Cocaine abuse by pregnant women is a serious problem; estimates of rates of maternal cocaine abuse range from 5-20%. Because of variations in administration and gestational timing, the consequences of prenatal cocaine exposure range from """"""""no effect"""""""" to fetal death and include physical and behavioral alterations. Animal models of prenatal cocaine exposure have reproduced many of the associated symptoms. Several lines of evidence suggest that the brain dopamine (DA) systems, which have been shown to be a primary site of action of cocaine and which develop prenatally, are altered by developmental cocaine exposure. Our research has demonstrated that our paradigm of gestational cocaine exposure in rats leads to initial alterations in brain DA systems of the offspring which tend to normalize as the animal ages. Examination of a number of markers identified no supporting neuroanatomical changes in the brain DA systems; however a serotonin hyperinnervation was observed in the striatum, one of the major DA terminal fields. In rats prenatally exposed to cocaine this enhanced innervation of the striatum by serotonin fibers becomes apparent at about three weeks after birth and persists into adulthood. The alterations in extracellular DA and its metabolites return to normal during the time that the enhanced serotonin ingrowth is occurring. Thus the normalization we observed in DA might have occurred directly in the DA system or there might have been compensations brought about by changes in serotonin and/or other systems. Our operating hypothesis is that prenatal cocaine exposure results in an insult to the brain DA systems, expressed as enhanced basal and stimulated release; and over time compensations occur that return the release/reuptake of DA to normal via changes in the DA system, serotonin system, and/or other systems. This application seeks to investigate questions about whether this serotonin hyperinnervation of the DA terminal fields produces the functional consequence of elevated levels of serotonin in the extracellular fluid and, hence, whether serotonergic controls on the release of DA are altered. In addition, we will determine whether there are residual alterations in more complex dopaminergic behaviors, such as self-administration, and whether serotonin's role in this behavior is altered.
