Powerful cocaine-like actions of 3,4-methylenedioxypyrovalerone (MDPV), a principal constituent of psychoactive 'bath salts' products.
The abuse of psychoactive 'bath salts' containing cathinones such as 3,4-methylenedioxypyrovalerone (MDPV) is a growing public health concern, yet little is known about their pharmacology. Here, we evaluated the effects of MDPV and related drugs using molecular, cellular, and whole-animal methods. In vitro transporter assays were performed in rat brain synaptosomes and in cells expressing human transporters, while clearance of endogenous dopamine was measured by fast-scan cyclic voltammetry in mouse striatal slices. Assessments of in vivo neurochemistry, locomotor activity, and cardiovascular parameters were carried out in rats. We found that MDPV blocks uptake of [(3)H]dopamine (IC(50)=4.1 nM) and [(3)H]norepinephrine (IC(50)=26 nM) with high potency but has weak effects on uptake of [(3)H]serotonin (IC(50)=3349 nM). In contrast to other psychoactive cathinones (eg, mephedrone), MDPV is not a transporter substrate. The clearance of endogenous dopamine is inhibited by MDPV and cocaine in a similar manner, but MDPV displays greater potency and efficacy. Consistent with in vitro findings, MDPV (0.1-0.3 mg/kg, intravenous) increases extracellular concentrations of dopamine in the nucleus accumbens. Additionally, MDPV (0.1-3.0 mg/kg, subcutaneous) is at least 10 times more potent than cocaine at producing locomotor activation, tachycardia, and hypertension in rats. Our data show that MDPV is a monoamine transporter blocker with increased potency and selectivity for catecholamines when compared with cocaine. The robust stimulation of dopamine transmission by MDPV predicts serious potential for abuse and may provide a mechanism to explain the adverse effects observed in humans taking high doses of 'bath salts' preparations.
Medicinal Chemistry Section of the Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD 21224, USA. mbaumann@mail.nih.gov
Michael H
MH
Baumann
John S
JS
Partilla
Kurt R
KR
Lehner
Eric B
EB
Thorndike
Alexander F
AF
Hoffman
Marion
M
Holy
Richard B
RB
Rothman
Steven R
SR
Goldberg
Carl R
CR
Lupica
Harald H
HH
Sitte
Simon D
SD
Brandt
Srihari R
SR
Tella
Nicholas V
NV
Cozzi
Charles W
CW
Schindler
D000818:Animals; D052117:Benzodioxoles / Q000737:chemistry / Q000494:pharmacology*; D003042:Cocaine / Q000737:chemistry / Q000494:pharmacology*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D015198:Designer Drugs / Q000737:chemistry / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009924:Organ Culture Techniques; D011619:Psychotropic Drugs / Q000737:chemistry / Q000494:pharmacology*; D011759:Pyrrolidines / Q000737:chemistry / Q000494:pharmacology*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012492:Salts / Q000737:chemistry / Q000494:pharmacology; D000094982:Synthetic Cathinone
D052117:Benzodioxoles; D015198:Designer Drugs; D011619:Psychotropic Drugs; D011759:Pyrrolidines; D012492:Salts; D003042:Cocaine; D004298:Dopamine; D000094982:Synthetic Cathinone