The objective of this proposed research is to investigate the mechanisms underlying the long-term neurobehavioral consequences of phencyclidine (PCP) exposure during development. PCP acts as a noncompetitive antagonist at the N-methyl-d-aspartate (NMDA) receptor. At high doses it also interacts with several other neurotransmitter sites. Earlier we have shown that chronic PCP administration in neonatal male rats altered seizure-susceptibility in an age-dependent manner. Chronic postnatal PCP treatment also produced significant impairment in spatial memory in juvenile rats. In the present application, (A) the detailed pharmacology of the behavioral effects of postnatal PCP will be examiner. 1. A range of PCP doses will be used to determine the dose-dependency of the behavioral responses. 2. Disposition of PCP in blood and brain will be measured to rule out that in immature rats chronic PCP administration leads to its accumulation in the body. 3. The time-course of changes in behavioral pattern will be determined to establish (i) when the immature behavioral pattern is replaced by the adult-like pattern, and (ii) how long the behavioral effects last. 4. Female rats treated postnatally with PCP will be tested behaviorally as juveniles and as adults and the data compared to that obtained from age-matched males to explore the possibility of any sex-specific effects of postnatal PCP treatment. (B) We will also determine the mechanistic basis of the behavioral effects of postnatal PCP exposure. 5. Experiments will be carried out to study the postnatal PCP-induced alterations in (i) glycine- and spermidine-induced modulation of L-glutamate activation of [3H]MK-801 binding in discrete brain areas. Rat pups will be injected daily 1.p, with one of three doses of PCP from Day 5 till Day 1 5. Controls will include 'pair-fed' vehicle-treated rats. A multidisciplinary approach in experimental design to be used will include Morris water maze testing, PTZ-induced seizure susceptibility, in vitro radioligand binding. Together, these studies will provide insight into the neurochemical consequences of chronic PCP exposure during development and further our understanding of neural plasticity and mechanisms underlying drug abuse.
| 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 |
