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D A Finn

Publications and source records attributed to D A Finn.

At least 37 records · Page 2Linked to original sources
PubMed1996

Sensitization of gamma-aminobutyric acidA receptors to neuroactive steroids in rats during ethanol withdrawal.

The anxiolytic and anticonvulsant effects of benzodiazepines, barbiturates, ethanol and neuroactive steroids are mediated by selective interactions with gamma-aminobutyric acidA (GABA(A)) receptors. Chronic ethanol exposure decreases the sensitivity of GABA(A) receptors to benzodiazepines, barbiturates and ethanol. Ethanol withdrawing rats are cross-tolerant to the anticonvulsant effects of benzodiazepines as shown by a 16% decrease in the anticonvulsant efficacy of diazepam compared to controls. In contrast, ethanol withdrawing rats are sensitized to the anticonvulsant effects of the neuroactive steroid 3 alpha-hydroxy-5 alpha-pregnan-20-one (3 alpha,5 alpha-THP), exhibiting a 46% increase in the anticonvulsant effect against bicuculline-induced seizures compared to control rats. This effect may involve a change in the sensitivity of GABA(A) receptors to 3 alpha,5 alpha-THP because potentiation of GABA(A) receptor mediated chloride uptake into cerebral cortical synaptoneurosomes is enhanced by 3 alpha,5 alpha-THP up to 50% in ethanol withdrawing rats compared to controls. 3 alpha,21-dihydroxy-5 alpha-pregnan-20-one (THDOC) potentiation of GABA(A) receptor-mediated chloride uptake is also enhanced during ethanol withdrawal. Moreover, the plasma levels of 3 alpha,5 alpha-THP and progesterone did not differ in ethanol withdrawing rats compared to controls. These alterations in neurosteroid sensitivity were also accompanied by selective alterations in cortical GABA(A) receptor subunit mRNA levels. Levels for the alpha 1 and alpha 4 subunit showed only slight alteration during withdrawal whereas we had previously observed a significant decrease in alpha 1 and a significant increase in alpha 4 mRNA levels in ethanol dependent (not withdrawing) animals. beta 2, beta and gamma 1 mRNA levels significantly increased during ethanol withdrawal. Taken together, these results suggest that ethanol withdrawal produces alterations in GABA(A) receptors that sensitize rats to the pharmacological effects of neuroactive steroids. Because ethanol-dependent or withdrawing rats are tolerant to the intoxicating, anxiolytic and anticonvulsant effects of ethanol and cross-tolerant to many effects of benzodiazepines and barbiturates, sensitization to the effects of neuroactive steroids could have significant therapeutic potential.

Animals↗
PubMed1995

Genetic analysis of the corticosterone response to ethanol in BXD recombinant inbred mice.

The genetic control over the corticosterone response to ethanol (EtOH) and its possible relationship to other EtOH-related traits was examined using BXD recombinant inbred (RI) strains derived from an F2 cross of C57BL/6J (B6) and DBA/2J (D2) progenitor strains. Quantitative trait locus (QTL) analysis of corticosterone levels 1 hr following EtOH suggested the influence of a single major gene on this trait. Two loci were predicted to account for 47% of the genetic variance in plasma corticosterone levels 6 hr following EtOH, whereas 3 loci were predicted to account for 78% of the genetic variance in corticosterone levels 7 hr following EtOH. Markers associated with corticosterone levels 7 hr following EtOH and corrected corticosterone levels 6 hr post-EtOH overlapped with ones found to influence acute and chronic EtOH withdrawal severity, suggesting some degree of common genetic determination between these traits. Overall these results indicate that gene action significantly influences stress responsiveness and suggest possible chromosomal locations of these genes.

Alcohol Drinking↗
PubMed1995

Neuroactive steroid sensitivity in withdrawal seizure-prone and -resistant mice.

