It is the aim of this paper to review and integrate relevant empirical findings and theoretical discussions concerning the molecular and cellular mechanisms and effects of MDMA-induced 5-HT neurotoxicity in laboratory animals. 3,4-methylenedioxymethamphetamine (MDMA) is a derivative of the synthetic psychostimulant methamphetamine (METH). It also shares some structural and pharmacological properties of mescaline, a naturally occurring psychedelic hallucinogen. At the molecular level, all three substances resemble the monoamine neurotransmitters epinephrine (E) and dopamine (DA). They mimic the neurophysiological actions and effects of E and DA, as well as serotonin (5-HT). METH and MDMA do so by binding to, and reversal of monoamine-specific transporter proteins at the presynaptic plasma membrane. While the psychological effects of METH are mainly due its action as a DA release agent and reuptake inhibitor, MDMA primarily affects the serotonergic system. It has a high affinity for the serotonin-specific transporter (SERT), which carries it into the presynaptic neuron. Inside the cell, MDMA inhibits the vesicular monoamine transporter type 2 (VMAT2), pre-venting intracellular 5-HT from being stored in synaptic vesicles. In addition, MDMA phos-phorylates SERT, which causes a reversal of its reuptake function and, hence, non-exocytotic efflux of 5-HT by the means of passive diffusion. Because neurotransmitter release normally only occurs in case of an action potential, and the released transmitter is partly reabsorbed and recycled, the reverse functioning of SERT depletes 5-HT stores. The equivalent effect of METH via reversal of the DA transporter (DAT) has been linked to its neurotoxic properties (Yamamoto & Zhu, 1998). As a derivative of methamphetamine, MDMA is sometimes believed to have inherited the severe dopaminergic neurotoxicity of METH and its parent compound amphetamine. Such neurotoxic potential has been found in mice but not in rats (Colado, O’Shea, and Green, 2004), and remains to be established for non-human primates. The probably most prominent publication claiming that MDMA caused irreversible damage to primate DA neurons (Ricaurte et al., 2002) was shown to be in error and had to be retracted. Instead of a recreational dose of MDMA (3 2 mg/kg), the monkeys had, in fact, been given METH, which, at such doses, is known to be neurotoxic in primates (Villemagne et al., 1998). [...]
Introduction
3,4-methylenedioxymethamphetamine (MDMA) is a derivative of the synthetic psychostimulant methamphetamine (METH). It also shares some structural and pharmacological properties of mescaline, a naturally occurring psychedelic hallucinogen. At the molecular level, all three substances resemble the monoamine neurotransmitters epinephrine (E) and dopamine (DA). They mimic the neurophysiological actions and effects of E and DA, as well as serotonin (5-HT). METH and MDMA do so by binding to, and reversal of monoamine-specific transporter proteins at the presynaptic plasma membrane.
While the psychological effects of METH are mainly due its action as a DA release agent and reuptake inhibitor, MDMA primarily affects the serotonergic system. It has a high affinity for the serotonin-specific transporter (SERT), which carries it into the presynaptic neuron. Inside the cell, MDMA inhibits the vesicular monoamine transporter type 2 (VMAT2), preventing intracellular 5-HT from being stored in synaptic vesicles. In addition, MDMA phosphorylates SERT, which causes a reversal of its reuptake function and, hence, non-exocytotic efflux of 5-HT by the means of passive diffusion. Because neurotransmitter release normally only occurs in case of an action potential, and the released transmitter is partly reabsorbed and recycled, the reverse functioning of SERT depletes 5-HT stores. The equivalent effect of METH via reversal of the DA transporter (DAT) has been linked to its neurotoxic properties (Yamamoto & Zhu, 1998).
As a derivative of methamphetamine, MDMA is sometimes believed to have inherited the severe dopaminergic neurotoxicity of METH and its parent compound amphetamine. Such neurotoxic potential has been found in mice but not in rats (Colado, O’Shea, and Green, 2004), and remains to be established for non-human primates. The probably most prominent publication claiming that MDMA caused irreversible damage to primate DA neurons (Ricaurte et al., 2002) was shown to be in error and had to be retracted. Instead of a recreational dose of MDMA (3Abbildung in dieser Leseprobe nicht enthalten 2 mg/kg), the monkeys had, in fact, been given METH, which, at such doses, is known to be neurotoxic in primates (Villemagne et al., 1998).
