The synthetic cathinones, butylone and pentylone, are stimulants that act as dopamine transporter blockers but 5-HT transporter substrates

• Published in: Psychopharmacology Vol. 236; no. 3; pp. 953 - 962
• Main Authors: Saha, Kusumika, Li, Yang, Holy, Marion, Lehner, Kurt R., Bukhari, Mohammad O., Partilla, John S., Sandtner, Walter, Sitte, Harald H., Baumann, Michael H.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01-03-2019; Springer; Springer Nature B.V
• Subjects: 3,4-Methylenedioxyamphetamine - analogs & derivatives; 3,4-Methylenedioxyamphetamine - chemistry; 3,4-Methylenedioxyamphetamine - pharmacology; Abuse; Alkaloids - chemistry; Alkaloids - pharmacology; Amphetamines - chemistry; Amphetamines - pharmacology; Animals; Biomedical and Life Sciences; Biomedicine; Brain; Central Nervous System Stimulants - chemistry; Central Nervous System Stimulants - pharmacology; Dopamine; Dopamine Antagonists - chemistry; Dopamine Antagonists - pharmacology; Dopamine Plasma Membrane Transport Proteins - antagonists & inhibitors; Dopamine Plasma Membrane Transport Proteins - metabolism; Dopamine transporter; Dose-Response Relationship, Drug; HEK293 Cells; Humans; Male; Methamphetamine - analogs & derivatives; Methamphetamine - chemistry; Methamphetamine - pharmacology; Microdialysis; Monoamines; Motor activity; Neurosciences; Nucleus accumbens; Nucleus Accumbens - drug effects; Nucleus Accumbens - metabolism; Original Investigation; Pharmacology/Toxicology; Phenols (Class of compounds); Psychiatry; Rats; Rats, Sprague-Dawley; Rodents; Stimulants; Substrates; Synaptosomes; Synaptosomes - drug effects; Synaptosomes - metabolism; Synthetic Drugs - chemistry; Synthetic Drugs - pharmacology; Neurochemistry; Dopamine; Microdialysis; 5-HT; Transporter; Cathinone
• ISSN: 0033-3158; 1432-2072
• DOI: 10.1007/s00213-018-5075-5

Rationale
Synthetic cathinones continue to emerge in recreational drug markets worldwide. 1-(1,3-Benzodioxol-5-yl)-2-(methylamino)butan-1-one (butylone) and 1-(1,3-benzodioxol-5-yl)-2-(methylamino)pentan-1-one (pentylone) are derivatives of the cathinone compound, 1-(1,3-benzodioxol-5-yl)-2-(methylamino)propan-1-one (methylone), that are being detected in drug products and human casework.
Objectives
The purpose of the present study was to examine the neuropharmacology of butylone and pentylone using in vitro and in vivo methods.
Methods
In vitro uptake and release assays were carried out in rat brain synaptosomes and in cells expressing human dopamine transporters (DAT) and 5-HT transporters (SERT). In vivo microdialysis was performed in the nucleus accumbens of conscious rats to assess drug-induced changes in neurochemistry.
Results
Butylone and pentylone were efficacious uptake blockers at DAT and SERT, though pentylone was more DAT-selective. Both drugs acted as transporter substrates that evoked release of [
3
H]5-HT at SERT, while neither evoked release at DAT. Consistent with the release data, butylone and pentylone induced substrate-associated inward currents at SERT but not DAT. Administration of butylone or pentylone to rats (1 and 3 mg/kg, i.v.) increased extracellular monoamines and motor activity, but pentylone had weaker effects on 5-HT and stronger effects on motor stimulation.
Conclusions
Our data demonstrate that increasing the α-carbon chain length of methylone creates “hybrid” transporter compounds which act as DAT blockers but SERT substrates. Nevertheless, butylone and pentylone elevate extracellular dopamine and stimulate motor activity, suggesting both drugs possess significant risk for abuse.