Effects of early chronic diazepam treatment on incorporation of glucose and β-hydroxybutyrate into cerebral amino acids: Relation to undernutrition

Abstract

The effects of early chronic diazepam (DZP) exposure on blood glucose and ketone body concentration and glucose and β-hydroxybutyrate (βHB) 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 or of the dissolution vehicle and studied at P5, P10, P14 and P21, together with an additional group of food-restricted rats obtained by an increase in litter size. DZP treatment induced a 9–26% decrease in body and brain weight. Undernutrition decreased body weight by 20–24% at all ages whereas brain weight was relatively spared. DZP and N-desmethyldiazepam concentrations decreased with age and were cleared from brain and plasma by 6–8 hrs after the injection. DZP decreased plasma glucose concentrations by 6–12% at P5, P14 and P21, whereas undernutrition did not change plasma glucose concentrations, except for a 7% decrease at P14. DZP treatment had no consequences on circulating concentrations of both ketone bodies while undernutrition increased their concentration by 45–362% at all ages. The conversion of [14C]glucose into cerebral amino acids was reduced by DZP at P5 and P10. The cerebral concentration of neurotransmitter amino acids was not affected by DZP treatment which only increased the amount of neutral amino acids mainly in the cerebellum at P5 and P10. After [U-14C]glucose injection, specific radioactivities of cerebral amino acids were mostly decreased by DZP from P5 to P14 and significantly increased at P21. With [3-14C]βHB as a precursor, specific radioactivities of neurotransmitter amino acids 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 concentrations compared to food restriction as well as the relative sparing of brain weight in undernourished rats confirms that the cerebral metabolic consequences of early DZP exposure on brain energy metabolism are mostly direct effects not mediated by sedation-induced undernutrition.