Effects of aromatic ring-substituted phenethylamines on the release of dopamine and serotonin

Purpose: Significant disturbances of the classical amphetamines on the dopamine (DA) and serotonin (5-HT) systems have been previously reported. However, few studies have been conducted on the effects of new psychoactive phenethylamines on the release of DA and 5-HT. In the present study, the effects of new psychoactive phenethylamines with a variety of aromatic ring substitutions (5-API, 3-FMA, 5-MAPB, and DMMA) on the release of DA and 5-HT were investigated. Methods: Changes of DA, 5-HT and their metabolites in brain microdialysates from rats following exposure to the drugs were examined using a validated liquid chromatography–tandem mass spectrometry method. Their potencies of DA and 5-HT uptake inhibition as well as dopamine transporter (DAT) and serotonin transporter (SERT) binding were also determined. Results: With the exception of DMMA, the drugs markedly affected the extracellular concentration of DA, 5-HT and/or their metabolites in rats and acted as potent inhibitors for DAT and/or SERT. Especially, 5-API potently induced the nonselective release of both DA and 5-HT, which was strongly correlated with a high degree of uptake inhibition and binding affinity to DAT and SERT. The 3-FMA, a methamphetamine analog with a halogen-substituted benzene, induced greater 5-HT release than DA. Conclusions: We found that new psychoactive phenethylamines, with a variety of aromatic ring substitutions, affected the extracellular levels of DA, 5-HT, and/or their metabolites in the nucleus accumbens of rats to varying degrees and in different ways. The current results may assist further research into monoamine neurotransmitter-related mechanisms of new psychoactive phenethylamines. Graphical abstract: [Figure not available: see fulltext.].