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A Smolen

Publications and source records attributed to A Smolen.

At least 37 records · Page 2Linked to original sources
PubMed1986

The effect of naloxone administration on pregnancy-associated seizures.

Pregnant mice are more susceptible to flurothyl-induced seizures than are non-pregnant controls. The possibility that the well-known increase in beta-endorphin concentration which accompanies pregnancy was involved in this effect was examined by testing whether naloxone administration could block the increased seizure susceptibility. Pregnant female, control female and male C3H mice were treated with 5-50 mg/kg naloxone 5 min before flurothyl seizure testing. Naloxone markedly increased clonic seizure susceptibility in all three groups at a dose of 50 mg/kg, but had little effect at lower doses. In contrast, naloxone had differential effects on myoclonic seizures in pregnant and control female mice, being anticonvulsant in the controls, but proconvulsant in the pregnant mice. A role for endogenous opiates is unlikely in mediating clonic seizures in pregnant mice, but may be involved in myoclonic seizures.

Animals↗
PubMed1986

Dissociation of decreased numbers of muscarinic receptors from tolerance to DFP.

Several studies have demonstrated that chronic treatment with organophosphates, such as DFP, elicits a decreased number of brain muscarinic receptors (measured by the binding of QNB) which has been presented as an explanation for tolerance to the organophosphates. The purpose of the studies presented here was to assess whether graded changes in QNB binding could be attained following different methods of chronic DFP treatment, and whether tolerance to DFP paralleled these changes. Male DBA mice were injected with DFP every 4 days or 2 days for 30 days or daily for 14 days. The animals were subsequently challenged with DFP or the muscarinic agonist, oxotremorine, and respiratory rate, heart rate, body temperature, Y-maze activity and rearing were recorded. Chronic DFP-treated animals were supersensitive to the effects of DFP on respiratory rate, heart rate, and body temperature whereas a modest tolerance to the effects of oxotremorine on respiratory rate, heart rate, and body temperature was seen. Neither tolerance nor supersensitivity were observed for the effects of DFP and oxotremorine on the Y-maze measures. Chronic DFP treatment elicited reduced binding of QNB in striatum, cortex, and hippocampus with the group that had been treated every other day exhibiting the greatest changes. The changes in drug response did not parallel changes in QNB binding which raises questions as to the cause of the reduction in binding.

Animals↗
PubMed1986

A strain comparison of physiological and locomotor responses of mice to diisopropylfluorosphosphate.

The effects of acute treatment with the organophosphate, diisopropylfluorophosphae (DFP), were studied in three inbred mouse strains. C57BL, DBA and C3H. A battery of physiological and locomotor tests including respiratory rate, heart rate, body temperature, Y-maze activity and rotarod performance was used. Dose-response and time course studies were carried out. Approximately 15 min after injection the animals were markedly affected by the drug with maximal effects occurring approximately 2 hours after injection. Strain comparisons were made at the 2 hr time point. In all strains, males and females were affected about equally except for respiratory rate and rotarod performance in which females were slightly more affected. Strain comparisons revealed that for most of the tests the C57BL mice were most affected by the DFP and the C3H mice were least affected. For the heart rate test the DBA mice were the most sensitive. Previous studies from our laboratory have demonstrated a similar rank ordering of the strains in their responses to oxotremorine and nicotine. The strain differences in response to these agents is not easily explained by differences in number or affinity of brain muscarinic or nicotinic receptors. The genetic influence on cholinergic drug response may involve receptor coupling mechanisms.

Animals↗
PubMed1985

Genetically determined differences in acute responses to diisopropylfluorophosphate.

The acute effects of diisopropylfluorophosphate (DFP) were assessed in DBA/2Ibg, C57BL/6Ibg and C3H/2Ibg mice. The DFP was administered by intraperitoneal injection in saline. Brain acetylcholinesterase (AChE) activity was maximally inhibited within 5 min after injection. All mice showed signs of organophosphate intoxication including salivation, lacrimation, diarrhea, respiratory distress, tremor and, at high doses, seizures. The C57BL mice were most susceptible to these effects of DFP. The LD50 values for DFP were 8.0, 7.6, and 6.8 mg/kg for male DBA, C3H, and C57BL mice, respectively. The LD50 values for females were nearly the same. Body temperature and brain AChE activity decreased in a dose-dependent manner following injections of DFP of 3.17, 4.22, 5.28, and 6.33 mg/kg. Maximum temperature depression occurred 2 hours after DFP administration; by 24 hours temperatures had returned to normal except for C57BL mice treated with the highest dose of DFP. The C57BL strain was most susceptible to the DFP-induced hypothermia, the C3H strain was the most resistant, and the DBA strain was intermediate. Maximum temperature depression and residual AChE activity, as measured 24 hours after injection, were linearly related. These strain differences do not seem to be explained easily by a differential inhibition of AChE activity.

