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A C Collins

Publications and source records attributed to A C Collins.

At least 217 records · Page 12Linked to original sources
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Ethanol-induced inhibition of GABA release from LS and SS mouse brain slices.

The effects of ethanol on K+-stimulated and spontaneous release of gamma-aminobutyric acid (GABA) were studied in cortical and cerebellar brain slices obtained from long-sleep (LS) and short-sleep (SS) mice. A superfusion technique was used. Tissue slices were perfused with ethanol (0-515 mM) for 20 min. Ethanol inhibited K+-stimulated 3H-GABA release at lower concentrations in LS cortical slices than in SS slices. Little or no inhibition of K+-stimulated 3H-GABA release was seen in both LS and SS cerebellar slices. The spontaneous release of 3H-GABA was inhibited to equal degrees in LS and SS cerebellar slices but was unaffected in cortical slices, at the concentrations used. The possibility that ethanol inhibits 3H-GABA release by stimulating prostaglandin production was partially tested by assessing the effects of prostaglandin F2 alpha (PGF2 alpha) on 3H-GABA release in cortical and cerebellar slices. No effect of PGF2 alpha on 3H-GABA release was seen in either brain region. These results support the notion that ethanol may elicit some of its actions by inhibiting neurotransmitter release. This effect appears to be influenced by genotype and brain region.

Animals↗
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Ethanol-induced inhibition of norepinephrine release from brain slices obtained from LS and SS mice.

The effects of ethanol or prostaglandin E2 (PGE2) on K+-ion-stimulated or spontaneous (3H)-norepinephrine release were assessed in slices prepared from cortex and cerebellum of long-sleep (LS) and short-sleep (SS) mice. These lines were selectively bred for differences in ethanol-induced sleep time. Ethanol inhibited K+-stimulated release from LS cortical slices at lower concentrations than that required to inhibit release from SS cortical slices. Spontaneous release, on the other hand, was enhanced at lower ethanol concentrations in SS cortical slices. Ethanol inhibited K+-stimulated release equally in LS and SS cerebellar slices. Similarly, ethanol increased spontaneous release equally in LS and SS cerebellar slices. Thus, genotype and brain region influence the effect of ethanol on norepinephrine release. Since PGE2 has been reported to inhibit norepinephrine release, the effect of PGE2 on K+-stimulated norepinephrine release was examined in LS and SS cortical slices. PGE2 inhibited norepinephrine release equally in the two mouse lines. These data indicate that ethanol may elicit some of its depressant effects by altering norepinephrine release. The difference between the lines in inhibition of release probably does not involve differences in sensitivity to PGE2. Differences in ethanol-induced PGE2 production could, however, explain the differences in sensitivity of LS and SS cortical slices to ethanol-induced inhibition of K+-stimulated norepinephrine release.

Animals↗
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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↗
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Body temperature influences on ethanol elimination rate.

The effects of varying doses of ethanol injected IP on body temperature and the linear elimination rate were determined in long-sleep (LS) and short-sleep (SS) and C57BL6 mice. As the ethanol dose was increased, decreases in body temperature and rate of ethanol elimination were detected in all three mouse stocks. The correlation coefficients between body temperature and ethanol elimination rate were 0.74, 0.82, and 0.75 for the LS, SS, and C57BL mice, respectively. The SS eliminated ethanol more quickly than did the LS at most ethanol doses but if elimination rates at equal body temperatures were measured the two mouse lines did not differ in elimination rate. The temperatures of C57BL mice were also modified by pretreating them with graded doses of phenobarbital or DFP 1 hr before injection with a 1 g/kg ethanol dose. These treatments resulted in graded decreases in body temperature and an attendant decrease in ethanol elimination rate with correlation coefficients of 0.82 for phenobarbital-treated and 0.85 for DFP-treated animals. Lastly, the hypothermia elicited by a 5 g/kg dose of DFP was prevented by incubating the animals at 37 degrees C. This treatment almost completely prevented the effects of this dose of DFP on ethanol elimination rate. These results demonstrate that body temperature influences the rate of ethanol elimination. Therefore, studies of ethanol elimination rate should take body temperature into account when attempting to measure parameters such as metabolic tolerance.

Animals↗
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Nicotine response and nicotinic receptors in long-sleep and short-sleep mice.

Nicotine response and nicotinic receptor binding were characterized in long-sleep (LS) and short-sleep (SS) mice which have been selectively bred for differential "sleep-time" following ethanol administration. LS mice are more sensitive than SS mice to nicotine as measured by a battery of behavioral and physiological tests and as measured by sensitivity to nicotine-induced seizures. The greater sensitivity of the LS mice is not due to differences in binding of [3H]nicotine. Unlike inbred mouse strains which differ in sensitivity to nicotine-induced seizures, these selected mouse lines do not differ in levels of binding of [125I]alpha-bungarotoxin (BTX) in the hippocampus. Significant differences in BTX binding were found in the cerebellum and striatum. Although these two mouse lines do not differ in blood levels of nicotine following nicotine administration, they differ slightly in brain levels of nicotine indicating differential distribution of the drug. Since this distribution difference is much smaller than the observed behavioral differences, these mice probably differ in CNS sensitivity to nicotine; however, follow-up studies are necessary to test whether the differential response of these mice is due to subtle differences in distribution of nicotine to the brain.

