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 within midbrain dopaminergic systems. Using the rhesus monkey, we have investigated the consequences of in utero cocaine exposure on the expression of DAT in the fetal brain. By using the selective DAT ligand [125I]RTI-121 and tyrosine hydroxylase (TH) immunocytochemistry, we found that DAT binding sites are highly developed by day 70 of gestation and show a distribution pattern similar to TH. The rank order of specific 3beta-(4-[125I]iodophenyl)tropane-2beta-carboxylic acid isopropyl ester ([125I]RTI-121) binding densities was substantia nigra-ventral tegmental area > putamen > caudate > lateral hypothalamus > accumbens > linear/interfascicular nuclei >/= globus pallidus > prefrontal cortex. Furthermore, we observed that DAT mRNA was differentially expressed within fetal midbrain dopamine neurons with the highest levels detected in the ventral tier of the substantia nigra pars compacta, and the lowest levels in the ventral tegmental area and the linear/interfascicular nuclei. In utero cocaine exposure between days 22 and 70 significantly increased DAT mRNA expression, and the density of [125I]RTI-121 binding sites within midbrain dopamine neurons in the 70-d-old fetus. This increased DAT expression is accompanied by other presynaptic and postsynaptic neuronal changes, which collectively suggest that midbrain dopamine neurons are hypoactive after prolonged cocaine exposure, a state that may be a contributing factor in the development of attention deficit disorders observed in subjects exposed prenatally to cocaine.
Fang
Y
Y
Department of Physiology and Pharmacology, Oregon Health Sciences University, Portland, Oregon 97201-3098, USA.
Ronnekleiv
O K
OK
D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D001921:Brain / Q000196:embryology*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D003042:Cocaine / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology*; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D005314:Embryonic and Fetal Development; D005333:Fetus / Q000166:cytology / Q000378:metabolism* / Q000502:physiology; D008253:Macaca mulatta / Q000196:embryology; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D008636:Mesencephalon / Q000166:cytology / Q000378:metabolism; D009419:Nerve Tissue Proteins; D009474:Neurons / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D014018:Tissue Distribution; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D015854:Up-Regulation
D002352:Carrier Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; C079213:RTI 121; D014446:Tyrosine 3-Monooxygenase; D003042:Cocaine