Animals↗
PubMed1985

Recovery of acetylcholinesterase activity after acute organophosphate treatment of CNS reaggregate cultures.

The effect of a single dose of diisopropylfluorophosphate on acetylcholinesterase (AChE) activity was examined in mouse CNS reaggregate cultures. At 17-24 days in culture, reaggregates were treated with 0.6 mg/liter DFP for 15 min. The recovery of AChE activity was examined in culture. After treatment, 5.4 +/- 1.19% of control AChE activity remained. By 24 hr, 31.6 +/- 6.4% of control activity had returned and the recovery of activity was essentially complete by 7 days after treatment. Recovery of AChE activity after DFP treatment required protein synthesis, since there was no recovery in the presence of cycloheximide. After treatment with the reversible inhibitor, physostigmine at 0.5 mg/ml, recovery of AChE activity was complete within 24 hr after treatment. These results indicate that CNS reaggregate cultures not only express differentiated functions of the CNS, but also have the capacity to turn over proteins, and thus may provide a good model system in which to examine mechanisms of toxicity.

Acetylcholinesterase↗
PubMed1982

Seizure susceptibility of the pregnant mouse.

The effect of pregnancy on chemically-induced seizures in mice was studied. Latencies to myoclonic and clonic seizures induced by inhalation of flurothyl were significantly reduced at days 12 through 18 of gestation. Parturition resulted in a return of seizure susceptibility to control levels. The possibility that this effect might be mediated by decreased neurotransmitter levels subsequent to the decreased vitamin B6 levels which are known to occur during pregnancy was suggested. A pregnancy-associated liver cytosolic aldehyde dehydrogenase (pi-AlDH) utilized pyridoxal as a substrate, and the peak of pi-AlDH activity was shown to coincide with the peak of seizure susceptibility. The activity of aldehyde oxidase, the major enzyme normally responsible for the metabolism of pyridoxal, was reduced in pregnant animals. The pyridoxal 5'-phosphate synthesizing enzymes, pyridoxal kinase and pyridoxamine phosphate oxidase, were marginally increased in activity during pregnancy. It was suggested that the increased activity of pi-AlDH was indirectly responsible for the increased seizure susceptibility due to increased metabolism of pyridoxal.

Aldehyde Dehydrogenase↗
PubMed1982

The influence of age, sex and genotype on the subcellular distribution of hepatic aldehyde dehydrogenase activity in the mouse.

1. The influence of age on hepatic aldehyde dehydrogenase (AlDH) was studied in both sexes of two selectively bred lines of mice (Mus musculus). 2. Whole liver AlDH activity increased from the 60-day-old level linearly up to 200 days of age. The enzyme activity of the females remained at the 200-day-old level, but in males. AlDH continued to increase up to 400 days of age. Males had higher AlDH activity than females. 3. The AlDH activities of 3 subcellular fractions: cytosol, mitochondria and microsomes also increased with age, but were more dependent on sex and genotype than was the whole liver activity. 4. It was concluded that AlDH activity increases with age in mouse liver but it was influenced greatly by sex, genotype and subcellular fraction studied.

Age Factors↗
PubMed1981

Liver cytosolic aldehyde dehydrogenase activity in the pregnant mouse.

A 3-fold increase in aldehyde dehydrogenase (A1DH) was found in the cytosolic fraction of mouse liver homogenates during pregnancy. The increase in A1DH activity began at day 10 of pregnancy, peaked at parturition, and declined in a biphasic manner with half-lives of 4.15 and 47.7 days. Enzymes from control (beta A1DH), pregnant (pi A1DH) and phenobarbital-treated (phi AlDH) were partially purified and compared. All had molecular weights of approximately 60,000 daltons. Substrate specificities were similar except that phi A1DH had a lower Km for propionaldehyde than beta or pi and both pi and phi oxidized 4-carboxybenzaldehyde poorly compared to beta. Electrophoretic and thermal denaturation studies showed some similarities between beta and pi, but phi A1DH behaved quite differently. It was concluded that pregnancy caused an increase in one of the A1DHs already present in control mice, while phenobarbital treatment resulted in induction of a unique cytosolic A1DH.

