Cocaine use during pregnancy is associated with neurobehavioral abnormalities in offspring that include alterations in attentiveness. Understanding the mechanisms by which maternal cocaine abuse adversely affects the developing fetus is critical for the development of appropriate treatments and intervention strategies. The actions of cocaine stem from nonselective inhibition of catecholaminergic neurotransmitter reuptake systems. New evidence shows that norepinephrine (NE) cell bodies within the locus coeruleus (LC), but not dopamine cell bodies with the substantia nigra, are affected following prenatal cocaine exposure using a clinically relevant model. This, combined with previous data showing that cocaine affects LC neuron behavior, give strong reason to pursue this system rigorously to refine previously held hypotheses and to determine new mechanisms for the deleterious effects of prenatal cocaine at the cell biological level. This study focuses on the LC neurons and one target, the hippocampus (limbic system), in rats prenatally exposed to cocaine in vivo and in vitro. Our hypothesis is: maternal cocaine use during a critical period of pregnancy causes selective alterations in the central noradrenergic system evidenced, in part, by effects on neuronal development such as neurite initiation, directed process outgrowth, appropriate neuronal pathfinding, and connectivity. We will test this hypothesis by first, determining effects of maternal cocaine exposure on the noradrenergic cells of the fetal rat LC using a well-established, clinically relevant model for fetal cocaine exposure, followed by analysis during critical outgrowth periods of neurite initiation, the rate of neurite outgrowth, total neurite length, growth cone behaviors (e.g. pathfinding), and characteristics of target (hippocampus) selectivity and connectivity. Second, we will determine effects of physiologically relevant concentrations of cocaine in tissue culture on the noradrenergic cells of the fetal rat LC, by analyzing neurite initiation, the rate of neurite extension, total neurite length, neuronal growth cone behaviors (e.g. pathfinding), and characteristics of target (hippocampus) selectivity and connectivity. The long term goal of this study is to uncover mechanisms of the adverse effects of prenatal cocaine on developing nerve cells that lead to inappropriate connectivity and impaired function. This study represents a novel and innovative approach toward an understanding of the basic cell biology of noradrenergic neurons as they respond to cocaine during development, and may ultimately permit the development of effective pharmacotherapeutic interventions for the treatment of cocaine-exposed offspring.
| Dey, S; Mactutus, C F; Booze, R M et al. (2007) Cocaine exposure in vitro induces apoptosis in fetal locus coeruleus neurons by altering the Bax/Bcl-2 ratio and through caspase-3 apoptotic signaling. Neuroscience 144:509-21 |
