Synchronous postnatal increase in alpha1 and gamma2L GABA(A) receptor mRNAs and high affinity zolpidem binding across three regions of rat brain.
The objective of this study was to correlate postnatal changes in levels of mRNAs encoding predominant GABA(A) receptor subunits with a functional index of receptor development. This study is the first to quantify the temporal relationship between postnatal changes in predominant GABA(A) receptor mRNAs and zolpidem-sensitive GABA(A) receptor subtypes. In Experiment 1, we measured zolpidem displacement of 3H-flunitrazepam from rat cerebral cortex, hippocampus, and cerebellum at 0, 6, 14, 21, 29, and 90 postnatal days. Three independent 3H-flunitrazepam sites with high (K(i)=2. 7+/-0.6 nM), low (K(i)=67+/-4.8 nM), and very low (K(i)=4.1+/-0.9 mM) affinities for zolpidem varied in regional and developmental expression. In Experiment 2, we used RNAse protection assays to quantify levels of alpha1, alpha2, beta1, beta2, gamma2S and gamma2L mRNAs in the above regions at the same postnatal ages. Although there was a high degree of regional variation in the developmental expression of zolpidem-sensitive GABA(A) receptors and subunit mRNAs, a dramatic increase in high affinity zolpidem binding sites and alpha1 mRNA levels occurred within all three regions during the second postnatal week. Furthermore, a temporal overlap was observed between the rise in alpha1 mRNA and high affinity zolpidem binding and a more prolonged increase in gamma2L in each region. These results point to the inclusion of the alpha1 and gamma2L subunits in a GABA(A) receptor subtype with a high zolpidem affinity and suggest that a global signal may influence the emergence of this subtype in early postnatal life.
Roberts
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Department of Brain and Cognitive Sciences, University of Rochester, Meliora Hall, Rochester, NY 14627, USA.
Kellogg
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D000375:Aging / Q000502:physiology; D000704:Analysis of Variance; D000818:Animals; D001665:Binding Sites / Q000502:physiology; D001667:Binding, Competitive / Q000187:drug effects; D001921:Brain / Q000254:growth & development* / Q000378:metabolism*; D002531:Cerebellum / Q000254:growth & development / Q000378:metabolism; D002540:Cerebral Cortex / Q000254:growth & development / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D005445:Flunitrazepam / Q000378:metabolism; D018757:GABA Modulators / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D006624:Hippocampus / Q000254:growth & development / Q000378:metabolism; D006993:Hypnotics and Sedatives / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D011725:Pyridines / Q000378:metabolism* / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D020318:Rats, Long-Evans; D011963:Receptors, GABA-A / Q000235:genetics* / Q000378:metabolism; D012260:Ribonucleases / Q000378:metabolism; D000077334:Zolpidem
D018757:GABA Modulators; D006993:Hypnotics and Sedatives; D011725:Pyridines; D012333:RNA, Messenger; D011963:Receptors, GABA-A; D005445:Flunitrazepam; D000077334:Zolpidem; D012260:Ribonucleases