The purpose of this series of studies is to understand the molecular basis for abnormalities in brain function that occur in neuropsychiatric abnormalities, especially including chronic adaptations in the brain in response to drug abuse. Some of these experiments have been focused on cell recognition molecules. The final form and organization of the CNS depends on interactions between cells; these interactions are dependent upon a number of specific classes of molecules, foremost among them being the cell recognition molecules (CRMs). In the mature CNS, CRMs continue to be crucial for interactions between cells as in, for example, synapse formation, neurite extension, and interactions between neurons and glia. Two particular molecules, N-CAM and L1 antigen, are abnormal in the cerebrospinal fluid of schizophrenic patients. The differences do not represent an acute drug effect, but appear to be related to long-term drug treatment. Moreover, the abnormalities are present in a specific pattern, with the abnormality being seen in certain forms of each molecule: An 105-115 kDa form of N-CAM which is found predominantly in cytosolic fractions from brain is increased about two-fold in schizophrenic patients, while the 140 kD form of L1 antigen is decreased to a similar degree. Similarly, although smaller, changes in N-CAM are also seen in patients with bipolar mood disorder. These changes in CSF are reflected in abnormalities of expression of cytosolic N-CAM in hippocampal tissue from post-mortem samples from human patients. Animal studies suggest that expression of N-CAM and L1 is altered in brain areas that are deafferented by injury, and that exogenous L1 can promote plasticity of dopaminergic neurites. These data suggest a possible role of CRMs in adaptation to chronic drug exposure and perhaps the predisposition to the development of neuropsychiatric disorders. Recently, microarray studies have also been undertaken in order to ascertain the categories of molecules that are altered in the brain in schizophrenia and drug abuse. Preliminary experiments have identified transcription factors, synapse-associated genes, and genes involved in signal transduction. Additional experiments are aimed at identifying subtle changes in glial function or activation in neuropsychiatric disorders and following chronic drug exposure. It is hoped that these experiments will help to define the kinds of changes, related to alterations in synaptic functions, changes in glial cells, and alterations in cell-cell interactions, that take place in the brain to mediate functional dysregulation that is seen in drug abuse and neuropsychiatric disorders.
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