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 dopami ne (DA), and blocks N-methyl-D-aspartate (NMDA) receptor-regulated ion channels. PCP also binds to sigma receptors in vivo and in vitro in r at brain. Prolonged exposure to PCP in adults has been observed to red uce the number of PCP binding sites in brain. We designed these experi ments 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 sti mulated DA release in striatal slices, the ontogeny of striatal DA con centrations, and the development of NMDA receptor channels and associa ted glutamate binding sites in frontal cortex. We compared these devel opmental profiles to those in rats exposed to prenatal PCP, in an atte mpt 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 post natal days (PND) 8, 21, 45, or 100, rats were sacrificed and brain tis sues 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+ increase d over 250% from PND 8 to PND 45, and glutamate-stimulated release was still significantly below adult levels at PND 45. In contrast, D-meth amphetamine (D-METH)-evoked [H-3]DA release, frontal cortical glutamat e binding sites and NMDA channels developed early, reaching adult leve ls on or before PND 21. At PND 8 but not thereafter prenatal PCP (10 o r 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 sign ificant effects of prenatal PCP exposure on the in vivo levels of DA o r serotonin or their metabolites in striatum at any PND. PCP exposure also had no effect on the NMDA receptor ion channel or the glutamate b inding site in frontal cortex at any age. These data indicate that pre natal exposure to PCP may selectively but transiently and moderately c hange glutamate evoked DA release early in development without affecti ng the in vivo levels of DA and serotonin or NMDA receptor complex lev els in developing brain.