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Analogs of the designer drug, 3,4‐methylenedioxymethcathinone (methylone), differentially affect monoamine transporters in rat brain
Author(s) -
Baumann Michael Howard,
Bukhari Mohammad Omar,
Lehner Kurt Richard,
Partilla John S
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.1186.8
Subject(s) - chemistry , pharmacology , dopamine transporter , cathinone , microdialysis , transporter , nucleus accumbens , dopamine , norepinephrine transporter , monoamine neurotransmitter , extracellular , biochemistry , medicine , amphetamine , serotonin , receptor , gene
The abuse of synthetic cathinone compounds, often sold as “bath salts” or “research chemicals”, is an emerging public health concern. 3,4‐Methylenedioxymethcathinone (methylone) is a popular synthetic cathinone that is now illegal, but new analogs are being marketed as replacements. The purpose of the present investigation was to examine the interaction of new methylone analogs with transporters for dopamine (DAT) and 5‐HT (SERT). β‐Keto‐ N ‐methylbenzodioxolylbutanamine (butylone) and β‐keto‐ N ‐methylbenzodioxolylpentanamine (pentylone) were the analogs studied. In vitro assays were carried out in rat brain synaptosomes to assess drug‐induced effects on transporter‐mediated uptake and release. In vivo microdialysis was carried out in the nucleus accumbens of conscious rats to assess drug‐induced changes in extracellular dopamine and 5‐HT. Methylone, butylone and pentylone were fully efficacious uptake blockers at DAT and SERT, but pentylone was more DAT‐selective than the other drugs. Methylone was a substrate‐type releaser at both transporters, while butylone evoked release at SERT but not at DAT. Pentylone failed to evoke release at either transporter. Administration of butylone (1–3 mg/kg, i.v.) increased extracellular concentrations of 5‐HT more than dopamine, while pentylone (1–3 mg/kg. i.v.) increased both neurotransmitters to the same extent. All drugs produced significant locomotor activation, but the effects of butylone were blunted compared to pentylone. Our data show that each of the compounds examined displays a unique profile of in vitro transporter activity. Butylone has “hybrid” transporter effects, acting as a substrate at SERT but a blocker at DAT. Pentylone is a DAT‐preferring uptake blocker which lacks substrate activity. Overall, the data show that increasing the α‐carbon chain length of methylone creates compounds with reduced releasing activity, converting them to DAT blockers. All of the compounds elevate extracellular dopamine and stimulate motor activity to some degree, suggesting the drugs possess a significant risk for abuse. Support or Funding Information This research was generously supported by the Intramural Research Program of NIDA, NIH, DHHS.