Assessing the role of dopamine in the differential neurotoxicity patterns of methamphetamine, mephedrone, methcathinone and 4-methylmethamphetamine

Abstract

Methamphetamine and mephedrone are designer drugs with high abuse liability and they share extensive similarities in their chemical structures and neuropharmacological effects. However, these drugs differ in one significant regard: methamphetamine elicits dopamine neurotoxicity and mephedrone does not. From a structural perspective, mephedrone has a β-keto group and a 4-methyl ring addition, both of which are lacking in methamphetamine. Our previous studies found that methcathinone, which contains only the β-keto substituent, is neurotoxic, while 4-methylmethamphetamine, which contains only the 4-methyl ring substituent, elicits minimal neurotoxicity. In the present study, it was hypothesized that the varying neurotoxic potential associated with these compounds is mediated by the drug-releasable pool of dopamine, which may be accessed by methamphetamine more readily than mephedrone, methcathinone, and 4-methylmethamphetamine. To test this hypothesis, L-DOPA and pargyline, compounds known to increase both the releasable pool of dopamine and methamphetamine neurotoxicity, were combined with mephedrone, 4-methylmethamphetamine and methcathinone. Methamphetamine was also tested because of its ability to increase releasable dopamine. All three regimens significantly enhanced striatal neurotoxicity and glial reactivity for 4-methylmethamphetamine. Methcathinone neurotoxicity and glial reactivity were enhanced only by L-DOPA. Mephedrone remained non-neurotoxic when combined with either L-DOPA or pargyline. Body temperature effects of each designer drug were not altered by the combined treatments. These results support the conclusion that the neurotoxicity of 4-methylmethamphetamine, methcathinone and methamphetamine may be differentially regulated by the drug-releasable pool of dopamine due to β-keto and 4-methyl substituents, but that mephedrone remains non-neurotoxic despite large increases in this pool of dopamine.

Psychoactive Drugs—From Chemical Structure to Oxidative Stress Related to Dopaminergic Neurotransmission. A Review

“…These substances penetrate the neuron and cause a massive release of the neurotransmitter into the synaptic cleft. Studies in rodents show that amphetamines increase the levels of oxidative stress markers such as MDA, SOD, glutathione (GSH/GSSG), 2,3-dihydroxybenzoic acid in the cortex, corpus striatum [ 133 ], and hippocampus [ 134 ]. Moreover, toxic doses of methamphetamine inhibit the ETC, by interfering with all four complexes, in the corpus striatum , hippocampus , amygdala, nucleus caudatus , and prefrontal cortex , being incriminated in the development of neurodegenerative diseases [ 135 , 136 , 137 ].…”

Cognitive deficits and neurotoxicity induced by synthetic cathinones: is there a role for neuroinflammation?

“…For example, methylone (4 × 30 mg/kg at 2 hr intervals) can enhance putative damage to dopamine nerve endings as measured by decreases in DAT levels or binding more robustly in the presence of methamphetamine, yet oddly the same doses of MDPV appear to exert neuroprotective effects (Anneken et al 2015). More predictably, additive or synergistic neurotoxic effects have been shown when mephedrone is administered in combination with methamphetamine (Anneken et al 2018) or ethanol (Ciudad-Roberts et al 2016). Thus, there are highly complex mechanism of action of synthetic cathinones with regards to their ability to produce neurotoxic or monoamine-altering effects, and it is clear that such effects are dependent on a plethora of variables such, dose and frequency of administration, the presence of other drugs of abuse.…”

“…(Angoa-Perez et al 2012;Angoa-Perez et al 2014;Lopez-Arnau et al 2015;Martinez- Clemente et al 2014;Motbey et al 2012). On the other hand, some investigators have reported increases in astrocyte or microglia number in regions such as the frontal cortex, striatum or hippocampus following repeated high dose administration of mephedrone, methcathinone, or methylone(Anneken et al 2018;Lopez-Arnau et al 2014a;Lopez-Arnau et al 2014b)…”

New psychoactive substances: Pharmacology influencing UK practice, policy and the law

“…For many banned drugs, most notably mephedrone, the decision to ban was made without any real knowledge of its pharmacology let alone toxicology . This has since been rectified and mephedrone has been shown to lead to dopamine release but not to neurotoxicity . Similar research on synthetic cannabinoids is still relatively lacking…”

“…Heavy mephedrone use was associated with some deep depressive come‐downs that were thought to contribute to a few hanging suicides . Such behaviour is consistent with brain dopamine depletion since mephedrone has a major impact to release this neurotransmitter, although to my knowledge no measures of its concentration in the brain were made at postmortem, which represents a missed opportunity that is all too typical of research failings with new psychoactive substances.…”