Withdrawal Seizure-Prone (WSP) and -Resistant (WSR) mice, which were selectively bred for severe (WSP) or mild (WSR) handling-induced convulsions (HICs) following chronic ethanol inhalation, were found to differ in sensitivity to the anticonvulsant effects of the neuroactive steroid 3 alpha-hydroxy-5 alpha-pregnan-20-one (3 alpha,5 alpha-P. 3 alpha,5 alpha-P (5 or 10 mg/kg, ip) significantly increased seizure thresholds to pentylenetetrazol in ethanol-native males of both the WSP and WSR lines. In general, WSP mice were more sensitive than WSR mice to the anticonvulsant effect of 3 alpha,5 alpha-P. Subsequent studies in male WSP mice exposed to ethanol vapor or air for 24 hr demonstrated enhanced sensitivity to the anticonvulsant effect of 3 alpha,5 alpha-P (0.5-20 mg/kg, ip) during ethanol withdrawal. Only the highest dose affected HICs in air-exposed animals, whereas both the two highest doses significantly reduced HICs in ethanol-exposed mice. These results provide the first demonstration that 3 alpha,5 alpha-P attenuates ethanol withdrawal convulsions and indicate enhanced sensitivity to the anticonvulsant effect of 3 alpha,5 alpha-P in animals withdrawing from ethanol dependence.

Alcohol Withdrawal Delirium↗
PubMed1994

Temperature dependence of ethanol depression in mice: dose response.

Manipulation of body temperature during intoxication significantly alters brain sensitivity to ethanol. The current study tested the generality of this effect within the hypnotic dose range. Drug naive, male C57BL/6J mice were injected with 3.2, 3.6, or 4.0 g/kg ethanol (20% w/v) and were exposed to 1 of 7 designated temperatures from 13 degrees to 34 degrees C to manipulate body temperature during intoxication. Rectal temperature at return of righting reflex (RORR) was significantly, positively correlated with loss of righting reflex (LORR) duration and significantly, negatively correlated with blood ethanol concentration (BEC) at RORR at all three doses. These results indicate that increasing body temperature during intoxication increased ethanol sensitivity in C57 mice at all three doses tested and demonstrate the generality of temperature dependence across hypnotic doses in these animals. Interestingly, the LORR duration was dose-dependent at each ambient temperature, but the degree of body temperature change and the BEC at RORR were not dose-dependent. Overall, these results emphasize the importance of body temperature as a variable in ethanol research.

Acclimatization↗
PubMed1994

The estrus cycle, sensitivity to convulsants and the anticonvulsant effect of a neuroactive steroid.

Recent in vitro work in our laboratory suggests that functional sensitivity of the gamma-aminobutyric acidA receptor complex to the neuroactive progesterone metabolite 3 alpha-hydroxy-5 alpha-pregnan-20-one (3 alpha,5 alpha-P) changes during the estrus cycle. Therefore, the current in vivo studies were conducted to evaluate estrus cycle-related differences in sensitivity to convulsants and the anticonvulsant effect of 3 alpha, 5 alpha-P. The threshold dose for onset to myoclonic twitch, running bouncing clonus and tonic hind-limb extension was measured by constant i.v. infusion of (+)-bicuculline, picrotoxin, pentylenetetrazol, strychnine and methyl-6,7-dimethoxy-4-ethyl-beta- carboline-3-carboxylate. Females in estrus were more sensitive than females in diestrus 1 or males to (+)-bicuculline and methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3- carboxylate. Administration of 3 alpha, 5 alpha-P (15 mg/kg i.p. in beta-cyclodextrin) 15 min before infusion of pentylenetetrazol significantly increased the threshold dose for onset to all three convulsions and provided equal protection against tonic convulsions. The dose for onset to myoclonic twitch was significantly higher in females in diestrus 1 than females in estrus or males. Plasma 3 alpha, 5 alpha-P did not differ between groups injected with 3 alpha, 5 alpha-P, suggesting that the difference in sensitivity to the anticonvulsant effect of 3 alpha, 5 alpha-P was not pharmacokinetic.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

A comparison of Ro 16-6028 with benzodiazepine receptor 'full agonists' on GABAA receptor function.

