Cocaine upregulates the dopamine transporter in fetal rhesus monkey brain

Cocaine is a highly addictive drug that binds to the dopamine transporter ( DAT), inhibits the reuptake of dopamine, and initiates multiple actions wit hin midbrain dopaminergic systems. Using the rhesus monkey, we have investi gated the consequences of in utero cocaine exposure on the expression of DA T in the fetal brain. By using the selective DAT ligand [I-125]RTI-121 and tyrosine hydroxylase (TH) immunocytochemistry, we found that DAT binding si tes are highly developed by day 70 of gestation and show a distribution pat tern similar to TH. The rank order of specific 3 beta-(4-[I-125]iodophenyl) tropane-2 beta-carboxylic acid isopropyl ester ([I-125]RTI-121) binding den sities was substantia nigra-ventral tegmental area > putamen > caudate > la teral hypothalamus > accumbens > linear/interfascicular nuclei greater than or equal to globus pallidus > prefrontal cortex. Furthermore, we observed that DAT mRNA was differentially expressed within fetal midbrain dopamine n eurons with the highest levels detected in the ventral tier of the substant ia nigra pars compacta, and the lowest levels in the ventral tegmental area and the linear/interfascicular nuclei. In utero cocaine exposure between d ays 22 and 70 significantly increased DAT mRNA expression, and the density of [I-125]RTI-121 binding sites within midbrain dopamine neurons in the 70- d-old fetus. This increased DAT expression is accompanied by other presynap tic and postsynaptic neuronal changes, which collectively suggest that midb rain dopamine neurons are hypoactive after prolonged cocaine exposure, a st ate that may be a contributing factor in the development of attention defic it disorders observed in subjects exposed prenatally to cocaine.