Chronic administration of phencyclidine (PCP) in rats has been reported to induce a modest sensitization to the locomotor activating effects of PCP challenge. The underlying mechanisms are unknown, but they appear to be distinct from those of amphetamines and cocaine in that PCP-sensitization is not blocked by the selective NMDA antagonist MK-801. This laboratory has developed a chronic regimen of moderately high-dose PCP that results in a long- lasting, robust behavioral sensitization to low-dose PCP challenge. This dosage regimen also produces morphological and biochemical alterations in the olfactory tubercle and piriform cortex consistent with programmed cell death or apoptosis. Other preliminary studies suggest that chronic PCP induces an upregulation of the NR1 subunit of the NMDA receptor in several areas of the forebrain, including the olfactory and piriform regions, but not in areas such as the hippocampus or cerebellum. Functional studies using NMDA-stimulated neurotransmitter release generally support the in situ hybridization and immunocytochemistry data. Acute PCP is known to increase DA turnover in most terminal regions of the mesocortical and mesolimbic pathways, with the olfactory tubercle and piriform cortex being the most sensitive. The P.I. postulates that behavioral sensitization is associated with an altered DA release in the mesolimbic cortex and that the selective vulnerability of the olfactory tubercle and piriform region is due to both upregulated NMDA receptors in this region and to the neurotoxic effects of DA. Although acute high-dose PCP has previously been demonstrated to cause necrotic toxicity in the retrosplenial, posterior cingulate, entorhinal and possibly other limbic regions, the P.I. postulates that these two forms of toxicity can be distinguished pharmacologically. This application proposes a series of experiments that will use a combination of behavioral, pharmacological, biochemical and molecular techniques to further characterize PCP-induced behavioral sensitization, necrosis, programmed cell death, DA turnover and NMDA receptor upregulation in order to determine the relationship between these phenomena. There are four specific hypotheses that will be used to drive these experiments. An additional two hypotheses will be used first to obtain a """"""""fingerprint' of apoptotic death gene activation and second, to use this pattern along with other results to begin to establish an in vitro cortical culture model of chronic PCP- induced apoptosis. In the future, the P.I. would like to use this model to establish more precisely the mechanisms underlying PCP- induced cell death.
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