We have developed a rhesus monkey model to study the ontogeny of the midbrain-rostral forebrain dopamine circuitry, and have used this model to study the consequences of gestational cocaine exposure. Fetuses from these pregnancies develop a repertoire of neural deficiencies including decreased mRNA expression of tyrosine hydroxylase in the midbrain and increased mRNA expression and binding densities of dopamine receptor subtypes in the rostral forebrain. In addition, maternal exposure to cocaine increases gene expression of dynorphin and enkephalin in presumed dopamine target neurons in the rostral forebrain at both day 60 and day 70 of gestation. These findings provide further evidence for a disrupted dopamine input to the striatal area of the cocaine exposed fetus. We have found previously that dopamine transporter (DAT) mRNA is present in low quantities in the midbrain of day 45 fetuses. By day 60 of gestation, the concentration of DAT mRNA in the midbrain is h ighly incr eased. Since cocaine may cause the neurological changes through an action at the DAT, we evaluated whether DAT mRNA and binding sites were present in the day 70 fetal primate. We also explored whether gestational cocaine exposure had an effect on the expression of DAT in the fetal brain, using quantitative autoradiography with the selective, high affinity DAT ligand [125I]-RTI-121 and in situ hybridization for DAT mRNA. We found that [125I]-RTI-121 binding to the DAT were highest in the substantia nigra and the ventral tegmental area (VTA), and cocaine treatment significantly increased DAT mRNA expression and ligand binding sites in the fetal midbrain.
The aim of current studies is to examine the more long-term effects of prenatal cocaine exposure and to assess the mechanisms involved in long-term changes of the midbrain-rostral forebrain dopaminergic neurocircuitry. The results from these studies will provide important information about normal development of the primate cent ral nervous system and help increase our understanding of the consequences of in utero cocaine exposure. FUNDING NIH DA07165 PUBLICATIONS Rxnnekleiv OK, Fang Y, Choi WS, Chai L. Changes in the midbrain-rostral forebrain dopamine circuitry in the cocaine-exposed primate fetal brain. Ann NY Acad Sci 846:165-182, 1998. Fang Y, Bosch MA, Rxnnekleiv OK. Dopamine transporter binding sites in fetal rhesus monkey brain Effects of gestational cocaine on [125]-RTI-121 binding densities. Soc Neurosci. Abstr 24:1966, 1998. Lai W, Bosch MA, Naylor BR, Kelly MJ, Rxnnekleiv OK. Alterations in the expression of fetal myocardial gap junctional proteins as a result of in utero exposure to cocaine. Soc Neurosci Abstr 24:872, 1998. Fang Y, Lu N, Rxnnekleiv OK. Mu-opioid receptor-stimulated [35S]GTP?S autoradiography in fetal monkey brain Effect of prenatal cocaine exposure. In 29th International Narcotics Research Conference, Garmisch-Partenkirchen, Germany. INRC Abstr 29:56, 1998.
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