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Decreased sensitivity to nicotine-induced seizures as a consequence of nicotine pretreatment in long-sleep and short-sleep mice.

Male and female long-sleep (LS) and short-sleep (SS) mice were pretreated with a subseizure-producing dose of nicotine (2.0 mg/kg) 7.5, 15 and 30 minutes prior to challenge with seizure-producing doses of this drug. Nicotine pretreated animals were less susceptible to nicotine-induced seizures than were saline pretreated animals. The latency to seizure following nicotine challenge was greater in nicotine pretreated animals than in saline controls. Nicotine pretreated LS mice show a greater decrease in nicotine-induced seizure susceptibility than do nicotine pretreated SS mice. This decrease in seizure susceptibility is consistent with induction of nicotinic receptor desensitization via nicotine pretreatment. It is hypothesized that LS and SS mice might differ in sensitivity to nicotine in part because they differ in baseline levels of desensitized versus functional nicotinic receptors.

Animals↗
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Behavioral desensitization to nicotine is enhanced differentially by ethanol in long-sleep and short-sleep mice.

In order to assess the anticonvulsant potency of ethanol, male and female long-sleep (LS) and short-sleep (SS) mice were pretreated with ethanol 7.5 min prior to challenge with an ED80 dose of nicotine (LS: 4.25 mg/kg; SS: 6.25 mg/kg). LS mice were more sensitive to the anticonvulsant effects of ethanol than were SS mice. In order to assess the effect of ethanol on the nicotine-induced behavioral desensitization to nicotine observed previously in these mice, animals were pretreated with saline, nonanticonvulsant doses of ethanol (0.25 g/kg, 0.75 g/kg or 1.5 g/kg), a subseizure-producing dose of nicotine (2.0 mg/kg) or a combination of these two drugs 15 or 30 min prior to nicotine challenge. Ethanol enhanced the nicotine-induced behavioral desensitization in both mouse lines; however, this effect was seen at lower ethanol doses and was more pronounced in LS mice. Ethanol pretreatment did not affect brain nicotine concentrations; therefore, the ethanol effect probably involves changes in brain sensitivity to nicotine.

Animals↗
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Ethanol-nicotine interactions in long-sleep and short-sleep mice.

The possibility that common genetic factors regulate initial sensitivities to ethanol and nicotine as well as the development of cross-tolerance between these agents was explored using the long-sleep (LS) and short-sleep (SS) mice. The LS mice proved to be more sensitive to an acute challenge with nicotine than were the SS mice. Segregation analysis (F1, F2, backcross) indicated that ethanol sensitivity and nicotine sensitivity segregate together. Acute pretreatment with nicotine did not significantly affect sensitivity to ethanol, but ethanol pretreatment altered nicotine responsiveness. The LS mice develop more tolerance to nicotine and ethanol than do the SS and they also develop more cross-tolerance. These genetically determined differences in initial sensitivities, and tolerance and cross-tolerance development are not readily explained by differences in brain nicotinic receptor numbers.

Animals↗
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Ethanol effects on 2-deoxyglucose uptake into tissues obtained from LS and SS mice.

The uptake of 2-deoxy-D-[14C]glucose (2-DG) has been used with some success to identify neuronal sites of drug action, and has also been useful in identifying brain regions that are differentially sensitive to ethanol in selectively bred rat lines, the alcohol tolerant (AT) and alcohol nontolerant (ANT) lines. The studies reported here utilized the 2-DG method in an attempt to ascertain whether the LS and SS mouse lines, which were selectively bred for differences in sensitivity to high dose, anesthetic effects of ethanol, do so because of disruption of specific neuronal sites. LS and SS mice were injected with saline or a 4.0-g/kg dose of ethanol 15 min before injection with 2-deoxy-D-[14C]glucose, and uptakes into blood, eight brain regions, the liver, and adrenal tissues were measured 2-60 min afterwards. Ethanol produced statistically significant decreases in 2-DG uptake into every region of the LS mouse brain, but only three brain regions showed significant decreases in uptake in the SS brain. Other SS brain regions showed a trend towards decreased uptake, but these trends were not significant. A comparison of percent decrease in 2-DG uptake across all brain regions showed that ethanol decreased 2-DG uptake approximately twice as much in LS brain regions as in SS brain regions. Since 2-DG uptake into adrenal and hepatic tissue was not affected by ethanol injection in either mouse line, it seems likely that the decreased 2-DG uptake, seen more readily in the LS brain, is due to ethanol-induced central nervous system (CNS) depression.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Glands↗
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Chronic intragastric infusion produces tolerance to ethanol in LS and SS mice.

