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In the present study, we measured basal local cerebral metabolic rates for glucose (LCMRglcs) in immature genetic absence epilepsy rats from Strasbourg (GAERS) at postnatal day 21 (P21), at which age no spike-and-wave discharges can be recorded. LCMRglcs in GAERS were compared to those in control non-epileptic (NE) rats of the same age selected from our breeding colony. LCMRglcs were measured in 60 structures by the quantitative [14C]2-deoxyglucose (2DG) autoradiographic technique. In P21 GAERS, LCMRglcs were similar to those of P21 NE rats in 46 areas. They increased over NE control levels in two groups of structures. First, metabolic increases were recorded in limbic structures such as entorhinal and piriform cortex, lateral septum as well as all hippocampal subfields and basolateral amygdala, although no spike-and-wave discharges can be recorded from those areas in adult GAERS. On the other hand, increases in LCMRglcs were also recorded in substantia nigra pars reticulata, superior colliculus and globus pallidus which are structures involved in the control of seizure activity. Finally, significant metabolic decreases in P21 GAERS were recorded in two posterior auditory regions, the inferior colliculus and the superior olive. In conclusion, our data show that the genetic mutation(s) underlying the cellular and molecular events responsible for the expression of spike-and-wave discharges in adult GAERS is(are) able to increase metabolic activity in limbic structures and in the nigral inhibitory system before the occurrence of absence seizures. Conversely, the full electrocortical maturation seems necessary for the expression of spike-and-wave discharges with the concurrent increase in LCMRglcs in adult GAERS.

The role of nitric oxide (NO) on the age-dependent selective vulnerability to the consequences of epileptic seizures was studied in 10-day old (P10) and 21-day old (P21) rats. At P10, the NO synthase (NOS) inhibitor, NG-nitro-l-arginine (LNA), increased severity of seizures while l-arginine (l-Arg), the NOS substrate, had no effect. At P21, l-Arg improved the outcome of seizures while LNA had no effect. These results demonstrated the age-dependent role of NO in epilepsy.

The quantitative autoradiographic [14C]iodoantipyrine technique was applied to measure the effects of an acute hypoxic exposure on rates of local cerebral blood flow (LCBF) in the 10 (P10)-, 14 (P14)- and 21 (P21)-day-old rat. The animals were exposed to hypoxic (7% O2/93% N2) or control gas mixtures (21% O2/79% N2) for 40 min before the initiation of the 1-min LCBF measurement. At P10, hypoxia induced a 142-415% increase in LCBF over control levels, which affected the 45 structures studied. The highest increases in LCBF were noticed in posterior midbrain and brainstem regions. These increases are in good accordance with hypoxia-induced increases in LCBF recorded during acute hypoxia exposure in both newborn and adult animals. At P14 and P21, rates of LCBF decreased with hypoxia. These decreases were significant in 23 and 21 brain regions, respectively, belonging to all systems studied. These changes in LCBF are in quite good correlation with our previous data on the effects of acute hypoxia exposure on cerebral glucose utilization but the decrease in LCBF is of higher amplitude than the one in cerebral glucose utilization translating into a relative hypoperfusion at a constant metabolic level at P14 and P21. However, arterial blood pressure was reduced by 16 mmHg and arterial pCO2 was significantly decreased at the two latter ages in hypoxic animals compared to controls. These two systemic factors, and mainly hypocapnia, are rather responsible for the cerebral hypoperfusion recorded at P14 and P21 in hypoxic rats whereas the circulatory response seems to be predominantly hypoxic at P10.

