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The Journal of Neuroscience, October 15, 1999, 19(20):8966-8978

Cocaine Upregulates the Dopamine Transporter in Fetal Rhesus Monkey Brain

Yuan Fang and Oline K. Rønnekleiv

Department of Physiology and Pharmacology, Oregon Health Sciences University, Portland, Oregon 97201-3098, and Division of Neuroscience, Oregon Regional Primate Research Center, Beaverton, Oregon 97006

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-121and 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 3-(4-[¹²⁵I]iodophenyl)tropane-2-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.

Key words: cocaine; dopamine transporter; tyrosine hydroxylase; fetus; rhesus monkey; [¹²⁵I]RTI-121; in situ hybridization histochemistry; autoradiography; immunocytochemistry

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Copyright © 1999 Society for Neuroscience  0270-6474/99/19208966-13$05.00/0

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