MATERNAL COCAINE ABUSE: EFFECTS ON FETAL NEUROGENESIS

The objective of these experiments is to elucidate the effects of fetal
cocaine exposure on neuronal development. Infants which are born to
mothers who use cocaine, have increased risk of neurological and
neurobehavioral deficiencies. These deficits imply that dopamine
neurotransmission is altered. In adult animals cocaine inhibits reuptake
of monoamines and thus, affects dopamine neurotransmission. However, very
little is known about the effects of cocaine on developing neurons. In order to characterize cocaine-induced changes in brain development, we
will focus on the dopaminergic neuronal systems, and explore the effects of
cocaine on the molecular, cellular and structural changes that occur during
the early stages of neuronal proliferation and migration. The first series of experiments will examine the effects of cocaine on the
early ontogeny of tyrosine-hydroxylase (TH)-containing neurons destined to
form the mesolimbic, nigrostriatal and tuberoinfundibular dopaminergic
neuronal groups. We will determine the time of origin, anatomical location
and maturation of cells containing TH within the ventral
tegmental/substantia nigra and hypothalamic areas, and the development of
their fiber projections using immunocytochemistry and in situ
hybridization. Secondly, we will explore the effects of cocaine on the
ontogeny of dopamine receptors in the nigrostriatal/mesolimbic and
hypothalamic systems. We will detect and quantify D-1 and D-2 receptor
mRNAs and measure receptor binding in the nucleus accumbens/striatum and
the hypothalamus during the early phase of dopaminergic neuronal
development. These experiments will be performed using in situ
hybridization and polymerase chain reaction (PCR) to localize and quantify
and mRNAs, and receptor autoradiography to quantify receptor binding. The
effects of cocaine on the development of the dopamine transporter will also
be investigated using [3H]CFT (WIN 35,428) as a ligand. The next series of
experiments will examine the effects of cocaine on the ontogeny of
dopaminergic target neurons, focusing on enkephalin neurons in the nucleus
accumbens and the striatum, and on GnRH neurons in the hypothalamus. These
experiments will be performed using immunocytochemistry and in situ
hybridization to study the maturation of peptide expression and migration.
Lastly, we will quantify proenkephalin mRNA and GnRH mRNA during peak
migration and during the post migration period in control and cocaine-
treated fetuses, using PCR. The results from these studies will provide important information about
normal development and the effects of cocaine on major dopaminergic
neuronal systems and their target neurons. Therefore, information will be
generated to understand the basic effects of cocaine on developing neurons.
This data can be used to develop treatment strategies to counter the
effects of cocaine in infants and young children.