The data generated in the initial project period provide convergence across a variety of disciplines that indicate prenatal cocaine is a neurobehavioral teratogen when administered by a clinically relevant route (IV) and at clinically relevant peak arterial plasma levels, and moreover, that the central noradrenergic system is a very important target for these effects. Thus, we can now refine our original hypothesis to propose a mechanism for the effects of prenatal cocaine. The proposed program continuation maintains the hypothesis: Maternal cocaine abuse during a restricted portion of pregnancy causes Long-term and selective alterations in 1) """"""""attentionally sensitive"""""""" neurobehavioral paradigms and 2) the structure and function of the central noradrenergic system: both of which are attributable to early noradrenergic cell dysfunction/loss in the locus coeruleus.
The specific aims of the program are: 1) To establish the critical exposure period for the neurobehavioral alterations which occur in the offspring consequent to intravenous maternal cocaine exposure during pregnancy. Using ontogenetic and longitudinal analyses, the proposed studies will replicate and extend our prior studies by specifically identifying the critical exposure period(s). We will use noradrenergically mediated and/or attentionally sensitive tasks to provide an assessment of both ascending and descending noradrenergic projections of the locus coeruleus. Multiple dependent measures within each task will provide the dissociation of specific neural and cognitive deficits from sensory or motor impairments. 2) To establish the critical exposure period for the structural and functional alterations in the central noradrenergic system alterations which occur in the offspring consequent to IV maternal cocaine exposure during pregnancy. Quantitative neuroanatomical measurements (unbiased cell-counting/optical dissector technique), immunocytochemistry, synthetic enzyme activity, and in situ hybridization will be utilized to fundamentally establish whether the observed alterations in the central noradrenergic system, presumably reflecting compensatory processes in the developing CNS, occur in response to noradrenergic cell loss or, alternatively, to a less permanent cellular dysfunction. The goal of the proposed program is to determine whether the early cell dysfunction/loss in the locus coeruleus may provide a potential underlying basis for the long-term and selective alterations in attentionally sensitive neurobehavioral paradigms consequent to prenatal cocaine exposure.
Showing the most recent 10 out of 51 publications
