Early developmental exposure to benzodiazepine ligands alters brain 31P-NMR spectra in young adult rats.
Alterations in brain high energy phosphate compounds, using 31P-NMR (nuclear magnetic resonance) spectroscopy, were measured in vivo in young adult (3-4 months) rats following prenatal exposure to ligands acting specifically at benzodiazepine (BDZ) binding sites. The exposure induced a decrease in intracellular pH that indicated a predominant interaction of the drugs in utero with central-type BDZ receptor sites. Late gestational exposure to BDZ ligands also induced changes in brain phosphocreatine (PCr) utilization. Exposure to the lowest dose of DZ (1.0 mg/kg) but not the higher dose (2.5 mg/kg) induced a significant change in PCr utilization. Exposure to the central-type BDZ receptor antagonist RO15-1788 alone clearly altered PCr utilization in adult offspring, and DZ (2.5 mg/kg) when administered concurrently was not able to prevent this effect. Though exposure to a peripheral-type ligand (PK11195) had no effect by itself, it converted the effect of the high dose of DZ to that of the low dose. Together, these results indicate an interaction during development between the central and peripheral-type BDZ binding sites on organization and/or regulation of cellular energy metabolism. Normalized ATP levels were not changed by any prenatal treatment indicating adequate buffering of intracellular ATP by phosphocreatine. The dopaminergic antagonist haloperidol did not alter intracellular pH or any index of phosphate metabolism indicating a selective receptor mediated role for BDZ ligands in influences on the long term organization of intracellular phosphate metabolism.
Miranda
R
R
Department of Psychology, University of Rochester, NY 14627.
Ceckler
T
T
Guillet
R
R
Kellogg
C
C
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D003975:Diazepam / Q000494:pharmacology*; D005260:Female; D005442:Flumazenil / Q000494:pharmacology; D006863:Hydrogen-Ion Concentration; D009682:Magnetic Resonance Spectroscopy; D010725:Phosphocreatine / Q000493:pharmacokinetics*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D051381:Rats; D011963:Receptors, GABA-A / Q000187:drug effects / Q000378:metabolism*
D011963:Receptors, GABA-A; D010725:Phosphocreatine; D005442:Flumazenil; D003975:Diazepam