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D A Finn

Publications and source records attributed to D A Finn.

At least 19 recordsLinked to original sources
PubMed2007

Mouse inbred strain differences in ethanol drinking to intoxication.

Recently, we described a simple procedure, Drinking in the Dark (DID), in which C57BL/6J mice self-administer ethanol to a blood ethanol concentration (BEC) above 1 mg/ml. The test consists of replacing the water with 20% ethanol in the home cage for 4 h early during the dark phase of the light/dark cycle. Three experiments were conducted to explore this high ethanol drinking model further. In experiment 1, a microanalysis of C57BL/6J behavior showed that the pattern of ethanol drinking was different from routine water intake. In experiment 2, drinking impaired performance of C57BL/6J on the accelerating rotarod and balance beam. In experiment 3, 12 inbred strains were screened to estimate genetic influences on DID and correlations with other traits. Large, reliable differences in intake and BEC were detected among the strains, with C57BL/6J showing the highest values. Strain means were positively correlated with intake and BEC in the standard (24 h) and a limited (4 h) two-bottle ethanol vs. water test, but BECs reached higher levels for DID. Strain mean correlations with other traits in the Mouse Phenome Project database supported previously reported genetic relationships of high ethanol drinking with low chronic ethanol withdrawal severity and low ethanol-conditioned taste aversion. We extend these findings by showing that the correlation estimates remain relatively unchanged even after correcting for phylogenetic relatedness among the strains, thus relaxing the assumption that the strain means are statistically independent. We discuss applications of the model for finding genes that predispose pharmacologically significant drinking in mice.

Alcohol Drinking↗
PubMed2006

Selected line difference in sensitivity to a GABAergic neurosteroid during ethanol withdrawal.

The neurosteroid allopregnanolone (ALLO) is a potent positive modulator of gamma-aminobutyric acid(A) (GABA(A)) receptors. Earlier work indicates that sensitivity to the anticonvulsant effect of ALLO was enhanced during ethanol (EtOH) withdrawal in rats and in C57BL/6 mice, an inbred strain with mild EtOH withdrawal. In contrast, ALLO sensitivity was reduced during EtOH withdrawal in DBA/2 mice, an inbred strain with severe EtOH withdrawal. Thus, the present studies examined ALLO sensitivity during EtOH withdrawal in another animal model of EtOH withdrawal severity, the Withdrawal Seizure-Prone (WSP) and Withdrawal Seizure-Resistant (WSR) selected lines. Male mice were exposed to EtOH vapor or air for 72 h. During peak withdrawal, animals were injected with ALLO [0, 3.2, 5, 10 or 17 mg/kg, intraperitoneally (i.p.)] and tested for their sensitivity to the anticonvulsant effect. In separate studies, potentiation of GABA-stimulated chloride uptake by ALLO (10 nm to 10 microm) was assessed in microsacs prepared from mouse brain mice during peak withdrawal. Notably, WSP mice were cross-tolerant to the anticonvulsant effect of ALLO during EtOH withdrawal (i.e. significant decrease in the efficacy of ALLO) when compared with values in air-exposed mice. In contrast, sensitivity to the anticonvulsant effect of ALLO was unchanged during EtOH withdrawal in the WSR line. Functional sensitivity of GABA(A) receptors to ALLO was significantly decreased during EtOH withdrawal in WSP mice in a manner consistent with the change in behavioral sensitivity to ALLO. These findings suggest that mice selectively bred for differences in EtOH withdrawal severity are differentially sensitive to ALLO during EtOH withdrawal.

Alcohol Withdrawal Seizures↗
PubMed2005

Scheduled access to ethanol results in motor impairment and tolerance in female C57BL/6J mice.

