, Beuhler MC, Judge BS, Moore PW, Engebretsen KM, McKeown NJ, Rosenbaum CD, Young AC, Rusyniak DE, On behalf of the ATIC (2015) Acute methylenedioxypyrovalerone toxicity. J Med Toxicol. doi:10.1007/s13181-014-0446-8

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

  • Gilpin NW, Wright MJ Jr, Dickinson G, Vandewater SA, Price JU, Taffe MA (2011) Influences of activity wheel access on the body temperature response to MDMA and methamphetamine. Pharmacol Biochem Behav 99:295–300

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Hadlock GC, Webb KM, McFadden LM, Chu PW, Ellis JD, Allen SC, Andrenyak DM, Vieira-Brock PL, German CL, Conrad KM, Hoonakker AJ, Gibb JW, Wilkins DG, Hanson GR, Fleckenstein AE (2011) 4-Methylmethcathinone (mephedrone): neuropharmacological effects of a designer stimulant of abuse. J Pharmacol Exp Ther 339:530–536

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Hodos W (1961) Progressive ratio as a measure of reward strength. Science (New York, NY) 134:943–944

    Article  CAS  Google Scholar 

  • Huang PK, Aarde SM, Angrish D, Houseknecht KL, Dickerson TJ, Taffe MA (2012) Contrasting effects of d-methamphetamine, 3,4-methylenedioxymethamphetamine, 3,4-methylenedioxypyrovalerone, and 4-methylmethcathinone on wheel activity in rats. Drug Alcohol Depend 126:168–175

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Kehr J, Ichinose F, Yoshitake S, Goiny M, Sievertsson T, Nyberg F, Yoshitake T (2011) Mephedrone, compared with MDMA (ecstasy) and amphetamine, rapidly increases both dopamine and 5-HT levels in nucleus accumbens of awake rats. Br J Pharmacol 164:1949–1958

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Kesha K, Boggs CL, Ripple MG, Allan CH, Levine B, Jufer-Phipps R, Doyon S, Chi P, Fowler DR (2013) Methylenedioxypyrovalerone (“bath salts”), related death: case report and review of the literature. J Forensic Sci 58:1654–1659

    Article  CAS  PubMed  Google Scholar 

  • King HE, Wetzell B, Rice KC, Riley AL (2014) 3,4-Methylenedioxypyrovalerone (MDPV)-induced conditioned taste avoidance in the F344/N and LEW rat strains. Pharmacol Biochem Behav 126:163–169

    Article  CAS  PubMed  Google Scholar 

  • Kitamura O, Wee S, Specio SE, Koob GF, Pulvirenti L (2006) Escalation of methamphetamine self-administration in rats: a dose–effect function. Psychopharmacology (Berl) 186:48–53

    Article  CAS  Google Scholar 

  • Kiyatkin EA, Kim AH, Wakabayashi KT, Baumann MH, Shaham Y (2015) Effects of social interaction and warm ambient temperature on brain hyperthermia induced by the designer drugs methylone and MDPV. Neuropsychopharmacology 40:436–445

    Article  CAS  PubMed  Google Scholar 

  • Kolanos R, Solis E Jr, Sakloth F, De Felice LJ, Glennon RA (2013) “Deconstruction” of the abused synthetic cathinone methylenedioxypyrovalerone (MDPV) and an examination of effects at the human dopamine transporter. ACS Chem Neurosci 4:1524–1529

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Malberg JE, Seiden LS (1998) Small changes in ambient temperature cause large changes in 3,4-methylenedioxymethamphetamine (MDMA)-induced serotonin neurotoxicity and core body temperature in the rat. J Neurosci 18:5086–5094

    CAS  PubMed  Google Scholar 

  • 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 33:1305–1313

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Miller ML, Creehan KM, Angrish D, Barlow DJ, Houseknecht KL, Dickerson TJ, Taffe MA (2013a) Changes in ambient temperature differentially alter the thermoregulatory, cardiac and locomotor stimulant effects of 4-methylmethcathinone (mephedrone). Drug Alcohol Depend 127:248–253