Aldehyde Dehydrogenase↗
PubMed1980

Synapse formation in the rat superior cervical ganglion during normal development and after neonatal deafferentation.

Ten per cent of the adult number of synapses are present in the neonatal rat superior cervical sympathetic ganglion on day 1 (day of birth taken as day 0). Synapses are formed rapidly over the first postnatal week, and then more slowly, reaching 80% of adult numbers by the end of the third week. Adult numbers are present at the end of the third month. Prominent axosomatic synapses are present for the first two weeks of life, but disappear later. Of the adult numbers of synapses, 20-40% are already present on days 2 and 4, and transection of the preganglionic chain on these days causes disappearance of all synapses by 2 days after operation. However, by 2 months after operation the numbers of synapses are the same as in unoperated ganglia from rats of the same age. Unoccupied postsynaptic densities were not seen either in normal development or after lesions.

Afferent Pathways↗
PubMed1980

The role of liver cytosolic aldehyde dehydrogenase in ethanol metabolism in DBA and C57Bl mice.

Cytosolic aldehyde dehydrogenase (AlDH) activity was increased in DBA and C57Bl mice following phenobarbital (Pb) treatment. The kinetic constants for the control and induced enzymes were similar in both inbred strains. The DBA mice showed enhanced rates of ethanol and acetaldehyde metabolism after Pb treatment, whereas the C57Bl mice did not. It was concluded that the cytosolic enzyme is more important for acetaldehyde metabolism in the DBA than in the C57Bl mice.

Acetaldehyde↗
PubMed1979

Muscarinic receptors in the central nervous system of the rat. IV. A comparison of the effects of axotomy and deafferentation on the binding of [3H]propylbenzilylcholine mustard and associated synaptic changes in the hypoglossal and pontine nuclei.

The reaction of axotomy has been studied in the rat hypoglossal nucleus by quantitative electron microscopical counts of numbers of synapses and by changes in muscarinic receptors assessed by counting silver grains in light microscope autoradiographs of the specific (atropine-sensitive) binding of [3H]propylbenzilylcholine mustard in cryostat sections. For the first 5 days after unilateral peripheral hypoglossal nerve axotomy the muscarinic ligand binding falls to 50% of control levels and then shows no further fall for up to 30 days. Synapse numbers decrease progressively over the first 10 days after operation, by which time they reach 50% of normal. Thus receptor changes reach completion at a time when synapse loss is still continuing. Later, both muscarinic ligand binding and synapse numbers recover to an extent which depends at least in part on the effectiveness of the peripheral nerve regeneration, suggesting that both the receptor and synapse changes may be dependent upon neuromuscular contacts. The reactions of muscarinic receptors to axotomy and deafferentation have been studied in the rat basilar pontine nuclei. Cerebellectomy, which causes axotomy of the pontine neurones and also removes their postsynaptic targets (the granule cells), causes no change in pontine muscarinic receptor over the first week after operation. This differs from the rapid fall in hypoglossal muscarinic receptors induced by axotomy. At longer survivals after cerebellectomy there is a partial loss of pontine muscarinic receptors associated with atrophy of the pontine neurones. Destruction of the neocortical afferents causes a loss of at least half of the synapses in the pontine neuropil. However, the light microscopic autoradiographic study revealed no obvious changes in the dentisy or distribution of the pontine muscarinic receptors from 4 days to more than 6 months after operation.

Afferent Pathways↗
PubMedDate not supplied

Aminotransferase activities in mouse, Mus domesticus, erythrocytes separated according to age.

Erythrocyte aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities are often used as indices of vitamin B-6 nutritional status; however, results using a mixed population of erythrocytes can be quite variable. Erythrocytes from two strains of mice (Mus domesticus), A/Ibg and DBA/Ibg, were separated according to age by centrifugation through discontinuous Percoll density gradients into three fractions: top (least dense, youngest), middle and bottom (most dense, oldest). A sufficient yield of age-fractionated erythrocytes was obtained from a single mouse for all of the enzyme measurements. The activities of AST, ALT and three age-marker enzymes, pyruvate kinase, acetylcholinesterase and hexokinase, were found to be significantly higher in the youngest cell fractions, and declined in the older, more dense fractions. A mice had significantly lower AST and ALT activities in the age separated fractions than did DBA mice. The measurement of enzyme activities in low density, young cells may be especially useful in studies involving conditions in which the proportion of young erythrocytes may be elevated with respect to the entire erythrocyte mass.