We recently reported a method where water-restricted mice were given scheduled access to ethanol followed by access to water. C57BL/6J mice would repeatedly self-administer ethanol in amounts that produced high and stable blood ethanol concentrations (BEC) [Finn DA, Belknap JK, Cronise K, Yoneyama N, Murillo A, Crabbe JC. A procedure to produce high alcohol intake in mice. Psychopharmacol 2005;178:471-480]. The studies reported here demonstrate that behavioral signs of motor impairment result from these high alcohol intakes, and that there was some evidence of tolerance development across repeated sessions. Female C57BL/6J mice were allowed 30 min access to ethanol (5% v/v) followed by 2.5 h access to water either: every 3rd day for 12 days; every 2nd day for 28 days; or every 2nd day for 9 days. On intervening days, mice had 3 h access to water. A control group had daily access to water only. Mice consumed 2-2.5 g/kg ethanol in 30 min, resulting in BECs of 1.4-1.5 mg/ml. Motor impairment was assessed using the accelerating or fixed speed rotarod, balance beam or screen test. In all studies, mice were tested for motor impairment immediately after 30 min access to ethanol or water. In Experiment 1, ethanol-exposed mice had shorter latencies to fall from the fixed speed rotarod and more foot slips on the balance beam than the control group, indicating motor impairment. After drinking ethanol, mice also fell from a screen more quickly than during sober pretraining. In Experiment 2, mice tested (without prior training) for motor impairment and tolerance on the fixed speed rotarod at 6.5 and 10 RPM showed repeated motor impairment in the ethanol group, but did not develop tolerance. In Experiment 3, mice were first given rotarod training at 10 RPM. Following each fluid access period, performance was impaired in mice self-administering ethanol at 10, but not 15 RPM, when compared to control mice. There was no evidence of tolerance across days. However, on the last day, all mice were tested at both RPM following an i.p. injection of 2 g/kg ethanol. Ethanol-experienced mice were less impaired at both RPM than the ethanol-naïve mice, indicating tolerance development according to this between-groups index. These results suggest that C57BL/6J mice will repeatedly consume alcohol in amounts that produce motor impairment under these scheduled fluid access conditions, and that a modest degree of tolerance can be detected using appropriate tests.

Alcohol Drinking↗
PubMed2004

Sex differences in the effect of ethanol injection and consumption on brain allopregnanolone levels in C57BL/6 mice.

The pharmacological profile of allopregnanolone, a neuroactive steroid that is a potent positive modulator of gamma-aminobutyric acidA (GABAA) receptors, is similar to that of ethanol. Recent findings indicate that acute injection of ethanol increased endogenous allopregnanolone to pharmacologically relevant concentrations in male rats. However, there are no comparable data in mice, nor has the effect of ethanol drinking on endogenous allopregnanolone levels been investigated. Therefore, the present studies measured the effect of ethanol drinking and injection on allopregnanolone levels in male and female C57BL/6 mice. One group was given 17 days of 2-h limited access to a 10% v/v ethanol solution in a preference-drinking paradigm, while another group had access to water only. The ethanol dose consumed in 2 h exceeded 2 g/kg. Then, separate groups of mice were injected with either 2 g/kg ethanol or saline. Mice were killed 30 min after the 2-h drinking session or injection. Blood ethanol concentration was significantly higher in the ethanol-injected versus ethanol-drinking groups, even though the dose was similar. Consumption of ethanol significantly increased brain allopregnanolone levels in male but not female mice, compared with animals drinking water, but did not alter plasma corticosterone levels. In contrast, injection of ethanol did not significantly alter brain allopregnanolone levels in male or female mice and only significantly increased plasma corticosterone levels in the male mice, when compared with saline-injected animals. The sex differences in the effect of ethanol administration on endogenous allopregnanolone levels suggest that the hormonal milieu may impact ethanol's effect on GABAergic neurosteroids. Importantly, these data are the first to report the effect of ethanol drinking on allopregnanolone levels and indicate that ethanol consumption and ethanol injection can produce physiologically relevant allopregnanolone levels in male mice. These results have important implications for studies investigating the potential role of endogenous allopregnanolone levels in modulating susceptibility to ethanol abuse.

Alcohol Drinking↗
PubMed2002

Altered forebrain neurotransmitter responses to immobilization stress following 3,4-methylenedioxymethamphetamine.

(+/-)3,4-Methylenedioxymethamphetamine (MDMA, "ecstasy") is an increasingly popular drug of abuse that acts as a neurotoxin to forebrain serotonin neurons. The neurochemical effects of the serotonin depletion following high doses of MDMA were investigated in response to acute immobilization stress. Male rats were treated with a neurotoxic dosing regimen of MDMA (10 mg/kg, i.p. every 2 h for four injections) or equivalent doses of saline. Seven days after treatment, in vivo microdialysis was used to assess extracellular dopamine and serotonin in the dorsal hippocampus and prefrontal cortex during 1 h of immobilization stress. In saline treated control rats, serotonin in the hippocampus and serotonin and dopamine in the prefrontal cortex were increased during immobilization stress. Rats pretreated with MDMA, however, showed blunted neurotransmitter responses in the hippocampus and the prefrontal cortex. In the drug pretreated rats, basal serotonin levels in the hippocampus, but not the prefrontal cortex, were lower compared to saline pretreated controls. Stress-induced increases in plasma corticosterone and body temperature were not affected by the pretreatment condition. From these studies we suggest that depletion of serotonin stores in terminal regions with the neurotoxin MDMA compromises the ability of the serotonergic neurons to activate central systems that respond to stressful stimuli. This altered responsiveness may have implications for long-term functional consequences of MDMA abuse as well as the interactions between the serotonergic system and stress.