The clinical features of kernicterus have been extensively described. However, there are still no data available on a possible correlation between the areas which appear to preferentially accumulate bilirubin and regional changes in cerebral functional activity. Therefore, we applied the quantitative autoradiographic [14C]2-deoxyglucose method to the measurement of local cerebral metabolic rates for glucose (LCMRglc) in immature rats receiving a bilirubin infusion. A loading dose of 160 mg/kg bilirubin in a buffered serum albumin solution was first given to the rats over 15 min. Thereafter, bilirubin was infused at a reduced rate, 64 mg/kg/h. Bilirubin infusion lasted from 2 to 3 h according to the age of the animal, in order to obtain a plasma concentration of bilirubin ranging from 200 to 300 mumol/l over the experimental period. Bilirubin entered the brain without any sign of blood-brain barrier alteration. The [14C]2-deoxyglucose was injected to the animals 45 min before the end of bilirubin infusion. Rats were studied at 3 postnatal ages, 10 (P10), 14 (P14) and 21 days (P21). Hyperbilirubinemia induced widespread decreases in LCMRglc's in all brain areas and at all ages. These decreases were mostly prominent in sensory areas, auditory and visual, as well as in hypothalamic and thalamic regions. Especially at P10, the distribution of LCMRglc's was strikingly heterogeneous in both cerebral cortex and caudate nucleus, appearing as alternate dark and white columns or as alternate dark and light dots, respectively. The data of the present study are in agreement with clinical observations reporting that bilirubin mostly accumulates in the striatum and cranial nerves and that the neurological sequelae of kernicterus are very often hearing loss as well as motor problems.

The influence of a chronic phenobarbital (PhB) treatment on postnatal evolution of local cerebral metabolic rates for glucose (LCMRglc) was studied in 58 cerebral structures of freely moving rats. The animals received a daily subcutaneous injection of PhB at a dose of 50 mg/kg between days 2 and 35 or an equivalent volume of saline for controls and were studied at 5 postnatal stages, i.e. 10, 14, 17, 21 and 35 days, and at the adult stage. Body and brain weights were both reduced by 6–21% over the whole period studied. PhB exposure induced significant decreases in LCMRglc during the period of pharmacological treatment, i.e. until 35 days, except at the stage of 17 days as well as long-term reductions in LCMRglc of adult rats in 36 out of the 58 brain regions studied. These decreases affected all systems studied, sensory systems as well as limbic, hypothalamic, motor and white matter areas. In addition to a growth retardation, PhB also seemed to be able to induce a delay in the acquisition of auditory function which matures early during postnatal life. The long-term deficits in cerebral energy metabolism due to PhB in the adult rat also confirm the behavioral deficits which have been shown previously after early PhB exposure.

The 3-oxo acid-CoA transferase and acetoacetyl-CoA synthetase activities were estimated in subcellular fractions isolated from the cerebral hemispheres, the optic lobes, the cerebellum and the liver of the chick between the twentieth day of embryonic life and the thirtieth day of postnatal development. In the 3 areas of chick brain, the tranferase activity increases during the whole postnatal development. Transferase is located both in mitochondria and microsomes unlike in the rat brain where this enzyme is specifically mitochondrial. There is no detectable activity of synthetase in the chick brain. These differences in enzyme localization imply that acetoacetate is converted into acetoacetyl-CoA only by 3-oxo acid-CoA transferase in the mitochondria and cytoplasm of the chick brain, whereas, in the rat brain, this reaction is performed by 3-oxo acid-CoA transferase in mitochondria and by acetoacetyl-CoA synthetase in the cytosol. There is no detectable activity either for transferase or for synthetase in the chick liver.

The influence of phenobarbital (PhB) on the utilization of glucose by the cerebral cortex and the cerebellum was studied in rats during postnatal development. The animals were treated from day 2 to day 35 after birth by a daily injection of 50 mg/kg PhB or by saline. The rats were studied at 5 postnatal stages: 7, 10, 14, 21 and 35 days. PhB treatment induced a 10% decrease in body and brain weight over the whole period studied and a transient significant decrease in circulating thyroxin levels at 14 days after birth. Amino acid levels in the cerebral cortex and particularly in the cerebellum were not greatly affected by the pharmacological treatment. The conversion of [2-14C]glucose into amino acids was significantly decreased in both cerebral structures between day 7 and day 14 after birth. The distribution of radioactivity between amino acids was not affected in the cerebral cortex but was significantly changed by PhB treatment in the cerebellum. Specific radioactivity values of amino acids were lower in PhB- than in saline-treated animals in both studied structures. The results of the present study show that glucose utilization is reduced in the brain of PhB-treated animals as compared to the controls and that the cerebellum seems to be more affected than the cerebral cortex.