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Miller ML, Moreno AY, Aarde SM, Creehan KM, Vandewater SA, Vaillancourt BD, Wright MJ Jr, Janda KD, Taffe MA (2013b) A methamphetamine vaccine attenuates methamphetamine-induced disruptions in thermoregulation and activity in rats. Biol Psychiatry 73:721–728

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Motbey CP, Clemens KJ, Apetz N, Winstock AR, Ramsey J, Li KM, Wyatt N, Callaghan PD, Bowen MT, Cornish JL, McGregor IS (2013) High levels of intravenous mephedrone (4-methylmethcathinone) self-administration in rats: neural consequences and comparison with methamphetamine. J Psychopharmacol 27:823–836

    Article  CAS  PubMed  Google Scholar 

  • Myles BJ, Jarrett LA, Broom SL, Speaker HA, Sabol KE (2008) The effects of methamphetamine on core body temperature in the rat—part 1: chronic treatment and ambient temperature. Psychopharmacology (Berl) 198:301–311

    Article  CAS  Google Scholar 

  • Nagai H, Saka K, Nakajima M, Maeda H, Kuroda R, Igarashi A, Tsujimura-Ito T, Nara A, Komori M, Yoshida K (2014) Sudden death after sustained restraint following self-administration of the designer drug alpha-pyrrolidinovalerophenone. Int J Cardiol 172:263–265

    Article  PubMed  Google Scholar 

  • Oakly AC, Brox BW, Schenk S, Ellenbroek BA (2014) A genetic deletion of the serotonin transporter greatly enhances the reinforcing properties of MDMA in rats. Mol Psychiatry 19:534–535

    Article  CAS  PubMed  Google Scholar 

  • Richardson NR, Roberts DC (1996) Progressive ratio schedules in drug self-administration studies in rats: a method to evaluate reinforcing efficacy. J Neurosci Methods 66:1–11

    Article  CAS  PubMed  Google Scholar 

  • Roberts DC, Phelan R, Hodges LM, Hodges MM, Bennett B, Childers S, Davies H (1999) Self-administration of cocaine analogs by rats. Psychopharmacology (Berl) 144:389–397

    Article  CAS  Google Scholar 

  • Schenk S, Hely L, Lake B, Daniela E, Gittings D, Mash DC (2007) MDMA self-administration in rats: acquisition, progressive ratio responding and serotonin transporter binding. Eur J Neurosci 26:3229–3236

    Article  PubMed  Google Scholar 

  • Segal DS, Kuczenski R (1997) Repeated binge exposures to amphetamine and methamphetamine: behavioral and neurochemical characterization. J Pharmacol Exp Ther 282:561–573

    CAS  PubMed  Google Scholar 

  • Segal DS, Mandell AJ (1974) Long-term administration of d-amphetamine: progressive augmentation of motor activity and stereotypy. Pharmacol Biochem Behav 2:249–255

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Simmler LD, Rickli A, Hoener MC, Liechti ME (2014) Monoamine transporter and receptor interaction profiles of a new series of designer cathinones. Neuropharmacology 79:152–160

    Article  CAS  PubMed  Google Scholar 

  • Taffe MA (2011) A comparison of intraperitoneal and subcutaneous temperature in freely moving rhesus macaques. Physiol Behav 103:440–444

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Taffe MA (2012) Delta9-Tetrahydrocannabinol attenuates MDMA-induced hyperthermia in rhesus monkeys. Neuroscience 201:125–133

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Taffe MA, Lay CC, Von Huben SN, Davis SA, Crean RD, Katner SN (2006) Hyperthermia induced by 3,4-methylenedioxymethamphetamine in unrestrained rhesus monkeys. Drug Alcohol Depend 82:276–281

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Taffe MA, Creehan KM, Vandewater SA (2015) Cannabidiol fails to reverse hypothermia or locomotor suppression induced by delta-tetrahydrocannabinol in Sprague–Dawley rats. Br J Pharmacol 172:1783–1791