Amphetamine-Related Disorders↗
PubMed2001

Genetic factors in addiction: QTL mapping and candidate gene studies implicate GABAergic genes in alcohol and barbiturate withdrawal in mice.

Quantitative trait locus (QTL) mapping has allowed dramatic progress toward the detection and chromosome mapping of minor and major gene loci involved in murine responses to alcohol and other drugs of abuse. Here we focus on the identification of QTLs for one particular trait relevant to addiction, drug withdrawal following acute or chronic drug administration. To date, five significant QTLs (p < 5 x 10(-5)) and six suggestive QTLs (p < 0.001) have been mapped to specific murine chromosomes for alcohol and pentobarbital withdrawal, indicating the presence of a relevant gene or genes at each location. Overlapping QTLs for alcohol withdrawal and pentobarbital withdrawal are identified on murine chromosomes 1, 4, and 11, and may detect the influence of common genes. For many QTLs, candidate genes with relevant neurobiological function lie within the mapped region. Notably, several QTLs for alcohol and pentobarbital withdrawal are in proximity to genes that directly or indirectly affect GABAA receptor-mediated transmission, which has been implicated in some of the actions of alcohol and other drugs. These include a cluster of GABAA receptor genes and genes encoding the enzymes steroid 5 alpha-reductase-1 (involved in biosynthesis of the neuroactive steroid allopregnanolone) and glutamic acid decarboxylase-1 (involved in GABA biosynthesis). This paper will discuss data that examines the involvement of GABAergic genes in withdrawal and other drug responses, including genetic variation in gene sequence, expression and function.

Animals↗
PubMed2000

Acute neuroactive steroid withdrawal in withdrawal seizure-prone and withdrawal seizure-resistant mice.

Allopregnanolone (3alpha-hydroxy-5alpha-pregnan-20-one) is an endogenously derived metabolite of progesterone, and a potent positive modulator of gamma-aminobutyric acid(A) (GABA(A)) receptors. A withdrawal syndrome, characterized by central nervous system (CNS) hyperexcitability, has been demonstrated following abrupt discontinuation of high progesterone levels in rats, which was due in part to altered levels of allopregnanolone. The purpose of the present study was to determine if a single administration of pregnanolone or allopregnanolone could produce an acute withdrawal response in mice selected for susceptibility (Withdrawal Seizure-Prone, WSP) or resistance (Withdrawal Seizure-Resistant, WSR) to ethanol withdrawal convulsions. WSP mice administered 75 mg/kg pregnanolone showed a significant increase in handling-induced convulsion (HIC) scores over a 25-h testing period. In contrast, HIC scores in WSR mice were negligible after acute administration of 25, 50, 75, or 100 mg/kg pregnanolone. WSP mice also showed a similar increase in HIC after withdrawal from 75 mg/kg allopregnanolone. This effect was evident at both the 10-h and 25-h overall withdrawal severity assessment. These results demonstrate that neuroactive steroids can elicit an acute withdrawal response similar to that of other positive modulators of GABA(A) receptors in WSP mice, supporting the notion that a common set of genes underlie acute and chronic withdrawal severity from multiple agents with depressant effects on the central nervous system.

Animals↗
PubMed2000

Abnormal adaptations to stress and impaired cardiovascular function in mice lacking corticotropin-releasing hormone receptor-2.

