The objective of the proposed research is to establish how exposure to phencyclidine (PCP) during development alters neural development. PCP and PCP-like drugs mediate their neurobehavioral effects by interacting with specific receptors in the brain which are functionally linked to the NMDA receptor. The PCP receptor is located within the NMDA channel. The proposed research tests 2 hypothesis. The first hypothesis is that chronic postnatal PCP exposure modulates the PCP-NMDA receptor complex. This study will be carried out in two parts. In Part 1, the ontogeny of the functional coupling between the PCP and NMDA receptor will be determined, i.e. age at which PCP receptor binding becomes sensitive to the modulations by NMDA receptor agonists, antagonists and modulators. In Part II, the effects of chronic postnatal PCP treatment on the PCP-NMDA receptor complex will be studied. Experiments will determine alterations in (a) the binding characteristics of the PCP receptor, (b) the distribution patterns of the PCP and NMDA receptor, and (c) the sigma receptor binding, in weanling and adult rats following postnatal chronic PCP administration. Rat pups will be injected daily with one of three doses of PCP i.p. from postnatal day 5 to 15. Controls will include """"""""pair-fed"""""""" vehicle-treated pups and a non- handled control group. Groups of experimental and control rats will be sacrificed on postnatal days 21 and 60, respectively, and well-washed, frozen-thawed, osmotically-shocked synaptosomal membranes (CSMs) prepared from their forebrains (cortex and hippocampus). Detailed in vitro PCP receptor binding assays will be performed in experimental and control rats to measure the PCP receptor density, affinity and kinetics of binding, using the specific PCP receptor ligand [3H]MK-801. Precise neuroanatomical localization of the PCP and NMDA receptor changes will be determined by quantitative light microscopic autoradiography. To determine the specificity of the effect of PCP on the PCP-NMDA receptor system, the effect of postnatal PCP treatment on the 1,3-di(2-[5-3H]toly)guanidine ([3H]DTG)-labeled sigma receptor binding will be examined. A second hypothesis is that chronic PCP exposure in adult rats produce alterations in the PCP-NMDA receptor complex. Data from this project will be used to interpret the developmental study. Adult animals will be injected daily with PCP (doses identical to those in the postnatal study) for 11 days. PCP- and saline-treated animals will be sacrificed 6 days and 5 weeks after the last injection. Besides saline controls, an acute control group will also be included. Effects of chronic PCP administration on [3H]MK-801 binding, and on the PCP and NMDA receptor distribution patterns will be studied. Together, these studies are hoped to provide insight into the neurochemical consequences of chronic PCP exposure during development and further our understanding of neural plasticity.
| Sircar, R; Li, C S (1994) PCP/NMDA receptor-channel complex and brain development. Neurotoxicol Teratol 16:369-75 |
| Sircar, R; Veliskova, J; Moshe, S L (1994) Chronic neonatal phencyclidine treatment produces age-related changes in pentylenetetrazol-induced seizures. Brain Res Dev Brain Res 81:185-91 |