Ro 16-6028 (bretazenil) has a pharmacological profile characteristic of a partial agonist at the gamma-aminobutyric acidA (GABAA) receptor-linked benzodiazepine site. The present study utilized modulation of [35S]t-butylbicyclophosphorothionate ([35S]TBPS) binding and enhancement of GABA-stimulated 36Cl- uptake to further assess Ro 16-6028's partial agonist profile in vitro. Ro 16-6028 was the most potent benzodiazepine examined, exhibiting an IC50 (concentration at which half-maximal inhibition of specific [35S]TBPS binding occurs) of 6.1 nM, compared to clonazepam (7.9 nM), flunitrazepam (13.6 nM) and diazepam (91.1 nM). The rank order of potency for inhibition of [35S]TBPS binding was identical to that for inhibition of [3H]flunitrazepam binding. However, Ro 16-6028 was less efficacious in that it produced 27% inhibition of specific [35S]TBPS binding, compared to clonazepam (34%), flunitrazepam (41%) or diazepam (49%). Ro 16-6028 antagonized the inhibition of [35S]TBPS binding produced by 10 microM diazepam. Ro 16-6028 was also more potent and less efficacious than diazepam in potentiating GABA-stimulated 36Cl- uptake. These results provide further evidence that Ro 16-6028 is acting as a partial agonist at the benzodiazepine receptor in modulating function of the GABAA receptor complex.

Animals↗
PubMed1993

The influence of estrus cycle on neurosteroid potency at the gamma-aminobutyric acidA receptor complex.

The reduced metabolites of progesterone (3 alpha-hydroxy-5 alpha-pregnan-20-one or 3 alpha,5 alpha-P) and deoxycorticosterone (3 alpha,21-dihydroxy-5 alpha-pregnan-20-one or 5 alpha-THDOC) exhibit a gamma-aminobutyric acid (GABA) agonist pharmacological profile and bind with high affinity to a unique steroid recognition site on the GABAA receptor complex (GRC). In female rats, peak levels of 3 alpha,5 alpha-P occur between proestrus and estrus and at concentrations which appear sufficient to affect GRC-mediated inhibitory events. Therefore, steroid modulation of the binding of [35S]t-butylbicyclophosphorothionate was conducted to examine sensitivity of the GRC during the estrus cycle. The results in unwashed tissue (cortex, cerebellum, hippocampus and striatum) indicated that 3 alpha, 5 alpha-P was most potent in estrus. Subsequent studies in washed tissue and in washed tissue plus 3 microM (+)bicuculline indicated that 3 alpha,5 alpha-P was more potent in diestrus 1 than in estrus. Brain regional differences in potency of 3 alpha,5 alpha-P were also observed. Overall, the results in washed tissue suggest that an inherent change in the sensitivity of the GRC occurs during the estrus cycle, whereas the results in unwashed tissue may be influenced by the presence of endogenous GRC-active neurosteroids and GABA. The change in sensitivity of the GRC during the estrus cycle may occur to help maintain homeostatic regulation of brain excitability.

Animals↗
PubMed1992

Genetically determined differences in the antagonistic effect of pressure on ethanol-induced loss of righting reflex in mice.

Hyperbaric exposure antagonizes ethanol's behavioral effects in a wide variety of species. Recent studies indicating that there are genetically determined differences in the effects of body temperature manipulation on ethanol sensitivity suggested that genotype might also influence the effects of hyperbaric exposure on ethanol intoxication. To investigate this possibility, ethanol injected long sleep (LS)/Ibg (2.7 g/kg), short sleep (SS)/Ibg (4.8 g/kg), 129/J (2.9 g/kg), and C57BL/6J (3.6 g/kg) mice were exposed to one atmosphere absolute (ATA) air or to one or 12 ATA helium-oxygen (heliox) at ambient temperatures selected to offset ethanol and helium-induced hypothermia. Hyperbaric exposure significantly reduced loss of righting reflex (LORR) duration in LS, 129, and C57 mice, but not in SS mice. A second experiment found that hyperbaric exposure significantly reduced LORR duration and increased the blood ethanol concentration (BEC) at return of righting reflex (RORR) in LS mice, but did not significantly affect either measure in SS mice. These results indicate that exposure to 12 ATA heliox antagonizes ethanol-induced LORR in LS, 129 and C57 mice, but not in SS mice. Taken with previous results, the present findings suggest that the antagonism in LS, 129, and C57 mice reflects a pressure-induced decrease in brain sensitivity to ethanol and that the lack of antagonism in SS mice cannot be explained by pressure-induced or genotypic differences in ethanol pharmacokinetics.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Ethanol-induced depression of aggression in mice antagonized by hyperbaric exposure.

