[The dopamine transporter: characterization and physiopathologic implications].

Abstract

The dopamine transporter (DAT) is the carrier protein that transports dopamine across the presynaptic membrane. The DAT terminates the action of dopamine (DA) in the synapse via reuptake and thus regulates DA neurotransmission. The transporter has been studied by direct binding techniques using a variety of ligands which are inhibitors of DA transport. DAT binding, both in vivo (positron emission tomography) and in vitro (post mortem) may serve as a presynaptic marker to measure altered DA innervation in several neuropsychiatric diseases such as idiopathic Parkinson's disease, Tourette's disease, schizophrenia or cocaine addiction. In Parkinson's disease, a reduction in the density of binding sites could be due either to a degeneration of the terminal dopaminergic projections or to a compensatory readjustment in the level of dopamine synaptic transmission. This dopaminergic cell specific marker could also aid in attempts to elucidate the rate at which dopaminergic cells are lost in this disease. MPTP (a neurotoxin which induces a parkinsonian-like syndrome after conversion in MPP+) uses DAT to enter the neuron and exert its toxic effect which may be prevented by pretreatment with DA uptake blockers. In cocaine abuse, DAT mediates the addictive properties of cocaine. Cocaine binding sites on the carrier may be distinct from DA binding sites allowing the development of medication sparing the DA function but impairing the cocaine effects. In schizophrenia, functional DA uptake was reported to be increased in the striatum in post mortem brains, whereas the kinetic parameters of the uptake sites were unchanged using different transporter labeling ligands. Thus, this marker does not provide any evidence for the dopaminergic hypothesis, but an impairment of the DAT itself could possibly be involved in the etiology of schizophrenia. However, the possible interaction of drugs such as L-Dopa or neuroleptic treatment with transporter binding may be taken into account in the results analysis. Finally, the DAT gene is also an important candidate gene for psychiatric diseases such as schizophrenia or cocaine abuse.