While MDMA interacts with the DA system to a lesser extent than amphetamines and evidence for its dopaminergic neurotoxicity remain controversial, it has been repeatedly demonstrated to cause long-term changes in 5-HT systems of rodents and primates. Although there is an ongoing debate about appropriate research designs, transferability of species-specific data as well as implications for clinical and recreational use of MDMA, it can be assumed that MDMA is selectively neurotoxic to serotonergic neurons (Baggott & Mendelson, 2001). It is the aim of this paper to review and integrate relevant empirical findings and theoretical discussions concerning the molecular and cellular mechanisms and effects of MDMA-induced 5-HT neurotoxicity in laboratory animals. Given the almost unmanageable quantity of publications on this topic and the multidimensionality of their scientific and clinical ramifications, this summery will by no means be exhaustive.
Serotonergic changes and neurotoxicity
In various laboratory animals, MDMA has been found to cause long-lasting (Abbildung in dieser Leseprobe nicht enthalten 7 days) decreases in serotonergic markers such as the brain concentrations of 5-HT and its major metabolite 5-hydroxyindoleacetic acid (5-HIAA), the intracellular level of tryptophan hydroxylase (TPH) – the rate-limiting enzyme of 5-HT biosynthesis – and the density of presynaptic SERT (Sprague, Everman, and Nichols, 1998). It has been suggested that such neurochemical and morphological abnormalities result from adaptive down regulation rather than damage or permanent loss of serotonergic axons (e.g., O'Callaghan & Miller, 2001). Indeed, non-lasting downregulation of 5-HT synthesis and postsynaptic receptor expression could be interpreted as an adaptive response to the excessive release of 5-HT during the acute action of MDMA. Conversely, the eventual decrease in 5-HT release would predict an upregulation of these components. In fact, serotonergic functioning does temporarily recover from the acute effects of MDMA. However, depletion of 5-HT as well as diminished expression of other serotonergic markers can last for months (in rodents) or even years (in non-human primates) after administration of MDMA (Green et al., 2003). Solely, the availability of postsynaptic receptor sites (e.g. 5-HT2A) seems to be subject to chronic upregulation (following acute downregulation), possibly as compensation for chronic 5-HT shortage as a late effect of MDMA (Reneman et al., 2000).
As indicated above, MDMA has a biphasic effect on serotonergic functioning. In rats, the acute 5-HT dump is followed by a partial recovery and eventually (within 24 h of dosing) a sustained decrease (Abbildung in dieser Leseprobe nicht enthalten 2 weeks) of 5-HT and 5-HIAA tissue levels (Schmidt, 1987; Stone 1987). Severe reductions in 5-HT and 5-HIAA concentrations occur in the rat neocortex, striatum and hippocampus, and have been associated with axonal damage (De Souza, Battaglia, & Insel, 1990). MDMA-induced inactivation of TPH, which shows 15 minutes after administration, shows less short-term recovery than 5-HT levels, and can last for up to two weeks (Schmidt & Taylor, 1987). Loss of SERT occurs within 7 days post-administration (Xie et al., 2006). Regionally confined regeneration of 5-HT uptake sites is possible even after high doses of MDMA (e.g., 2 Abbildung in dieser Leseprobe nicht enthalten 20 mg/kg Abbildung in dieser Leseprobe nicht enthalten 4 days), and may take up to a year, but functional 5-HT uptake may still be permanently impaired (De Souza et al. 1990). However, it is not entirely ruled out that persistent changes in 5-HT systems reflect either a state of “metabolic quiescence” (Baumann, Wang, & Rothman, 2007) or even “healthy and adaptive neuroplasticity” (Grob & Polond, 1997) rather than neurotoxic damage.
In addition to biochemical markers, there is histological and physiological evidence for degeneration, long-term impairment and even axonal loss of 5-HT neurons throughout the neocortex and striatum as well as in the thalamus and dorsal raphe nucleus (Lyles & Cadet, 2003). O’Hearn et al. (1988), for instance, reported swelling and fragmentation of immunohistochemically stained serotonergic axon terminals in the forebrain of rats, occurring shortly after administration of MDMA (2 Abbildung in dieser Leseprobe nicht enthalten 20 mg/kg Abbildung in dieser Leseprobe nicht enthalten 2 days). It has been argued that such terminal degenerations are also seen with high-dose regimens of selective 5-HT reuptake inhibitors (SSRIs) such as fluoxetine (Prozac), and yet these compounds are recognized as therapeutic drugs rather than neurotoxins (Baumann, Wang, & Rothman, 2007). Interestingly enough, fluoxetine does not deplete brain 5-HT levels, which suggests that the morphological changes induced by MDMA or SSRIs are not a consequence of 5-HT depletion (Kalia et al., 2000). What actually causes these deformations and to what degree they reflect long-term effects on serotonergic neurons, remains to be resolved. The fact remains, however, that later measurements (at 2 and 4 weeks) done by O’Hearn et al. (1988) showed a persistent decrease in stained axons, which presumably indicates their loss. This assumption is backed up by findings gained through other techniques than immunohistochemistry. Ricaurte et al. (2000) measured rats’ anterograde transport of [ 3H ] proline in ascending 5-HT axons that originate in the dorsal raphe nuclei and project to various forebrain regions. Their results suggest a loss of axons at least at some neurotoxic regimens of MDMA. The same team also measured the density of VMAT2 proteins on synaptic vesicles in striatal 5-HT axon terminals of baboons. Neurotoxic regimens of MDMA have been shown to decrease VMAT2, which suggests that nerve terminals and axons have been lost (Ricaurte et al., 2000).
