T. Steinkellner et al.
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Amphetamine and congeners.The chemical structures of amphetamines and the congeners areshown as indicated (the chemical names in parentheses representthe IUPAC names): amphetamine
street name: ‘Speed’;
street name:‘crank’ or ‘Crystal meth’;
, 3,4-methylenedioxymethamphetamine or MDMA
streetname: ‘Ecstasy’; 1-(1,3-benzodioxol-5-yl)-
amino and carboxy termini are located within the cell andcontain multiple consensus sites for protein kinase C (PKC),protein kinase A and Ca
/calmodulin-dependent proteinkinase (Vaughan, 2004). A crystal structure of a bacterialtransporter LeuT
has been available for several years(Yamashita et al., 2005). LeuT
was originally thought tobe a leucine transporter (hence its name), but it transportsother substrates such as alanine more efficiently. LeuT
isa bacterial homolog of the NSS and its structure has provideda template for educated guesses on the structure-functionrelationship in SLC6 family members (Forrest et al., 2008;Shi et al., 2008; Zhao et al., 2010).Amphetamines act as competitive substrates at NAT, DATand SERT. Therefore, the reuptake of endogenous neuro-transmitters is reduced in their presence. Concomitantly and– more importantly – they also induce reverse transport of endogenous neurotransmitter and hence non-exocytotic neuro-transmitter release (Sitte and Freissmuth, 2010). Such actionslead to a significant increase in the levels of extracellularserotonin (5-HT), NA and dopamine (DA) and are thoughtto account for the majority of acute amphetamine-inducedbehavioural and psychological effects (Green et al., 2003).Amphetamines also inhibit the action of vesicular mono-amine transporters (VMATs) and monoamine oxidases(MAOs), although at significantly lower concentrations thanthat required for non-exocytotic neurotransmitter release. Forexample, MDMA inhibits MAO-A 10 times more potentlythan MAO-B, yet possesses an IC
value of only 44
atMAO-A (Leonardi and Azmitia, 1994) and approximately30
(Partilla et al., 2006) when analysed in rattissue
, both of which are approximately 500-foldhigher than its EC
) for 5-HT release in ratsynaptosomes (Baumann et al., 2007). Furthermore, phar-macological doses (0.3–1 mg/kg) of MDMA, METH and
-AMPH do not block MAO activity when administered tomale Sprague-Dawley rats
(Zolkowska et al., 2006),whereas the MAO-A inhibitor clorgyline has been shown tosynergistically enhance the effects of higher doses of MDMA(10–40 mg/kg) on serotonin mediated behaviour, body tem-perature and 5-HT release in rats (Hewton et al., 2007; Alveset al., 2009b). In contrast to MAO-A, both the gene silencingand inhibition of MAO-B protected against MDMA-induced5-HT neurotoxicity and oxidative mitochondrial damage inrats (Sprague and Nichols, 1995; Falk et al., 2002; Hrometzet al., 2004; Alves et al., 2007), whereas 5-HT (but not DAdepletions) are reduced in MAO-B deficient mice followingchronic MDMA administration (Fornai et al., 2001). Thus,although MAOs clearly play a role in the mediation of chron-ic MDMA-induced neurotoxicity in rodents, the overall sig-nificance of MDMA-induced VMAT and MAO inhibition inacute central drug effects at pharmacological doses
is as yet unclear.The affinity for DAT, NAT and SERT differs amongamphetamines: for instance, the addition of the 3,4-methy-lenedioxy group to the phenyl ring of MDMA significantlyincreases its affinity for SERT and NAT over DAT (Capelaet al., 2009). The selectivity of METH, MDMA and
-AMPH for different monoamine transporters has also beenassociated with the specificity of their neurotoxic actions tothe underlying monoaminergic neuronal systems. For exam-ple, METH has been reported to exert selective neurotoxicityin the dopaminergic nigrostriatal system, comparable to thatof the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyri-dine (MPTP). Subsequently, both MPTP and METH are usedto produce animal models of Parkinson’s disease (PD) (Son-salla et al., 1996; Harvey et al., 2000; Granado et al., 2010),even though an increased risk of PD in chronic humanMETH abusers has yet to be confirmed by epidemiologicaldata (Guilarte, 2001; Chang et al., 2007).
-AMPH has alsobeen reported to induce dopaminergic neurotoxicity in non-human primates when administered at doses equivalent tothose used in the treatment of ADHD (Ricaurte et al., 2005).In contrast, MDMA is regarded as a selective serotonergicneurotoxin and has been associated with cognitive dysfunc-tion in humans (Karlsen et al., 2008). All three drugs haveaddictive potential and can lead to varying degrees of drugdependence.
Acute MDMA toxicity and death in humans
MDMA abuse can lead to death. However, in comparison tothe widespread use of MDMA, fatal intoxications are rareevents (EMCDDA, 2009), the majority of which are accom-panied by acute hyperthermia, hyponatramia, cardiovascularcollapse and rhabdomyolysis (Lyles and Cadet, 2003; Halland Henry, 2006). The direct mechanisms that underlie thetoxic actions are difficult to elucidate because, in the major-ity of cases, MDMA is not the only drug involved. AcuteMDMA toxicity in humans appears to be mainly due to the