| Description |
The process of chemical neurotransmission involves a dynamic balance between signal initiation and/or signal termination. Psychostimulants have long been known as drugs that alter both of these processes associated with monoaminergic neurotransmission. Specifically, it has been known for many years that cocaine and methylphenidate prevent signal termination by inhibition of dopamine (DA) and serotonin (5HT) transporters (DAT and SERT, respectively). In addition, amphetamine analogs such as amphetamine (AMPH), methamphetamine (METH), and methylenedioxymethamphetamine (MDMA), enhance signal initiation by causing release of DA and/or 5HT. More recently it has been discovered that psycho stimulants alter additional processes. In particular, amphetamines reduce the transport activity of DAT and/or SERT. The first part of this dissertation is focused on elucidating the mechanism whereby amphetamines decrease monoamine transport function. Results reveal that the METH- and MDMA-induced decrease in DAT and SERT activity can be prevented with NPC15437, a protein kinase C inhibitor. In addition, a novel mechanism of transporter regulation was discovered that involves the lipid second messenger, ceramide. The ceramide-induced alterations in monoamine transporter function appear distinct from those of METH, uncovering an interesting phenomenon: C2-ceramide reduces DA transported through the DAT while concurrently increasing the transport of 5HT through the DAT. This dissertation also contains the first evidence that psychostimulants alter the trafficking of synaptic vesicles. Cocaine and methylphenidate (drugs that are not neurotoxic to DA neurons) appear to influence the trafficking of vesicles in a manner somewhat opposite to the amphetamines (drugs which are neurotoxic to DA neurons). Results demonstrate that these vesicle trafficking events are specific for monoamine containing vesicles and occur at high as well as low, clinically relevant, doses. Data presented in this dissertation help to increase our understanding of neurotransmission and psychostimulant-induced alterations in neurotransmission. These data may be useful for understanding and treating various related neurological disorders. |
