the dopamine transporter is the target or """"""""receptor"""""""" for psychostimulant drugs such as cocaine, amphetamine and methamphetamine. It is also the target or receptor for the therapeutic drug, methylphenidate, and the mediator of the neurotoxic effects of methamphetamine and MPTP. It is a unique marker for dopaminergic neurons and, imortantly, the mechanism of inactivation of released dopamine at the synapse. Moreover, administratio of drugs such a cocaine are known to alter the transporter levels indicating that it may be involved in regulating dopaminergic function in a dynmic way. Therefore, understanding the factors that regulate transporter levels is critical. The goal of this proposal is to elucidate these factors by; first, obtaining estimates of transporter synthesis rate and the degradatio rate consant in brain; second, measuring these after cocaine; and tird, identifying the role of dopamine receptor stimulation and/or dopamine levels in influencing synthesis and degradation. Since the brain is the organ of interest, these studies must be carried out in situ. But cells expressing the transporter are available and lend themselves to similar studies without the complexities of intact brain. Accordinaly will be carry out estimates of synthesis rate and degradation rate constant in cells in culture as well as studies of transporter movement of trafficking. This combined approach using both brain and cells in culture seems the most effective way to elucidate foctors controlling transporter synthesis, degradation and therefore levels. These studies will be lollowed up by identifying the molecular step(s) causing the changes in synthesis and degradation, and by suggesting new approaches for developing medications for drug abuseers.
| Kimmel, H; Vicentic, A; Kuhar, M J (2001) Neurotransmitter transporters synthesis and degradation rates. Life Sci 68:2181-5 |
| Kuhar, M J; Joyce, A R (2001) Slow onset of CNS drugs: can changes in protein concentration account for the delay? Trends Pharmacol Sci 22:450-6 |
| Vicentic, A; Battaglia, G; Carroll, F I et al. (1999) Serotonin transporter production and degradation rates: studies with RTI-76. Brain Res 841:1-10 |
| Kuhar, M J; McGirr, K M; Hunter, R G et al. (1999) Studies of selected phenyltropanes at monoamine transporters. Drug Alcohol Depend 56:9-15 |
