2,5-bis-(Glutathion-S-yl)-α-methyldopamine, a putative metabolite of (±)-3,4-methylenedioxyamphetamine, decreases brain serotonin concentrations
Introduction
The ring-substituted amphetamines, 3,4-methylenedioxyamphetamine (MDA) and 3,4-methylenedioxymethamphetamine (MDMA), are well established serotonergic neurotoxicants (Ricaurte et al., 1985; Commins et al., 1987; Battaglia et al., 1988). Peripheral administration of MDA or MDMA causes decreases in markers of serotonergic function, including decreases in levels of serotonin (5-hydroxytryptamine, 5-HT) and in the 5-HT carrier protein in serotonergic nerve terminal fields (Ricaurte et al., 1985; Commins et al., 1987). The serotonergic deficits are long-lasting since recovery of these parameters is not observed for up to 18 months following administration of MDMA to nonhuman primates (Ricaurte et al., 1988, Ricaurte et al., 1992). These observations are of concern to the general population because non-human primates appear to be especially susceptible to the toxicity of these agents (Ricaurte et al., 1988). Moreover, the recreational use of MDMA (Peroutka, 1987) appears to be increasing in both the United States (Cuomo et al., 1994; McDowell and Kleber, 1994; Newmeyer, 1994) and Europe (Henry, 1992; Randall, 1992).
The neurotoxic component(s) of MDA and MDMA is not known, but roles for endogenous dopamine (Stone et al., 1988), and for the 5-HT2 receptor (Schmidt et al., 1990, Schmidt et al., 1991) have been proposed. However, it appears that systemic metabolism is important for eliciting the neurotoxic response, because direct injection of MDA or MDMA into brain does not cause long-term serotonergic deficits (Molliver et al., 1986; Schmidt and Taylor, 1988), and administration of α-methyldopamine or 3-O-methyl-α-methyldopamine, major metabolites of MDA and MDMA, into brain also fails to produce long-term serotonergic neurotoxicity (McCann and Ricaurte, 1991). Although direct central injection of 2,4,5-trihydroxyamphetamine or 2,4,5-trihydroxymethamphetamine, putative in vivo metabolites of MDA and MDMA, are toxic to the serotonergic neurotransmitter system, they also target the dopaminergic system (Johnson et al., 1992; Elayan et al., 1992; Zhao et al., 1992), and thus do not exhibit the selectivity of the parent amphetamines. In addition, mechanisms by which these metabolites gain access to the brain have not been determined.
MDA is metabolized to α-methyldopamine (Marquardt et al., 1978; Midha et al., 1978) and MDMA to N-methyl-α-methyldopamine and α-methyldopamine (Lim and Foltz, 1988; Kumagai et al., 1991) both of which are catechols that can undergo oxidation to the corresponding ortho-quinones, followed by the reductive addition of glutathione (GSH) to form GSH conjugates (Hiramatsu et al., 1990; Patel et al., 1991). Since quinone-thioethers retain their biological (re)activity (Monks and Lau, 1992), we have been investigating the potential role of thioether metabolites of α-methyldopamine in the neurotoxicity of MDA. 5-(Glutathion-S-yl)-methyldopamine is metabolized via the mercapturic acid pathway within the central nervous system (CNS), forming 5-(cystein-S-yl)-α-methyldopamine and 5-(N-acetylcystein-S-yl)-α-methyldopamine (Miller et al., 1995). 5-(Glutathion-S-yl)-α-methyldopamine is also readily oxidized to the corresponding quinone-GSH conjugate and undergoes addition of a second molecule of GSH to form 2,5-bis-(glutathion-S-yl)-α-methyldopamine. The brain uptake of peripherally administered 5-(glutathion-S-yl)-α-methyldopamine has also been demonstrated (Miller et al., 1996). However, long-term deficits in brain 5-HT levels were not observed following a single i.c.v. infusion of 720 nmol 5-(glutathion-S-yl)-α-methyldopamine (Miller et al., 1996). Because multiple dose regimens have been employed in models of MDMA and MDA neurotoxicity, and because such regimens might produce shifts in the metabolism and/or accumulation of a neurotoxic metabolite in brain tissue, the present study was undertaken to determine the effects of 5-(glutathion-S-yl)-α-methyldopamine, 5-(N-acetylcystein-S-yl)-α-methyldopamine and 2,5-bis-(glutathion-S-yl)-α-methyldopamine on rat brain dopamine and 5-HT concentrations following multiple-dose administration.
Section snippets
Chemicals
Dopamine, dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 5-HT, 5-hydroxyindole acetic acid (5-HIAA), GSH and mushroom tyrosinase (5600 U/mg) were obtained from Sigma (St. Louis, MO, USA). 5-HT-hemihydrate and N-acetyl-l-cysteine were obtained from Aldrich (Milwaukee, WI, USA). α-Methyldopamine was a generous gift from Anthony Y.H. Lu at Merck Research Laboratories (Rahway, NJ, USA). (±)-MDA was provided by the Research Technology Branch, National Institute on Drug Abuse
Acute behavioral response to MDA, α-methyldopamine, 5-(glutathion-S-yl)-α-methyldopamine, 5-(N-acetylcystein-S-yl)-α-methyldopamine and 2,5-bis-(glutathion-S-yl)-α-methyldopamine
Following multiple i.c.v. administration of 5-(glutathion-S-yl)-α-methyldopamine and 5-(N-acetylcystein-S-yl)-α-methyldopamine, animals became hyperactive, aggressive, displayed forepaw treading, Straub tails, and most displayed splayed hind limbs (Table 1). Some animals began circling away from the side of the i.c.v. injection of 5-(N-acetylcystein-S-yl)-α-methyldopamine. These behaviors appeared abruptly (within 1–2 min following administration) and continued for approximately 30 min. With
Discussion
Administration of MDA subcutaneously, or 5-(glutathion-S-yl)-α-methyldopamine by i.c.v. injection, to rats, produces a very similar behavioral response (Table 1). This behavioral syndrome, termed the `serotonin syndrome', typically occurs following administration of 5-HT releasers such as MDA, and consists of forepaw treading, Straub tail, head weaving, hyperactivity and `wet dog' shakes. Although both 5-(glutathion-S-yl)-α-methyldopamine and MDA produced this behavioral syndrome, the
Acknowledgements
R.T.M. was supported by an award from the NIEHS (T32 ES 07247). This work was supported by a grant from NIDA (DA 10832).
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Present address: University of Texas Health Science Center at San Antonio, Department of Biochemistry, 7703 Floyd Curl Drive, San Antonio, TX 78284-7760, USA.