Neurobehavioural deficits resulting from prenatal exposure to cocaine suggest that cocaine targets the developing CNS. Using an animal model in which cocaine is administered intravenously twice a day, we studies morphological development, and development of neurotransmitters. We observed no effects of prenatal cocaine exposure on cortical growth and cytoarchitectonics. However, in the anterior cingulate cortex (ACC) of cocaine exposed offspring, we found that (I) the number of neurons which are GABA immunoreactive is increased, and (ii) in a subset of the GABA neurons, an increased number of dendrites are immunoreactive for the calcium binding protein parvalbumin (PV). We interpret these results as indicating a dysfunction of the GABA ergic system, which contributes to an imbalance of excitatory and inhibitory influences in the ACC. In the present proposal, we follow up our observations by investigating the molecular mechanisms by which in utero cocaine exposure regulates the GABA transmitter (in experiments studying GAD mRNA and GAD expression), and GABA receptors (in experiments studying mRNA of selected GABAA receptor subunits). We will also determine the time, during fetal and postnatal development, when these changes occur. Parallel experiments will explore the functional correlates of cocaine-elicited changes in the molecular regulation of the transmitter and its receptors. Additional experiments are proposed which will determine what changes in cortical circuitry are associated with changes in the GABAergic system. Finally, we will explore interactions between the dopaminergic (DA) and the GABAergic system. Cocaine blocks re-uptake of DA, and its addicting effects act through limbic system structures. Results obtained so far show the effects of cocaine in the DA rich ACC, but not in the dopamine poor visual cortex. We hypothesise that cocaine's effects are mediated by the DA system, and specifically by dysfunction of the D1-like dopamine receptor. We will examine other CNS areas which differ in their DA innervation and in their association with limbic areas which have been implicated in the addicting properties of cocaine, and determine to what extent GABA system changes are restricted to DA rich areas and to limbic areas. Abs against two D1-like receptors -- D1 and D5 will be used.
| Shumsky, Jed S; Wu, Yunxing; Murphy, E Hazel et al. (2002) Differential effects of prenatal cocaine exposure on selected subunit mRNAs of the GABA(A) receptor in rabbit anterior cingulate cortex. J Chem Neuroanat 24:243-55 |
