| Description |
Single and multiple high-dose administrations of methamphetamine (METH) rapidly and differentially decrease dopamine transporter (DAT) function, as assessed by measuring [3H]dopamine uptake into rat striatal synaptosomes 1 h after treatment. It has been demonstrated that dopamine, reactive oxygen species (ROS), and METH-induced hyperthermia contribute to long-term monoaminergic deficits induced by high-dose METH treatment. In addition, dopamine and ROS alter DAT function in vitro. Hence, the purpose of this dissertation research was to determine if these factors contribute to the acute diminution in DAT function by METH treatment. Experiments described in Chapter 2 assessed the involvement of dopamine and hyperthermia in the reductions in DAT function by a single and multiple administrations of METH. Results from this study suggest that dopamine and hyperthermia contribute to the decrease in DAT function by multiple administrations, but not a single administration. In addition, data presented in this chapter suggest a relationship between the effect induced by single administration and that induced by multiple administrations. Specifically, the reduction in DAT activity observed after a single administration likely constitutes a part of the reduction observed following multiple administrations. In Chapter 3, the role of dopamine in the rapid decrease in DAT function by multiple METH administrations was characterized further. In addition, the contribution of ROS to this effect was assessed. Results presented in this study suggest that dopamine receptors and ROS contribute to the decrease induced by multiple administrations of METH. Additional data presented in this chapter suggest that, in addition to activating dopamine receptors, dopamine may influence DAT function by promoting ROS formation. In Chapter 4, the effects of other psychostimulants, such as 3,4-methylenedioxymethamphetamine (MDMA), on DAT function were examined in an effort to understand better the nature of the METH-induced rapid diminution in DAT function. This study revealed that other amphetamine analogs, but not cocaine, induce similar effects on the DAT, suggesting that the rapid diminution in DAT function may be an effect unique to drugs similar in structure or action to METH. These findings may have important implications regarding mechanisms that underlie METH-induced long-term neurotoxic changes and other neurodegenerative disorders. |