The present study investigated the effect of hyperbaric exposure on ethanol-induced depression of aggressive behavior measured by resident-intruder confrontations. Adult male CFW mice (residents) were paired with females and housed together for 26 days. Then, resident mice were intubated with either ethanol (2 g/kg) or water (20 ml/kg) and were exposed to 1 atmosphere absolute (ATA) air, 1 ATA helium oxygen (heliox) or 12 ATA heliox using a within-subjects counterbalanced design. Thirty minutes after intubation an intruder was introduced. Ethanol significantly decreased aggressive behaviors (attack latency, attack bites, sideways threats, tail rattles and pursuit) in 1 ATA-treated animals. Pressure completely antagonized the depression of aggression induced by ethanol. Ethanol alone and pressure alone did not significantly affect nonaggressive behaviors. There were no statistically significant differences between groups in blood ethanol concentrations 50 minutes after intubation. These results suggest that ethanol's effects on aggressive behavior result from the same membrane actions leading to loss of righting reflex, depression of locomotor activity, tolerance and dependence.

Aggression↗
PubMed1991

Brain temperature and ethanol sensitivity in C57 mice: a radiotelemetric study.

This study investigated the relationship between ethanol sensitivity and brain temperature using radiotelemetric techniques. Radiotelemetric brain probes were implanted in the lateral cerebral ventricle of C57BL/6 mice. Rectal and brain temperatures, duration of loss of righting reflex (LORR), and blood and brain ethanol concentrations at the return of righting reflex (RORR) were measured following intraperitoneal (IP) injection with 3.6 g/kg ethanol and exposure to 12, 15, 22 or 34 degrees C. Rectal and brain temperatures were significantly correlated in untreated and intoxicated mice. Brain temperatures were lower than rectal temperatures in untreated mice, but were not different than rectal temperatures in intoxicated mice. Ethanol sensitivity, measured by the duration of LORR and ethanol concentrations at RORR, was significantly correlated with brain as well as rectal temperatures at RORR. Brain probe implantations did not significantly affect ethanol sensitivity. The direct positive relationship between brain temperature and ethanol sensitivity in C57 mice fits predictions based on membrane actions of ethanol and supports the hypothesis that temperature-induced changes in behavioral sensitivity to ethanol are mediated through changes in brain membrane temperature.

Alcoholic Intoxication↗
PubMed1991

The relationship between brain temperature during intoxication and ethanol sensitivity in LS and SS mice.

The present study characterized the relationship between brain temperature, rectal temperature, and ethanol sensitivity in the selectivity bred long-sleep (LS) and short-sleep (SS) mice. Radiotelemetric brain probe implanted and nonimplanted LS/lbg and SS/lbg male mice were injected with 2.5 and 4.9 g/kg ethanol, respectively, before exposure to ambient temperatures of 15 degrees C, 22 degrees C, or 34 degrees C. Ambient temperature significantly affected rectal temperature, brain temperature, and ethanol sensitivity, measured by impairment of righting reflex. Brain and rectal temperatures at return of righting reflex (RORR) were highly correlated. In SS mice brain and rectal temperatures at RORR were significantly positively correlated with loss of righting reflex (LORR) duration and significantly negatively correlated with blood ethanol concentration (BEC) at RORR. In LS mice rectal temperature at RORR was significantly negatively correlated with LORR duration, while both brain and rectal temperature at RORR were significantly positively correlated with BEC at RORR. The strength of the correlations and r2 values generated from linear regression analysis indicates that body temperature during intoxication can explain up to 52% of the variability in ethanol sensitivity in SS mice, but only 19% of the variability in ethanol sensitivity in LS mice. The correlational analyses are consistent with previous results based on comparisons between rectal temperature and ethanol sensitivity and extend to direct brain temperature measurement the evidence that decreasing temperature during intoxication decreases ethanol sensitivity in SS mice and increases ethanol sensitivity in LS mice.(ABSTRACT TRUNCATED AT 250 WORDS)

Alcoholic Intoxication↗
PubMed1990

Interactions between benzodiazepine antagonists, inverse agonists, and acute behavioral effects of ethanol in mice.

