NEONATAL ASPHYXIA IN THE RAT: GREATER VULNERABILITY OF MALES AND PERSISTENT EFFECTS ON BRAIN MONOAMINE SYNTHESIS

In the rat, neonatal asphyxia produced by suffocation did not leave permanent visible lesions in thc brain, nor did it result in permanent motor impairment, although a delay in the development of some reflexes was observed. A transient retardation of body and brain growth, which was more pronounced in males, was found. By 5-6 weeks of age, body and brain weights of asphyxiated rats were no longer significantly different from control animals. However, an increase in brain norepinephrine synthesis was found to persist after maturation. An alteration of serotonin metabolism was found after maturation only in asphyxiated males. The possibility that neonatal asphyxia in the rat is a model for abnormal development of monoamine metabolism, relevant to early childhood behavior disorders such as infantile autism or the syndrome of minimal brain dysfunction, is discussed.     

Daily rhythms of benzodiazepine receptor numbers in frontal lobe and cerebellum of the rat

Behavioural, biochemical and neurophysiological evidence suggests that gamma-aminobutyric acid (GABA) may play an important role in the neural control of circadian rhythms. Central receptors for benzodiazepines are functionally coupled to GABA receptors and appear to mediate behavioural effects of exogenous benzodiazepines. The binding of 3H-flunitrazepam to synaptic plasma membranes prepared from various regions of rat brain was examined at 6-hour intervals over a 36-hour period. Prominent daily rhythms in receptor number (Bmax) were observed in the frontal lobe and the cerebellum but not in the temporoparietal regions, hypothalamus or medulla/pons. Binding was highest during periods of sleep/low activity with a significant decrease occurring just prior to waking. These results suggest that daily fluctuations in benzodiazepine receptor numbers may be related to the temporal control of sleep/wake and muscle activity cycles.     

Evidence for major gene inheritance of Alzheimer disease in families of patients with and without apolipoprotein E epsilon 4.

Apolipoprotein E (APOE) genotype is the single most important determinant to the common form of Alzheimer disease (AD) yet identified. Several studies show that family history of AD is not entirely accounted for by APOE genotype. Also, there is evidence for an interaction between APOE genotype and gender. We carried out a complex segregation analysis in 636 nuclear families of consecutively ascertained and rigorously diagnosed probands in the Multi-Institutional Research in Alzheimer Genetic Epidemiology study in order to derive models of disease transmission which account for the influences of APOE genotype of the proband and gender. In the total group of families, models postulating sporadic occurrence, no major gene effect, random environmental transmission, and Mendelian inheritance were rejected. Transmission of AD in families of probands with at least one epsilon 4 allele best fit a dominant model. Moreover, single gene inheritance best explained clustering of the disorder in families of probands lacking epsilon 4, but a more complex genetic model or multiple genetic models may ultimately account for risk in this group of families. Our results also suggest that susceptibility to AD differs between men and women regardless of the proband's APOE status. Assuming a dominant model, AD appears to be completely penetrant in women, whereas only 62%-65% of men with predisposing genotypes develop AD. However, parameter estimates from the arbitrary major gene model suggests that AD is expressed dominantly in women and additively in men. These observations, taken together with epidemiologic data, are consistent with the hypothesis of an interaction between genes and other biological factors affecting disease susceptibility.     

Presence of Two Benzodiazepine Binding Sites in the Rat Hippocampus

Abstract: Characteristics of receptor binding of diazepam and flunitrazepam in three brain areas were compared. It was found that in the cerebral cortex and cerebellum the number of sites was similar for both ligands and that the affinity of diazepam was four times lower than the affinity of flunitrazepam. In contrast, when binding in the hippocampus was analyzed (assuming the presence of homogenous binding sites), it was found that the number of binding sites was higher and that the affinity was 17 times lower for diazepam than for flunitrazepam. This difference is due to the presence of two diazepam binding sites in this brain area, as demonstrated by a Scatchard analysis.     

Effect of ethanol on cyclic AMP levels in the rat brain

Ethanol decreased in a dose-dependent manner the cyclic AMP level in the rat brain and separation of the brain into several parts showed that this decrease was limited to the cerebellum. High doses of ethanol (4–6 g/kg) blocked the rise of cyclic AMP levels induced by decapitation in all brain areas studied. Pentobarbital treatment which produced central depression similar to that caused by a high dose of ethanol, also decreased the cyclic AMP level in the cerebellum but it prevented the postdecapitation rise only in the pons and medulla oblongata. Lower doses of ethanol (1–2 g/kg) enhanced the decapitation-induced rise of cyclic AMP levels in the pons and medulla oblongata.     

Cyclic nucleotide levels in brains of control and hypertensive rats.

