MATERNAL COCAINE TREATMENT ALTERS DYNORPHIN AND ENKEPHALIN MESSENGER-RNA EXPRESSION IN BRAINS OF FETAL RHESUS MACAQUES

Cocaine exposure in utero is known to cause a variety of behavioral an d motor deficits that may be attributable to alterations in the dopami ne neurocircuitry. To ascertain cocaine effects in the fetus, we devel oped a nonhuman primate model in which pregnant monkeys were administe red cocaine from day 20 through day 60 or 70 of gestation. Fetuses fro m these pregnancies develop a repertoire of neural deficiencies, inclu ding decreased mRNA expression of tyrosine hydroxylase in the midbrain and increased mRNA expression of dopamine receptor subtypes in the ro stral forebrain. Presently, we studied the effects of maternal cocaine treatment on the mRNA expression of the endogenous opioids preprodyno rphin (PPD) and preproenkephalin (PPE) in fetal monkey brains. Fetuses exposed to saline (0.9%) or cocaine (3 mg/kg) were delivered by Caesa rean section, the fetal brains were dissected, and tissue RNA was extr acted and quantified using ribonuclease protection assay analysis. The opioid peptides PPD and PPE were expressed in the fetal monkey brain by day 60, and even higher levels were found in day 70 fetuses. Matern al exposure to cocaine increased gene expression of PPD and PPE in the fetus at both day 60 and day 70 of gestation. Dynorphin mRNA levels w ere significantly elevated in the striatum, whereas enkephalin mRNA wa s elevated in both the frontal cortex and the striatal area of fetuses whose mothers received cocaine. Changes in the expression of these op ioid peptides in presumed dopamine target neurons, which mediate motiv ation and reward, as well as motor control, provide further evidence f or profound consequences of in utero cocaine exposure on the developin g dopamine neurocircuitry.