The behavioral manifestations of acute ethanol intoxication resemble those of benzodiazepines, barbiturates and general anesthetics. This has led to speculation that these drugs share common mechanisms or sites of actions within the brain. The discovery of a specific benzodiazepine receptor site, and the subsequent development of selective receptor antagonist and inverse agonist drugs, provides a framework to test the involvement of the benzodiazepine receptor complex in mediating ethanol's behavioral effects. The partial inverse agonist Ro15-4513, an analog of the benzodiazepine receptor antagonist Ro15-1788 (flumazenil), has been reported to block or reduce some of ethanol's acute effects in rodents by a benzodiazepine receptor-mediated action. There has been some controversy over whether the "antialcohol" effect of Ro15-4513 is a unique property of this compound or is shared by other benzodiazepine antagonists with inverse agonist activity. We have studied the effects of Ro15-4513 and other benzodiazepine receptor antagonists on acute ethanol intoxication in mice and have obtained evidence that 1) Ro15-4513 differentially affects acute effects of ethanol, 2) an "antialcohol" property is not a general feature of all benzodiazepine antagonists and inverse agonists, and 3) "antialcohol" activity may not be unique to Ro15-4513.

Animals↗
PubMed1990

Body temperature differentially affects ethanol sensitivity in both inbred strains and selected lines of mice.

Offsetting ethanol-induced hypothermia in five inbred strains of mice changed ethanol sensitivity within strains and markedly reduced differences between strains in brain sensitivity to hypnotic ethanol doses. The present study extended this work to mice selectively bred for sensitivity and resistance to ethanol-induced loss of righting reflex (LORR) and hypothermia. In all experiments LORR duration and ethanol concentrations at return of righting reflex were measured after i.p. hypnotic ethanol doses and exposure to 22 or 34 degrees C. In experiment 1, C57BL/6J, A/HeJ, 129/J, LS/lbg and SS/lbg mice were given 4.2 g/kg ethanol. In experiment 2, the same mouse genotypes were tested with different ethanol doses (2.5-4.9 g/kg) selected to produce an equivalent degree of impairment (60 min LORR duration). In experiment 3, HOT and COLD lines of mice were given 4.0 g/kg ethanol. In agreement with previous work, offsetting hypothermia reduced differences between genotypes in ethanol sensitivity. Comparisons within genotypes indicated that ethanol sensitivity in C57, A/He, SS, HOT and COLD mice increased as body temperature increased. In contrast, ethanol sensitivity in 129 and LS mice decreased as body temperature increased. These results extend previous findings indicating that body temperature during intoxication contributes to differences between genotypes in ethanol sensitivity. The present findings also suggest that there are qualitative differences in the effects of temperature on ethanol sensitivity within genotypes.

Animals↗
PubMed1989

Temperature affects ethanol lethality in C57BL/6, 129, LS and SS mice.

The effect of ambient and body temperature on ethanol lethality in inbred strains and selected lines of mice was investigated. C57BL/6J, 129/J, LS/Ibg and SS/Ibg mice were exposed to 23 or 34 degrees C following IP injection of lethal ethanol doses (8.2, 6.0, 6.5 or 7.0 g/kg ethanol, respectively). All mice exposed to 23 degrees C during intoxication became markedly hypothermic, with mean body temperatures dropping to lows of 27.9, 30.3, 33.0 and 33.3 degrees C in C57, LS, SS and 129 animals, respectively. Compared to the 23 degrees C groups, exposure to 34 degrees C offset the ethanol-induced hypothermia and significantly increased percent mortality in all four mouse genotypes. Exposure to 34 degrees C increased mortality at 24 hours postinjection from 15% to 95% in SS mice, from 37.5% to 100% in 129 mice and from 50% to 100% in LS and C57 mice. Blood ethanol data suggest that the present results cannot be explained by temperature-related changes in ethanol elimination. These results provide further evidence that body temperature during intoxication can have major effects on mortality rates in mice.

Animals↗
PubMed1988

Antagonism of ethanol-induced depression of mouse locomotor activity by hyperbaric exposure.

