AbstractsBiology & Animal Science

Neuropharmacology and toxicology of novel amphetamine-type stimulants

by Bjørnar den Hollander




Institution: University of Helsinki
Department: Institute of Biomedicine, Pharmacology
Year: 2015
Keywords: medicine
Record ID: 1146043
Full text PDF: http://hdl.handle.net/10138/152655


Abstract

In recent years there has been a large increase in the use of a new kind of amphetamine- type stimulants known as substituted cathinones. These compounds have a short history of human use, and little is known about their potential neurotoxicity. Two of the most popular substituted cathinones, 4-methylmethcathinone (4-MMC, mephedrone) and 3,4- methylenedioxymethcathinone (MDMC, methylone} are, aside from their β-ketone group, close structural analogues of potentially neurotoxic amphetamines such as methamphetamine (METH) and 3,4-methylenedioxymethamphetamine (MDMA, ecstasy). This has led to concern about the potential neurotoxicity of these novel compounds, and warrants a closer investigation into their possible long-term neurotoxic effects. METHODS The long-term effects of METH and MDMA as well as 4-MMC and MDMC were assessed using a range of biochemical assays, including assessment of monoamine levels and their transporters. The effects on brain activity were investigated using manganese-enhanced magnetic resonance imaging. Furthermore, behavioral experiments assessing cognition and neuropsychiatric function were performed. Finally, in vitro experiments in a neuroblastoma cell line were performed to identify mechanisms responsible for the observed differences in toxicity between the amphetamines and cathinones. RESULTS Unlike METH and MDMA, which produced strong reductions in dopamine and serotonin levels or brain activation, 4-MMC produced few notable effects on monoamine levels and had only minor effects on brain activation, although MDMC produced a reduction in 5-HT levels similar to MDMA. No clear effects on behavioral tests of memory function were observed as both increases and decreases in test performance were seen following 4- MMC and MDMC. In vitro experiments revealed that cathinones differ from amphetamines in their redox properties, and 4-MMC produced different effects than METH on the mitochondrial electron transport chain. CONCLUSIONS The substituted cathinones 4-MMC and MDMC do not appear to be more neurotoxic than METH and MDMA. If anything, they show a more favorable safety profile. Therefore, these substances do not appear to present an imminent and severe threat to public health. From a harm reduction perspective, these compounds may be good alternatives toMETH and MDMA. However, future work is needed to assess with certainty the long- term effects of amphetamine-type stimulants in humans. Miten myrkyllisiä muuntohuumeet ovat? Viime vuosina on tullut saataville uusia huumaavasti vaikuttavia aineita, jotka on hieman muutettu aikaisemmin tunnetuista laittomista huumeista. Näitä muuntohuumeita olivat mm. mefedroni, metyloni, MDPV ja alfa-PVP. Niitä myytiin aluksi internetin kautta, kunnes viranomaiset saivat ne luokitelluksi huumausaineiksi. Suurena huolena näiden uusien aineiden käytössä oli se, ettei niiden myrkyllisyydestä tai pitkäaikaisista haitoista ollut tutkimustuloksia. Käyttäjät ottivatkin suuren riskin kokeillessaan näitä laillisia huumeita (legal highs) heti niiden tullessa…