MDMA-induced neuronal oxidative stress
Although MDMA has repeatedly been shown to induce persistent serotonergic changes interpreted as selective neurotoxicity, the molecular and cellular mechanisms underlying its toxic effects are not fully understood. Sprague et al. (1998) proposed an “integrated hypothesis for the serotonergic axonal loss”, which states that MDMA itself is not neurotoxic and that the associated neural damage is actually caused by metabolites of MDMA and DA. Other (complementary) explanations involve neuronal energy exhaustion (Huether, Zhou, and Rüther, 1997), hyperthermia, 5-HT metabolites or excess of intraneuronal calcium, nitric oxide or glutamate (Lyles & Cadet, 2003). For reasons of brevity and clarity, this section will focus on the role of MDMA and DA metabolism in intracellular oxidative stress as mediator of MDMA-induced neurotoxicity.
Oxidative stress is caused by increased formation of reactive oxygen species (ROS), such as free radicals and peroxides, which are byproducts of oxygen (O2) metabolism. ROS ions and molecules can damage proteins, lipids and the DNA of organic cells but are usually readily detoxified by intra- and extracellular enzymes as well as antioxidant molecules (e.g. Vitamin C). However, sufficient concentrations of ROS can overwhelm the protective capabilities of the body’s ROS scavenging system. It has been demonstrated that MDMA regimens with neurotoxic effects increase the amount of extracellular ROS, namely hydroxyl radicals, in the striatum (Shankaran, Yamamoto, and Gudelsky, 1999) and hippocampus (Colado et al., 1999). Their formation may result, for instance, from metabolism of 3,4-dihydro-xymethamphetamine (HHMA), the major metabolite of MDMA (Hiramatsu et al., 1990). They react with any oxidizable compound in their proximity, and can induce a chain reaction of lipid and protein destruction, “analogous to a ‘spark’ that starts a fire” (McKersie, 1996).
Hydroxyl radicals are believed to suppress 5-HT synthesis through oxidation of TPH enzymes (Baggott & Mendelson, 2001). To exert this effect, they would need to enter the nerve cell, or rather be generated there, as their in vivo half-life (Abbildung in dieser Leseprobe nicht enthalten) is too short for diffusion. Therefore, it seems likely that some toxic MDMA metabolites, like 5-HT and MDMA itself, are substrates for SERT proteins. Once inside the cell, they are further metabolized, with free radicals as byproducts. Since direct injections of MDMA into rat or mice brain do not cause the neurotoxic effects seen with the same brain concentrations (e.g. 100 Abbildung in dieser Leseprobe nicht enthalteng) following administration via peripheral routes (Escobedo et al., 2005; Esteban et al., 2001), it appears that toxic metabolites of MDMA are only formed in the periphery.
HHMA is formed in the liver by Cytochrome P450 2D6 (CYP2D6) and metabolized by Catechol-O-methyl transferase (COMT), an intraneuronal enzyme. However, COMT is only found in postsynaptic neurons, where it degrades catecholamine neurotransmitters (i.e. DA, E, and norepinephrine, NE), while MDMA-induced neurotoxicity is selective for 5-HT neurons. Therefore, HHMA itself can be ruled out as a selectively SERT-affine metabolite that induces intracellular oxidative stress. So far, only one centrally administered metabolite of MDMA has been demonstrated to produce neurotoxic profiles that match those of systemic MDMA administration: 2,5-bis-(glutathion-S-yl)- Abbildung in dieser Leseprobe nicht enthalten -methyldopamine, a compound down the minor metabolic pathway of MDMA with 3,4-methylenedioxyamphetamine (MDA) as the immediate metabolite (Bai et al., 2001; Miller, Lau, and Monks, 1997). Evidence that the related compound and metabolite MDA induced neurotoxicity in 5-HT axon terminals of rats is one of the reasons why MDMA in 1985 was added to Schedule 1 of the Controlled Substances Act (Morton, 2005).
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- Dominik Buchmüller (Autor), 2009, MDMA-induced serotonergic neurotoxicity, Múnich, GRIN Verlag, https://www.grin.com/document/135936
