In vivo potency and efficacy of the novel cathinone α-pyrrolidinopentiophenone and 3,4-methylenedioxypyrovalerone: self-administration and locomotor stimulation in male rats
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”).
This study aimed to directly compare the efficacy and potency of alpha-PVP with that of MDPV.
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.).
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.
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.
KeywordsStimulants Substance abuse Bath salts Self-administration Cathinone Reward
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.
The authors report no financial conflicts that are relevant to the conduct of this study.
- 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 37:1192–1203PubMedCentralPubMedCrossRefGoogle 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 38:552–562PubMedCentralPubMedCrossRefGoogle Scholar
- Borek HA, Holstege CP (2012) Hyperthermia and multiorgan failure after abuse of “Bath Salts” containing 3,4-methylenedioxypyrovalerone. Ann Emerg Med 60:103–105Google 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 13:1315–1327Google 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 87:11–19Google 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 32:1195–1206PubMedCrossRefGoogle Scholar
- DEA (2011) Schedules of controlled substances: temporary placement of three synthetic cathinones in Schedule I. Final order. Fed Regist 76:65371–65375Google Scholar
- Drug Enforcement Administration DJ (2014) Schedules of controlled substances: temporary placement of 10 synthetic cathinones into Schedule I. Final order. Fed Regist 79:12938–12943Google 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 20:884–894Google Scholar
- 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 24:437–447Google 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 339:530–536PubMedCentralPubMedCrossRefGoogle 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 126:168–175PubMedCentralPubMedCrossRefGoogle 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 127:248–253PubMedCentralPubMedCrossRefGoogle 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 27:823–836PubMedCrossRefGoogle 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):1–8Google 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
- 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, e44652PubMedCentralPubMedCrossRefGoogle 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 16:241–246Google Scholar