Mephedrone induces partial release at human dopamine transporters but full release at human serotonin transporters
Felix P. Mayer, Marco Niello, Simon Bulling, Yuan-Wei Zhang, Li Yang, Oliver Kudlacek, Marion Holy, Fatemeh Kooti, Walter Sandtner, Gary Rudnick, Diethart Schmid, Harald H. Sitte
Neuropharmacology September 11, 2023 DOI: 10.1016/j.neuropharm.2023.109704 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | In vitro pharmacological study Peer reviewed |
|---|---|
| Population | Human embryonic kidney 293 cells heterologously expressing human dopamine and serotonin transporters |
| Interventions | Mephedrone GF109203X S(+)-amphetamine para-chloroamphetamine |
| Topics | Serotonin |
| Citations | 4 |
| Key points | Mephedrone evokes carrier-mediated release via hDAT and hSERT, is actively transported by both, and acts as a full substrate of hSERT but a partial substrate of hDAT. It shows greater releasing efficacy at hSERT than at hDAT, which the authors propose may relate to its empathogenic versus stimulant effects. |
Abstract
Mephedrone (4-methylmethcathinone) is a cathinone derivative that is recreationally consumed for its energizing and empathogenic effects. The stimulating properties are believed to arise from the ability of mephedrone to interact with the high-affinity transporters for dopamine (DA) (DAT) and norepinephrine (NET), whereas the entactogenic effect presumably relies on its activity at the serotonin (5-HT) transporter (SERT). Early studies found that mephedrone acts as a releaser at NET, DAT and SERT, and thus promotes efflux of the respective monoamines. Evidence linked drug-induced reverse transport of 5-HT via SERT to prosocial effects, whereas activity at DAT is strongly correlated with abuse liability. Consequently, we sought to evaluate the pharmacology of mephedrone at human (h) DAT and SERT, heterologously expressed in human embryonic kidney 293 cells, in further detail. In line with previous studies, we report that mephedrone evokes carrier-mediated release via hDAT and hSERT. We found this effect to be sensitive to the protein kinase C inhibitor GF109203X. Electrophysiological recordings revealed that mephedrone is actively transported by hDAT and hSERT. However, mephedrone acts as a full substrate of hSERT but as a partial substrate of hDAT. Furthermore, when compared to fully efficacious releasing agents at hDAT and hSERT (i.e. S(+)-amphetamine and para-chloroamphetamine, respectively) mephedrone displays greater efficacy as a releaser at hSERT than at hDAT. In summary, this study provides additional insights into the molecular mechanism of action of mephedrone at hDAT and hSERT.
Comparable studies
Other preclinical and animal studies on serotonin, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Mice | 2021 | Observational cohort | |
| Neurotoxicity of the psychedelic amphetamine, methylenedioxymethamphetamine. Rats (implied by typical neurochemical study context) | 1987 | Experimental study | |
| Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors In vitro and in vivo (rodent) models | 2023 | Experimental study | |
| 3,4-Methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine destroy serotonin terminals in rat brain: quantification of neurodegeneration by measurement of [3H]paroxetine-labeled serotonin uptake sites. Rat brain | 1987 | Animal experiment | |
| Comparison of the monoamine transporters from human and mouse in their sensitivities to psychostimulant drugs Human and mouse dopamine, norepinephrine, and serotonin transporters expressed in cells | 2006 | In vitro laboratory study |
Citations in the library
Cites 18
- Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin Synapse 2000
- Serotonin transporter-ibogaine complexes illuminate mechanisms of inhibition and transport. Nature May 1, 2019
- Designer drugs: mechanism of action and adverse effects Archives of Toxicology April 1, 2020
- Which neuroreceptors mediate the subjective effects of MDMA in humans? A summary of mechanistic studies Human Psychopharmacology: Clinical and Experimental December 1, 2001
- Ibogaine, a noncompetitive inhibitor of serotonin transport, acts by stabilizing the cytoplasm-facing state of the transporter. Journal of Biological Chemistry October 5, 2007
and 13 more in the library