Adenosine 3′, 5′-monophosphate (cyclic AMP) and guanosine 3′,5- monophosphate (cyclic GMP) levels were measured in seven brain areas of spontaneously hypertensive rats (SHR) and two groups of control rats. In cerebral cortex, hypothalamus, pons-medulla oblongata and cerebellum cyclic AMP levels were higher in SHR than in Wistar-Kyoto controls. Cyclic GMP levels were higher in SHR than in Wistar-Kyoto rats in all brain areas except for the striatum and hippocampus where the levels were lower. There were also some differences in cyclic nucleotide levels between Wistar-Kyoto and Wistar-Charles River controls.     

Effect of morphine sulfate on adenylate cyclase and phosphodiesterase activities in rat corpus striatum.

The effect of morphine sulfate (MS) on adenylate cyclase (AC) and phosphodiesterase (PDE) activities in the rat striatum was investigated. MS produced a dose-dependent increase in basal AC activity and did not alter sodium fluoride-induced stimulation both $\text{in}$$\text{vivo}$ (7.5–30 mg/kg, 1 hr pretreatment, i.p.) and $\text{in}$$\text{vitro}$ (1–100μM). $\text{in}$$\text{vitro}$, when submaximal effective concentrations of dopamine and MS were combined, there was an additive effect. However, administration of MS $\text{in}$$\text{vivo}$ did not alter dopamine-induced stimulation of AC activity. MS, $\text{in}$$\text{vitro}$ and $\text{in}$$\text{vivo}$ inhibited PDE activity in a dose-dependent manner only with the high substrate concentration (3.3 × 10⁻³M cyclic AMP). Preliminary results from this study indicate that morphine affects the cyclic AMP system.     

Salt-induced hypertension in chronic renal failure: Evidence for a neurogenic mechanism

We investigated the possibility that blood pressure elevation induced by salt excess may be secondary to a neurogenic mechanism. The compound SK&F 64139 (50 mg/kg) known to inhibit central and peripheral phenylethanolamine N-methytransferase (PNMT) the enzyme necessary for the conversion of norepinephrine to epinephrine, was given by oral gavage to two groups of subtotally nephrectomized rats maintained for five days on either a high salt (HS) or low salt (LS) diet respectively. Blood urea nitrogen (BUN) and hematocrit were not different between the two groups, while body weight and serum Na were significantly higher in the HS animals. Baseline mean blood pressure (BP) was higher in the HS animals (HS 154 ± 4.7 vs LS 121 ± 3.7 mmHg, p<0.001) and decreased by 39 ± 6.9 mmHg one and one half hour post SK&F 64139 to normotensive levels in the HS as opposed to a decrease of 10 ± 1.8 mmHg in the LS group. Baseline heart rate (HR) was higher in the LS group (474 ± 17 beats/min) vs the HS group (408 ± 17, p<0.05), and decreased significantly after SK&F 64139 in both groups to the same extent (by 17.6% in the HS vs 13.3% in the LS). A third group of subtotally nephrectomized rats maintained for five days on a HS diet were given by oral gavage the compount SK&F 29661 (100 mg/kg), a PNMT inhibitor which does not cross the blood-brain barrier. Following SK&F 29661, there was no significant decrease in mean BP (153 ± 5 to 149 ± 4 mmHg) and a less than 2% decrease in HR. Baseline plasma norepinephrine (NE) was higher in the HS as compared to the LS group (1.50 ± 0.16 vs 0.904±0.15 ng/ml, respectively, p<0.05) and a significant correlation was found between plasma NE level and decrease in BP following SK&F 64139 (r=0.65, p<0.01). Not withstanding possible effects of some ancillary properties of SK&F 64139, these data support the hypothesis that a neurogenic component, possibly mediated via central epinephrine containing neurons, contributes to the BP elevation induced by salt excess.     

Sensitized guinea-pig lung: altered adenylate cyclase stimulation by epinephrine

Adenylate cyclase (AC) was measured in healthy and sensitized quinea-pig lungs. Basal activities were 24.49 ± 2.50 and 26.73 ± 3.03 pmols cyclic AMP mg protein/minute, respectively. NaF produced about threefold activity increase in both groups. Low concentrations of epinephrine (EPI) 10^?9 ? 10^?6M, maximally stimulated the enzyme in sensitized lungs. In contrast, these concentrations had no effect in healthy lungs. Higher EPI concentrations, 10^?5 ? 10^?2M, while progressively stimulating less the AC in sensitized lungs, increased the response in the healthy lungs. The maximal increase in AC activity, about 200%, was achieved with 10^?6 and 10^?3M EPI in sensitized and healthy lungs, respectively. Propranolol blocked the effect of EPI in both groups. The results indicate that sensitization altered the AC system in guinea-pig lungs.