The psychoactive aminoalkylbenzofuran derivatives, 5-APB and 6-APB, mimic the effects of 3,4-methylenedioxyamphetamine (
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ORIGINAL INVESTIGATION
The psychoactive aminoalkylbenzofuran derivatives, 5-APB and 6-APB, mimic the effects of 3,4-methylenedioxyamphetamine (MDA) on monoamine transmission in male rats Simon D. Brandt 1 & Hailey M. Walters 2 & John S. Partilla 2 & Bruce E. Blough 3 & Pierce V. Kavanagh 4 & Michael H. Baumann 2 Received: 27 May 2020 / Accepted: 20 August 2020 # This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply 2020
Abstract Rationale The nonmedical use of new psychoactive substances (NPS) is a worldwide public health concern. The so-called “benzofury” compounds, 5-(2-aminopropyl)benzofuran (5-APB) and 6-(2-aminopropyl)benzofuran (6-APB), are NPS with stimulant-like properties in human users. These substances are known to interact with monoamine transporters and 5-HT receptors in transfected cells, but less is known about their effects in animal models. Methods Here, we used in vitro monoamine transporter assays in rat brain synaptosomes to characterize the effects of 5-APB and 6-APB, together with their N-methyl derivatives 5-MAPB and 6-MAPB, in comparison with 3,4-methylenedioxyamphetamine (MDA) and 3,4-methylenedioxymethamphetamine (MDMA). In vivo neurochemical and behavioral effects of 5-APB (0.3 and 1.0 mg/kg, i.v.) and 6-APB (0.3 and 1.0 mg/kg, i.v.) were assessed in comparison with MDA (1.0 and 3.0 mg/kg, i.v.) using microdialysis sampling in the nucleus accumbens of conscious male rats. Results All four benzofuran derivatives were substrate-type releasers at dopamine transporters (DAT), norepinephrine transporters (NET), and serotonin transporters (SERT) with nanomolar potencies, similar to the profile of effects produced by MDA and MDMA. However, the benzofurans were at least threefold more potent than MDA and MDMA at evoking transportermediated release. Like MDA, both benzofurans induced dose-related elevations in extracellular dopamine and serotonin in the brain, but benzofurans were more potent than MDA. The benzofuran derivatives also induced profound behavioral activation characterized by forward locomotion which lasted for at least 2 h post-injection. Conclusions Overall, benzofurans are more potent than MDA in vitro and in vivo, producing sustained stimulant-like effects in rats. These data suggest that benzofuran-type compounds may have abuse liability and could pose risks for adverse effects, especially if used in conjunction with abused drugs or medications which enhance monoamine transmission in the brain. Keywords Benzofury . Designer drugs . Monoamine transporter . Release . Microdialysis . Locomotor activity . Synthetic stimulants . MDMA, MDA
Introduction * Michael H. Baumann [email protected] 1
School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Byrom Street, L3 3AF, Liverpool, UK
2
Designer Drug Research Unit, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, 333 Cassell Drive, Suite 4400, Baltimore, MD 21224, USA
3
Center for Drug Discovery
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