PT - JOURNAL ARTICLE AU - Nicole Centazzo AU - Michel R Chojnacki AU - Joshua S Elmore AU - Raider Rodriguez AU - Teeshavi Acosta AU - Masaki Suzuki AU - Kenner C Rice AU - Michael H Baumann AU - Marta Concheiro TI - <strong>Brain Concentrations of Methylone and its Metabolites After Systemic Methylone Administration: Relationship to Pharmacodynamic Effects</strong> AID - 10.1124/jpet.121.000531 DP - 2021 Jan 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - JPET-AR-2021-000531 4099 - http://jpet.aspetjournals.org/content/early/2021/03/30/jpet.121.000531.short 4100 - http://jpet.aspetjournals.org/content/early/2021/03/30/jpet.121.000531.full AB - 3,4-Methylenedioxy-N-methylcathinone (methylone) is a new psychoactive substance with stimulant properties and potential for abuse. Despite its popularity, limited studies have examined relationships between brain concentrations of methylone, its metabolites, and pharmacodynamic effects. The goal of the present study was two-fold: 1) to determine pharmacokinetics of methylone and its major metabolites, 4-hydroxy-3-methoxy-N-methylcathinone (HMMC), 3,4-dihydroxy-N-methylcathinone (HHMC), and 3,4-methylenedioxycathinone (MDC) in rat brain and plasma; 2) to relate brain pharmacokinetic parameters to pharmacodynamic effects including locomotor behavior and post-mortem neurochemistry. Male Sprague-Dawley rats received s.c. methylone (6, 12, or 24 mg/kg) or saline vehicle (n=16/dose), and subgroups were decapitated after 40 or 120 min. Plasma and prefrontal cortex were analyzed for concentrations of methylone and its metabolites by liquid chromatography-tandem mass spectrometry. Frontal cortex and dorsal striatum were analyzed for dopamine, 5-HT, and their metabolites by high-performance liquid chromatography-electrochemical detection. Brain and plasma concentrations of methylone and its metabolites rose with increasing methylone dose, but brain methylone and MDC concentrations were greater than dose-proportional. Brain-to-plasma ratios for methylone and MDC were &gt;3 (range 3-12), whereas those for HHMC and HMMC were &lt;0.2 (range 0.01-0.2). Locomotor activity score was positively correlated with brain methylone and MDC, whereas cortical 5-HT was negatively correlated with these analytes at 120 min. Our findings show that brain concentrations of methylone and MDC display non-linear accumulation. Behavioral and neurochemical effects of systemically administered methylone are related to brain concentrations of methylone and MDC, but not its hydroxylated metabolites, which do not effectively penetrate into the brain. Significance Statement Behavioral and neurochemical effects of methylone are related to brain concentrations of methylone and its metabolite MDC, but not its hydroxylated metabolites, HMMC and HHMC, which do not effectively penetrate into the brain. Methylone and MDC display non-linear accumulation in the brain, which could cause untoward effects on 5-HT neurons in vulnerable brain regions, including the frontal cortex.