Potential new insights into the molecular mechanisms of methamphetamine-induced neurodegeneration.

In the event that methamphetamine evokes HO. formation within serotonergic axon terminals, the resultant oxidation of 5-HT would be expected to generate not only 5,6-DHT but also T-4,5-D, 7-S-Glu-T-4,5-D, 6, 8, and 7,7'-D (figure 1), at least three of which (T-4,5-D, 7-S-Glu-T-4,5-D, and 6) are lethal in mouse brain. Furthermore, several intermediates/products formed in the in vitro oxidation of 5-HT by HO. are readily autoxidized (4,5-DHT, 5,6-DHT, 5, 7, and 9) or redox cycled (T-4,5-D, 6, 8, 7,7'-D, 7-S-Glu-T-4,5-D) in reactions that would be expected to yield O2-. and/or H2O2 as byproducts. These byproducts, in the presence of trace levels of transition metal ion catalysts, would be readily converted into HO. (Walling 1975; Halliwell and Gutteridge 1984). Together these putative aberrant oxidative metabolites of 5-HT and HO.-forming reactions might contribute to the degeneration of serotonergic nerve terminals. Similarly, the methamphetamine-induced intraneuronal formation of HO. in dopaminergic terminals might be expected to generate not only 6-OHDA (and 2-OHDA and 5-OHDA, figure 3) but also 5,-S-CyS-DA and 5-S-Glu-DA, precursors of DHBT 17 and other more complex dihydrobenzothiazines (figure 4). DHBTs 17 to 19 are lethal in mouse brain, although at this time the biochemical/chemical mechanisms underlying this toxicity and specific neuronal systems affected are unknown. However, 5-S-CyS-DA and 17 to 19 are much more easily oxidized than DA, and the latter DHBTs appear to be capable of redox cycling reactions (Zhang and Dryhurst 1994). Thus, the HO.-mediated oxidation of DA in dopaminergic nerve terminals induced by methamphetamine might be expected to generate aberrant oxidative metabolites that (as a result of autoxidation and redox cycling reactions) potentiate formation of O2-. and/or H2O2, and then HO. and neuronal damage. A number of lines of evidence, discussed previously, suggest that aberrant metabolite(s) of DA (other than or in addition to 6-OHDA) might contribute to the methamphetamine-induced degeneration of not only dopaminergic terminals but also serotonergic terminals. Similarly, aberrant metabolite(s) of 5-HT (other than or in addition to 5,6-DHT) might be involved in the degeneration of serotonergic and dopaminergic terminals and a subpopulation of cell bodies in the somatosensory cortex. Experimental evidence indicates that some of the neurodegenerative effects evoked by methamphetamine are mediated by NMDA and GABA receptors. Thus, it will be of considerable interest to investigate the neurotoxicity of putative aberrant oxidative metabolites of 5-HT (figures 1 and 2) and DA (figures 4 and 5) towards serotonergic, dopaminergic, and other neuronal systems and their interactions with NMDA, GABA, and other brain receptors. A central question relates to mechanisms by which methamphetamine might evoke the intraneuronal formation of oxygen radicals that appear to play important roles in the overall neurodegenerative processes evoked by this drug (DeVito and Wagner 1989; Cadet et al. 1994). Once putative oxidative metabolites of 5-HT such as T-4,5-D, 7-S-Glu-T-4,5-D, 5,6-DHT, 6, 8, and 7,7'-D (figure 1) are formed intraneuronally, autoxidation/redox cycling reactions should, in principle, be capable of generating O2-. and/or H2O2, the precursors of HO.. Similarly, intraneuronal formation of 6-OHDA, 5-S-CyS-DA, and DHBTs 17 to 19 and 22 would also be expected to potentiate elevated fluxes of O2-., H2O2, and HO. as a result of the facile autoxidation/redox cycling reactions of these putative aberrant metabolites. The presence of very low concentrations of 5-S-CyS-DA in DA-rich regions of human and other mammalian brains suggest that autoxidation (Rosengren et al. 1985; Fornstedt et al. 1986, 1989, 1990) or perhaps some other form of DA oxidation is a normal reaction in vivo. Furthermore, available evidence suggests that it is cytoplasmic DA that is oxidized to give 5-S-CyS-DA (Fornstedt et al. 1989; Fornstedt and