Previous studies have shown that exposure to hyperbaric helium + oxygen (HEOX) antagonizes the acute depressant effect of hypnotic doses of ethanol on rodent behavior, precipitates and exacerbates withdrawal in ethanol-dependent mice, and attenuates the development of chronic functional ethanol tolerance. The present study extends these investigations to the sub-hypnotic dose range by determining the effect of hyperbaric exposure on ethanol-induced depression of locomotor activity. Male C57BL/6J mice were given two treatments, 2.5 g/kg ethanol and saline, spaced one week apart according to a within subjects, balanced crossover design. Following injection, animals were exposed individually to 1 atmosphere absolute (ATA) air or to 1 ATA or 12 ATA HEOX inside a 15 liter hyperbaric chamber. Chamber temperatures were adjusted to offset ethanol hypothermia and the cooling effect of helium. Locomotor activity was measured continuously, beginning 10 min after injection, and recorded at prescribed intervals for 60 min. Multivariate analysis of variance of the measured activity revealed statistically significant differences between groups based on atmospheric condition, treatment, and time after injection. Within group comparisons indicated that ethanol treatment induced a significant reduction in locomotor activity in mice exposed to either 1 ATA air or 1 ATA HEOX. In contrast, ethanol-injected mice exposed to 12 ATA HEOX did not show a significant ethanol-induced decrease in locomotor activity, indicating antagonism of ethanol's effect. Hyperbaric exposure did not significantly alter blood ethanol concentrations measured 70 min after ethanol injection, thus making a pharmacokinetic explanation for these results unlikely. These findings are consistent with, and extend, previous evidence suggesting that hyperbaric exposure antagonizes molecular actions of ethanol leading to intoxication.

Animals↗
PubMed1988

Genetically determined differences in ethanol sensitivity influenced by body temperature during intoxication.

The present study investigated the importance of body temperature during intoxication in mediating differences between five inbred strains of mice (C57BL/6J; BALB/cJ; DBA/2J; A/HeJ; 129/J) in their acute sensitivity to the hypnotic effects of ethanol. Mice exposed to 22 degrees C after ethanol injection became hypothermic and exhibited statistically significant differences between strains in rectal temperatures at the return of the righting reflex (RORR), duration of loss of the righting reflex (LORR), and blood and brain ethanol concentrations at RORR. Exposure to 34 degrees C after injection offset ethanol-hypothermia and markedly reduced strain-related differences in rectal temperatures and blood and brain ethanol concentrations at RORR. Brain ethanol concentrations at RORR were significantly lower in C57, BALB, DBA and A/He mice exposed to 34 degrees C compared to mice exposed to 22 degrees C during intoxication suggesting that offsetting hypothermia increased ethanol sensitivity in these strains. Taken with previous in vitro studies, these results suggest that genetically determined differences in acute sensitivity to the behavioral effects of ethanol reflect differences in body temperature during intoxication as well as differences in sensitivity to the initial actions of ethanol at the cellular level.

Acclimatization↗
PubMed1987

Chronic functional ethanol tolerance in mice influenced by body temperature during acquisition.

Previous studies have found that body temperature during intoxication influences brain sensitivity to ethanol with the sensitivity being less at cool than at warm body temperatures. If this effect of temperature reflects alterations in the acute membrane perturbing action of ethanol, as suggested by in vitro studies, then body temperature reduction (hypothermia) during tolerance acquisition should reduce the effectiveness of a given ethanol concentration and, in turn, should reduce the development of chronic functional ethanol tolerance. To test this hypothesis, adult drug-naive C57BL/6J mice were injected i.p. once daily for five days with 3.6 g/kg ethanol (20% w/v) and were exposed to 34 degrees C or 25 degrees C for five hours following injection. On day 6, both ethanol acquisition groups and naive mice were injected i.p. with 4.0 g/kg ethanol and exposed to 25 degrees C. During acquisition, the group exposed to 34 degrees C had significantly higher body temperatures than the mice exposed to 25 degrees C, and there were no statistically significant differences in blood ethanol concentrations between treatment conditions. The extent of tolerance on day 6, measured by sleep-times and wake-up blood and brain ethanol concentrations versus naive mice, was significantly greater in the 34 degrees C acquisition group than in the 25 degrees C acquisition group. The results demonstrate that body temperature influences tolerance development in the manner predicted by membrane perturbation theories of anesthesia and adaptation based tolerance theories.

Alcoholism↗