Tolerance to ethanol's effects is seen after chronic injections and after chronic treatment with ethanol-containing liquid diets. However, tolerance associated with injections is often associated with environmental cuing (learned tolerance) and liquid diets do not allow for careful control of dose. The studies reported here demonstrate that chronic (3 g/kg every 6 h for 7 days) intragastric infusion of ethanol produces tolerance to ethanol in both LS and SS mice, as measured by sleep time and effects on open field activity and body temperature. LS mice developed more tolerance for all measures than the SS. The rate of ethanol elimination was increased slightly in both the LS and SS mouse lines following chronic ethanol infusion, which suggests that both lines developed a modest metabolic tolerance to ethanol. In contrast, the waking blood ethanol levels were altered only in the LS mice, which argues that some of the tolerance to ethanol seen in the LS mice is pharmacodynamic tolerance. Thus, chronic intragastric infusion of ethanol is a reliable method for treating animals chronically with ethanol that allows for the precise control of dose and dose interval, oral administration of ethanol, and minimal animal handling that can be associated with drug delivery, thereby reducing the risk of developing learned tolerance to ethanol.

Animals↗
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Genotype regulates the development of tolerance to ethanol and cross-tolerance to nicotine.

The long-sleep (LS) and short-sleep (SS) mouse lines were selectively bred for differential sensitivity to the anesthetic actions of ethanol, but they also differ in sensitivity to nicotine. A recent study suggested that the LS mice develop more tolerance to ethanol and cross-tolerance to nicotine than do the SS following chronic ethanol treatment. The studies reported here expand on these previous studies by assessing potential tolerance to ethanol and cross-tolerance to nicotine using additional behavioral and physiological measures. In addition, the effects of chronic ethanol treatment on ethanol and nicotine metabolism were measured. The LS mice developed tolerance to ethanol as measured by effects on open-field activity, body temperature, and sleep time, whereas the SS mice did not develop consistent tolerance to ethanol's effects on any of these measures. Cross-tolerance to nicotine's effects on open-field activity and body temperature developed, but only in the LS mice. The ethanol tolerance is likely due to changes in CNS sensitivity to ethanol, but altered elimination of nicotine may explain much of the cross-tolerance to nicotine seen in chronic ethanol-treated LS mice.

Absorption↗
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Bioavailability of ethanol is reduced in several commonly used liquid diets.

Liquid diets are often used as a vehicle for chronically treating laboratory animals with ethanol. However, a recent report suggested that one or more components of these diets may bind ethanol which could result in a decrease in the bioavailability of ethanol. Consequently, we compared the blood ethanol concentration vs. time curves obtained following the intragastric (i.g.) administration of ethanol dissolved in water or in one of three liquid diets (Bioserv AIN-76, Sustacal, or Carnation Slender) using the long-sleep (LS) and short-sleep (SS) mouse lines. The initial rates of absorption were generally the same for the water-ethanol and diet-ethanol groups, but the diets generally produced lower peak levels and the areas under the ethanol concentration-time curves were less for all of the liquid diets than for the control, ethanol-water solution. In vitro dialysis experiments indicated that the Bioserv diet binds ethanol in a saturable manner. Therefore, it may be that the slower release of ethanol, which should occur as a result of binding, serves to increase the role of first pass metabolism in regulating ethanol concentrations following oral administration. Because the effects of the diets were seen even after pyrazole treatment, it may be that the lower blood ethanol levels arise because metabolism by gastric ADH, rather than hepatic ADH, is responsible for a major portion of ethanol metabolism as ethanol is slowly released by the diets. If so, the observation that the diet/water differences were uniformly greater in the LS mice may indicate that LS-SS differences in gastric ADH exist.(ABSTRACT TRUNCATED AT 250 WORDS)

Absorption↗
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Different levels of [3H]MK-801 binding in long-sleep and short-sleep lines of mice.

The long-sleep (LS) and short-sleep (SS) lines of mice were selectively bred for differential sensitivity to the hypnotic effects of ethanol. Several studies suggest that excitatory amino acid receptor systems are involved in these genetically determined differences in sensitivity to ethanol. The experiments described in this article examine further the potential role of NMDA excitatory amino acid receptors in genetically determined differences in hypnotic sensitivity to ethanol by measuring [3H]MK-801 binding in eight brain regions of LS and SS lines of mice. Significantly greater levels of binding were found in SS hippocampus and striatum. Binding levels in the remaining brain regions revealed no significant between-line differences. Affinity differences between regions were seen but no between-line differences in affinity were found in any brain region. These findings lend support to the hypothesis that differences in NMDA receptor systems are part of the genetically determined biochemistry that produces differential hypnotic sensitivity to ethanol in LS and SS mice.

