EFFECTS OF EARLY CHRONIC DIAZEPAM TREATMENT ON INCORPORATION OF GLUCOSE AND BETA-HYDROXYBUTYRATE INTO CEREBRAL AMINO-ACIDS - RELATION TO UNDERNUTRITION

The effects of early chronic diazepam (DZP) exposure on blood glucose and ketone body concentration and glucose and beta-hydroxybutyrate (be ta HB) utilization for regional cerebral amino acid biosynthesis were studied in suckling rats. The animals were treated from postnatal day 2 (P2) to 21 (P21) by a daily subcutaneous injection of 10 mg/kg DZP o r of the dissolution vehicle and studied at P5, P10, P14 and P21, toge ther with an additional group of food-restricted rats obtained by an i ncrease in litter size. DZP treatment induced a 9-26% decrease in body and brain weight. Undernutrition decreased body weight by 20-24% at a ll ages whereas brain weight was relatively spared. DZP and N-desmethy ldiazepam concentrations decreased with age and were cleared from brai n and plasma by 6-8 hrs after the injection. DZP decreased plasma gluc ose concentrations by 6-12% at P5, P14 and P21, whereas undernutrition did not change plasma glucose concentrations, except for a 7% decreas e at P14. DZP treatment had no consequences on circulating concentrati ons of both ketone bodies while undernutrition increased their concent ration by 45-362% at all ages. The conversion of [C-14]glucose into ce rebral amino acids was reduced by DZP at P5 and P10. The cerebral conc entration of neurotransmitter amino acids was not affected by DZP trea tment which only increased the amount of neutral amino acids mainly in the cerebellum at P5 and P10. After [U-C-14]glucose injection, specif ic radioactivities of cerebral amino acids were mostly decreased by DZ P from P5 to P14 and significantly increased at P21. With [3-C-14]PHB as a precursor, specific radioactivities of neurotransmitter amino aci ds were increased by DZP. In conclusion, P5 and P10 rats appear to be most sensitive to DZP effects whereas some tolerance to the drug seems to develop by P21. The lack of effects of DZP on blood ketone body co ncentrations compared to food restriction as well as the relative spar ing of brain weight in undernourished rats confirms that the cerebral metabolic consequences of early DZP exposure on brain energy metabolis m are mostly direct effects not mediated by sedation-induced undernutr ition.