| Description |
The national Drug Enforcement Agency has called the amphetamine analog methamphetamine (METH) "the most lethal substance to hit the streets during the entire 35-year war on drugs," and its abuse continues to escalate. Due to the global proportions of the METH abuse problem, much contemporary research has been dedicated to the clarification of mechanisms by which METH compromises central nervous system function. A recent theory suggested that reactive oxygen species (ROS) produced by METH diminish dopamine transporter (DAT) function in rat striatal tissue. In order to test this theory, a series of experiments were carried out on three related compounds: L-DOPA, fenfluramine, and methylphenidate. First, the IC50 of each compound for [3H]dopamine uptake was determined using striatal synaptosomes from non-treated rats. The results indicated that L-DOPA and fenfluramine have very low affinities for the DAT transporter while methylphenidate has a high affinity similar to that of cocaine. In the second set of experiments, rats were given single or multiple injections of either L-DOPA or fenfluramine to examine the drugs' effects in vivo. In contrast, a single administration of L-DOPA caused a statistically significant 27% decrease in DAT activity in comparison with the saline-treated control. A single injection of fenfluramine did not decrease [3H]dopamine uptake into striatal synaptosomes. Neither L-DOPA nor 11 fenfluramine significantly affected the DAT after four intraperitoneal injections at twohour intervals. Examination of all results reveals that changes in DAT activity after drug treatment do not correlate with their respective affinities for the transporter protein. However, the transporter is, as the hypothesis in question predicted, susceptible to inactivation by ROS. This statement is supported by the observation that L-DOPA, which forms ROS via autooxidation and metabolism, reduces DAT function: metabolism of this drug produces dopamine (DA), a compound capable of increasing ROS concentration via its own autooxidation and enzyme-mediated metabolism. METH acts similarly to L-DOPA, increasing extracellular DA and subsequent ROS concentrations to produce its effect. Compared to L-DOPA, METH is more effective at reducing DAT activity. This phenomenon may be due to the fact that METH binds directly to the transporter and can therefore create a higher concentration of ROS within the DAT region. The loss of effect in multiple-dose L-DOPA experiments may be explained by the counteracting power of L-DOPA-induced increases in levels of bilirubin, a powerful antioxidant. |