    Article  CAS  PubMed  Google Scholar 

  • Von Huben SN, Lay CC, Crean RD, Davis SA, Katner SN, Taffe MA (2007) Impact of ambient temperature on hyperthermia induced by (+/−)3,4-methylenedioxymethamphetamine in rhesus macaques. Neuropsychopharmacology 32:673–681

    Article  Google Scholar 

  • Watterson LR, Hood L, Sewalia K, Tomek SE, Yahn S, Johnson CT, Wegner S, Blough BE, Marusich JA, Olive MF (2012) The reinforcing and rewarding effects of methylone, a synthetic cathinone commonly found in “Bath Salts”. J Addict Res Ther S9(002):1–8

    Google Scholar 

  • Watterson LR, Burrows BT, Hernandez RD, Moore KN, Grabenauer M, Marusich JA, Olive MF (2014a) Effects of alpha-Pyrrolidinopentiophenone and 4-Methyl-N-Ethylcathinone, two synthetic cathinones commonly found in second-generation “Bath Salts,” on intracranial self-stimulation thresholds in rats. Int J Neuropsychopharmacol 18(1). doi:10.1093/ijnp/pyu014

  • Watterson LR, Kufahl PR, Nemirovsky NE, Sewalia K, Grabenauer M, Thomas BF, Marusich JA, Wegner S, Olive MF (2014b) Potent rewarding and reinforcing effects of the synthetic cathinone 3,4-methylenedioxypyrovalerone (MDPV). Addict Biol 19:165–174

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Wee S, Anderson KG, Baumann MH, Rothman RB, Blough BE, Woolverton WL (2005) Relationship between the serotonergic activity and reinforcing effects of a series of amphetamine analogs. J Pharmacol Exp Ther 313:848–854

    Article  CAS  PubMed  Google Scholar 

  • Wee S, Carroll FI, Woolverton WL (2006) A reduced rate of in vivo dopamine transporter binding is associated with lower relative reinforcing efficacy of stimulants. Neuropsychopharmacology 31:351–362

    Article  CAS  PubMed  Google Scholar 

  • Wright MJ Jr, Angrish D, Aarde SM, Barlow DJ, Buczynski MW, Creehan KM, Vandewater SA, Parsons LH, Houseknecht KL, Dickerson TJ, Taffe MA (2012) Effect of ambient temperature on the thermoregulatory and locomotor stimulant effects of 4-methylmethcathinone in Wistar and Sprague-Dawley rats. PLoS One 7, e44652

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Wurita A, Hasegawa K, Minakata K, Gonmori K, Nozawa H, Yamagishi I, Suzuki O, Watanabe K (2014) Postmortem distribution of alpha-pyrrolidinobutiophenone in body fluids and solid tissues of a human cadaver. Leg Med Tokyo 16:241–246

Download references

Acknowledgments

This work was funded by support from the US Public Health Service National Institutes of Health (R01 DA024105), which had no direct input on the design, conduct, analysis, or publication of the findings. This is manuscript #28012 from The Scripps Research Institute.

Financial disclosures

The authors report no financial conflicts that are relevant to the conduct of this study.

Author information

Authors and Affiliations

  1. Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, SP30-2400; 10550 North Torrey Pines Road, La Jolla, CA, 92037, USA

    Shawn M. Aarde, Kevin M. Creehan, Sophia A. Vandewater & Michael A. Taffe

  2. Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA

    Tobin J. Dickerson

Authors
  1. Shawn M. Aarde
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kevin M. Creehan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sophia A. Vandewater
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tobin J. Dickerson
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Michael A. Taffe
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michael A. Taffe.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Aarde, S.M., Creehan, K.M., Vandewater, S.A. et al. 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 (2015). https://doi.org/10.1007/s00213-015-3944-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-015-3944-8

Keywords

  • Stimulants
  • Substance abuse
  • Bath salts
  • Self-administration
  • Cathinone
  • Reward