Alanine Transaminase↗
PubMedDate not supplied

Ethanol and temperature effects on five membrane bound enzymes.

The effects of ethanol on the activities of five membrane bound enzymes were determined using a crude membrane preparation obtained from cortex of long-sleep (LS) and short-sleep (SS) mice. These two mouse lines were selectively bred for differences in duration of ethanol-induced sleep time. The enzymes studied were two forms of NaK-ATPase, Mg-ATPase, 5'nucleotidase, and acetylcholinesterase. Arrhenius plots of the ethanol-temperature-enzyme activity studies indicate specificity in ethanol's actions. NaK-ATPase activity consists of two enzymes which were distinguished by sensitivity to ouabain. The Arrhenius plot of the high ouabain sensitivity enzyme (low Ki) exhibited a transition temperature which was reduced twice as much by ethanol in LS membranes as in SS membranes. Ethanol did not affect the transition temperature of the high Ki NaK-ATPase but the control (no ethanol) transition temperature was 2.7 degrees higher in SS membranes. Arrhenius plots of Mg-ATPase activity did not exhibit a transition temperature and ethanol did not alter enzyme activity. Ethanol did not alter the transition temperatures of 5'nucleotidase or acetylcholinesterase but the control transition temperature for acetylcholinesterase was 2.3 degrees higher in SS membranes. These results indicate specificity in ethanol's actions on membranes and that inhibition of the lipid-enzyme interactions for the low Ki NaK-ATPase is correlated with the difference in sensitivity to ethanol seen between the LS and SS mice.

5'-Nucleotidase↗
PubMedDate not supplied

Sensitivity of inbred and selectively bred mice to ethanol.

The Long-Sleep (LS) and Short-Sleep (SS) mice were bred for differences in sensitivity to ethanol as measured by duration of loss of the righting response (sleep time). The foundation population was a heterogeneous stock (HS) which was derived from a cross of eight inbred strains. Ethanol-induced sleep time and waking blood and brain ethanol levels were measured in the eight inbred strains, LS, SS and HS mice. The C3H and ISBI strains were quite resistant to ethanol as measured by sleep time, and only one, RIII, was very sensitive. Waking ethanol concentrations were similar for all of the inbreds, implying a narrow range of central nervous system sensitivity to ethanol. The HS mice had relatively short sleep times and blood ethanol levels equal to most of the inbred. The LS mice were significantly more, and the SS mice significantly less sensitive to ethanol than any of the inbreds or HS mice. These studies suggest that the extremes of CNS sensitivities to ethanol manifested by the LS and SS mice cannot be traced to any of the inbred strains, and must have arisen through the selection process by changes in allelic frequencies of those genes conferring ethanol sensitivity and resistance.

Animals↗
PubMedDate not supplied

Blood and brain ethanol concentrations during absorption and distribution in long-sleep and short-sleep mice.

It is often assumed that blood ethanol content accurately reflects brain ethanol content. In previous studies we have found that at the time of regaining the righting response blood and brain ethanol levels were identical, and blood ethanol could be used to predict brain ethanol level. It is likely, however that shortly after the administration of ethanol, blood and brain ethanol levels would differ. For this study, venous blood (orbital sinus) and brain ethanol levels were measured in long-sleep and short-sleep mice within the first 30 min following ethanol administration (2.5-6.0 g/kg). Ethanol was administered intraperitoneally or intragastrically. For both lines of mice and for every dose, brain ethanol concentrations were significantly greater (as much as 100 mg/dl) than blood ethanol levels for the first 6 min, and peak blood and brain ethanol levels were reached 4 to 6 min after dosing. Approximately 6 to 10 minutes (depending on dose and line of mouse) was required for blood and brain concentrations to reach equilibrium. At the time of loss of the righting response, brain ethanol levels were significantly higher than blood ethanol levels. These results indicate that within the first 6 min after administration of ethanol, blood ethanol level is not suitable for the assessment of brain ethanol content.

Absorption↗