Animals↗
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Chronic corticosterone treatment alters sensory gating in C3H mice.

Two methods of evaluating inhibitory sensory processing are prepulse inhibition of acoustic startle (PPI) and gating of auditory evoked potentials. Studies using both methods suggest nicotinic acetylcholinergic receptor modulation of gating, specifically the alpha-bungarotoxin (alpha-BTX) binding site (alpha7 receptor subtype). However, recent assessment of alpha7 null mutant mice failed to demonstrate any effect of the loss of this receptor in either gating paradigm. An alternate approach to assessing the effects of the alpha7 receptor is to reduce its numbers in mature inbred mice, thus, avoiding the twin problems of background and developmental compensation inherent in null mutant mouse studies. Numerous studies have shown that chronic corticosterone (CCS) treatment selectively reduces alpha-BTX binding sites. C3H mice were adrenalectomized and implanted with corticosterone or cholesterol (control) pellets. After 8 days, they were tested in one of the gating paradigms. PPI and auditory gating were significantly diminished in corticosterone-treated mice concomitant with a reduction in alpha-BTX binding in several brain regions. Cholesterol-treated mice had no change in either paradigm. Nicotine treatment (1 mg/kg) produced significant improvement in both paradigms in corticosterone-treated mice. These data agree with previous pharmacological studies suggesting modulation of gating occurs through a nicotinic receptor.

Acoustic Stimulation↗
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Long-term ethanol treatment elicits changes in nicotinic receptor binding in only a few brain regions.

Chronic nicotine treatment will produce an upregulation of brain nicotinic receptors, and rats treated for 5 months with ethanol had increased [3H]nicotine binding in two of the three brain regions that were studied. However, studies using short-term treatment did not detect an effect of ethanol on mouse brain nicotinic receptor numbers. Therefore, LS and SS mice were force-fed ethanol (15%, v/v) in the drinking water for 6 months. The LS mice developed tolerance to ethanol as measured by Y-maze crossing and rearing activity, body temperature, and sleep time. No evidence for tolerance to ethanol was seen in the SS mice. However, the SS mice showed increases in [3H] nicotine binding in thalamus and an increase in [125I]alpha-bungarotoxin binding in the cerebellum and superior colliculus. LS mice had reduced levels of hippocampal [125I]alpha-bungarotoxin binding. Thus, long-term ethanol treatment may affect brain nicotinic receptor binding but the effect is limited to only a few brain regions and may be influenced by genetic factors.

Animals↗
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Brain NaK-ATPases in mice differentially sensitive to alcohols.

The isozymes of NaK-ATPase were studied in the particulate fraction of homogenates prepared from cortex of LS and SS mice, two lines of mice that have been selectively bred for differential response to ethanol. In addition to a ouabain-insensitive Mg-ATPase, ouabain dose-response curves have suggested the presence, in brain, of two NaK-ATPase activities with different sensitivities to ouabain. These are designated low Ki (4 X 10(-7) M) and high Ki (2 X 10(-4) M). Ethanol differentially inhibited the ATPases: The ouabain-insensitive activity was less sensitive to ethanol inhibition than were the two ouabain-inhibitable activities. The low Ki (brain specific) NaK-ATPase was more sensitive than was the high Ki activity. However, ethanol inhibited all three components of the ATPase activity in an identical fashion in the two mouse lines. The low Ki activity was also more labile to thermal and p-hydroxymercurobenzoate denaturation than was the high Ki activity. These measures did not differ between the LS and SS lines. SDS-polyacrylamide electrophoresis of particulate fraction of cortical homogenates obtained from LS and SS mice revealed the presence of two protein bands with similar 32P labeling in both lines. Given that electrophoretic pattern and heat or p-hydroxymercurobenzoate inhibition were identical, it seems unlikely that differences in ATPase activity, or inhibition by ethanol, are responsible for the different response of LS and SS mice to ethanol.

Animals↗
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A genetic analysis of ethanol, pentobarbital, and methyprylon sleep-time response.

The sleep-time responses to ethanol, pentobarbital, and methyprylon were assessed in various generations derived from crossing the long-sleep (LS) and short-sleep (SS) mouse lines in order to assess whether common or different genes regulate response to these agents. The LS and SS mice were selectively bred for differences in duration of ethanol-induced sleep time. Ethanol and pentobarbital responses segregate in a different fashion into F1 and F2 generations derived from the LS and SS lines, indicating different genic control and probably different mechanisms of action for these two agents. Ethanol and methyprylon response segregated similarly but fewer genes seem to influence methyprylon response. These results support the notion that water-soluble depressants have common mechanisms of action.

Anesthetics↗