Our aim is to understand how prenatal exposure to cocaine alters cortical organization and the role that serotonin (5-HT) may play in these abnormalities. Exposure to cocaine in utero produces profound behavioral consequences as well as changes in cortical neurochemistry and structure, but little is known about how cocaine-induced neurochemical changes may be linked to alterations in cortical structure and function. Our Preliminary Results suggest that prenatal cocaine exposure increases cortical 5-HT levels and reduces the transient expression of high-affinity 5-HT uptake sites by thalamocortical axons. Preliminary anatomical studies have suggested further that prenatal exposure to cocaine reduces the size of thalamocortical axon arbors. We believe the this may result from cocaine increasing the effective 5- HT concentration in the developing cerebral cortex and thus enhancing the presynaptic inhibition of thalamocortical afferents caused by the action of this amine at 5-HT 1B receptors transiently expressed by these fibers. This inhibition reduces the ability of thalamocortical axons to compete with other inputs for functional control over cortical neurons and decreases their terminal arborizations. We will test this hypothesis in the vibrissae representation of the rat's primary somatosensory cortex, the most well-studied cortical area in rodents, and perhaps all mammals, by accomplishing the following experiments. 1) We will confirm our Preliminary Results regarding the effects of prenatal cocaine exposure on the development of the 5-HT innervation of the cerebral cortex, 5-HT uptake sites, and 5-HT 1B receptors using immunocytochemistry, high performance liquid chromatography, and radioligand binding techniques. 2) We will determine the effect of prenatal cocaine administration on the organization of specific thalamocortical afferents using single axon labelling and reconstruction techniques. 3) We will determine whether the cocaine- induced increase in 5-HT and reduction in the number of 5-HT uptake sites in the developing cortex enhances the presynaptic inhibitory effect of 5-HT on thalamocortical transmission using intracellular and whole-cell patch- clamp recording techniques in a thalamocortical slice preparation. 4) We will assess the effects of prenatal cocaine exposure on the organization of a non-thalamic input to the primary somatosensory cortex that might be expected to expand its territory when thalamocortical afferents are placed at a """"""""competitive disadvantage"""""""" during development. 5) We will determine whether cocaine-induced alterations in cortical organization are dependent upon changes in cortical activity and increased activation of the 5-HT 1B receptor by combining prenatal cocaine exposure with blockage of cortical activity or specific blockade of the 5-HT 1B receptor.
