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 [3H]DA release from striatal slices evoked by either 40 microM 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 [3H]DA release, frontal cortical glutamate binding sites and NMDA channels developed early, reaching adult levels on or before PND 21.(ABSTRACT TRUNCATED AT 250 WORDS)
Ali
S F
SF
National Center for Toxicological Research, Jefferson, AR 72079-9502.
Holson
R R
RR
Newport
G D
GD
Slikker
W
W
Bowyer
J F
JF
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000375:Aging / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D003342:Corpus Striatum / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism*; D005260:Female; D005625:Frontal Lobe / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism*; D005971:Glutamates / Q000494:pharmacology; D018698:Glutamic Acid; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D008297:Male; D008694:Methamphetamine / Q000494:pharmacology; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010622:Phencyclidine / Q000494:pharmacology*; D010875:Pipecolic Acids / Q000378:metabolism; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D051381:Rats; D017207:Rats, Sprague-Dawley
D005971:Glutamates; D010875:Pipecolic Acids; D015102:3,4-Dihydroxyphenylacetic Acid; D018698:Glutamic Acid; D008694:Methamphetamine; C053672:selfotel; D006897:Hydroxyindoleacetic Acid; D016202:N-Methylaspartate; D010622:Phencyclidine; D004298:Dopamine