DEVELOPMENT OF DOPAMINE AND N-METHYL-D-ASPARTATE SYSTEMS IN RAT-BRAIN - THE EFFECT OF PRENATAL PHENCYCLIDINE EXPOSURE

Phencyclidine (PCP) inhibits the uptake of the neurotransmitter dopamine (DA), and blocks N-methyl-D-aspartate (NMDA) receptor-regulated ion channels. PCP also binds to sigma receptors in vivo and in vitro in rat brain. Prolonged exposure to PCP in adults has been observed to reduce the number of PCP binding sites in brain. We designed these experiments to evaluate whether prolonged prenatal exposure to PCP produces alterations in the development of DA and NMDA systems in brain. To do so, we characterized the normal course of development of basal and stimulated DA release in striatal slices, the ontogeny of striatal DA concentrations, and the development of NMDA receptor channels and associated glutamate binding sites in frontal cortex. We compared these developmental profiles to those in rats exposed to prenatal PCP, in an attempt to characterize the effect of prenatal PCP exposure on the pattern of brain development. Pregnant CD rats were injected s.c. with either 0, 10 or 20 mg/kg PCP daily on gestational days 8 through 20. On postnatal days (PND) 8, 21, 45, or 100, rats were sacrificed and brain tissues isolated for in vitro assessment. In vitro [H-3]E)A release from striatal slices evoked by either 40 muM glutamate or 15 mM K+ increased over 250% from PND 8 to PND 45, and glutamate-stimulated release was still significantly below adult levels at PND 45. In contrast, D-methamphetamine (D-METH)-evoked [H-3]DA release, frontal cortical glutamate binding sites and NMDA channels developed early, reaching adult levels on or before PND 21. At PND 8 but not thereafter prenatal PCP (10 or 20 mg/kg) appeared to increase glutamate-evoked [H-3]DA release but not K+- and METH-evoked release in striatal slices. There were no significant effects of prenatal PCP exposure on the in vivo levels of DA or serotonin or their metabolites in striatum at any PND. PCP exposure also had no effect on the NMDA receptor ion channel or the glutamate binding site in frontal cortex at any age. These data indicate that prenatal exposure to PCP may selectively but transiently and moderately change glutamate evoked DA release early in development without affecting the in vivo levels of DA and serotonin or NMDA receptor complex levels in developing brain.