The actions of corticotropin-releasing hormone (Crh), a mediator of endocrine and behavioural responses to stress, and the related hormone urocortin (Ucn) are coordinated by two receptors, Crhr1 (encoded by Crhr) and Crhr2. These receptors may exhibit distinct functions due to unique tissue distribution and pharmacology. Crhr-null mice have defined central functions for Crhr1 in anxiety and neuroendocrine stress responses. Here we generate Crhr2-/- mice and show that Crhr2 supplies regulatory features to the hypothalamic-pituitary-adrenal axis (HPA) stress response. Although initiation of the stress response appears to be normal, Crhr2-/- mice show early termination of adrenocorticotropic hormone (Acth) release, suggesting that Crhr2 is involved in maintaining HPA drive. Crhr2 also appears to modify the recovery phase of the HPA response, as corticosterone levels remain elevated 90 minutes after stress in Crhr2-/- mice. In addition, stress-coping behaviours associated with dearousal are reduced in Crhr2-/- mice. We also demonstrate that Crhr2 is essential for sustained feeding suppression (hypophagia) induced by Ucn. Feeding is initially suppressed in Crhr2-/- mice following Ucn, but Crhr2-/- mice recover more rapidly and completely than do wild-type mice. In addition to central nervous system effects, we found that, in contrast to wild-type mice, Crhr2-/- mice fail to show the enhanced cardiac performance or reduced blood pressure associated with systemic Ucn, suggesting that Crhr2 mediates these peripheral haemodynamic effects. Moreover, Crhr2-/- mice have elevated basal blood pressure, demonstrating that Crhr2 participates in cardiovascular homeostasis. Our results identify specific responses in the brain and periphery that involve Crhr2.

Adaptation, Physiological↗
PubMed2000

Differential change in neuroactive steroid sensitivity during ethanol withdrawal.

The progesterone metabolite 3alpha-hydroxy-5alpha-pregnan-20-one (3alpha,5alpha-P or allopregnanolone) is a potent positive modulator of gamma-aminobutyric acid(A) (GABA(A)) receptors. Although it is well documented that chronic ethanol (EtOH) administration produces cross-tolerance to the positive modulatory effect of benzodiazepines and GABA at GABA(A) receptors, recent findings suggest that sensitivity to 3alpha,5alpha-P is enhanced during EtOH withdrawal. In addition, EtOH-naive inbred strains of mice, which differ in EtOH withdrawal severity (DBA/2 >> C57BL/6), had marked differences in behavioral sensitivity to 3alpha,5alpha-P. Therefore, the present study was conducted to determine whether C57BL/6 (B6) and DBA/2 (D2) mice would be differentially sensitive to several of the pharmacological effects of 3alpha,5alpha-P during EtOH withdrawal. Male mice were exposed to EtOH vapor or air for 72 h. During withdrawal from EtOH, animals were injected with 3alpha,5alpha-P (0, 3.2, 10, or 17 mg/kg i.p.) and tested for activity and anxiolysis on the elevated plus maze, muscle relaxation, ataxia, and seizure protection following pentylenetetrazol. Sensitivity to the anticonvulsant effect of 3alpha,5alpha-P was enhanced during EtOH withdrawal in B6, but not D2 mice. In contrast, sensitivity to the muscle relaxant effects of 3alpha,5alpha-P was reduced in EtOH-withdrawing B6 and D2 mice, with a suggestion of decreased sensitivity to the anxiolytic effect of 3alpha,5alpha-P during EtOH withdrawal in B6. These results suggest that sensitization to the anticonvulsant effect of 3alpha,5alpha-P during EtOH withdrawal does not generalize across all genotypes nor does it generalize to all of the pharmacological effects of 3alpha,5alpha-P.

Administration, Inhalation↗
PubMed1999

In vivo and in vitro hyperbaric studies in mice suggest novel sites of action for ethanol.

The present study uses increased atmospheric pressure as an ethanol antagonist to test the hypothesis that allosteric coupling pathways in the GABA(A) receptor complex represent initial sites of action for ethanol. This was accomplished using behavioral and in vitro measures to determine the effects of pressure on ethanol and other GABAergic drugs in C57BL/6 and LS mice. Behaviorally, exposure to 12 times normal atmospheric pressure (ATA) of a helium-oxygen gas mixture (heliox) antagonized loss of righting reflex (LORR) induced by the allosteric modulators ethanol and pentobarbital, but did not antagonize LORR induced by the direct GABA agonist 4,5,6,7-tetrahydroisoxazolo-pyridin-3-ol (THIP). Similarly, exposure to 12 ATA heliox antagonized the anticonvulsant effects verses isoniazid of ethanol, diazepam and pentobarbital. Biochemically, exposure to 12 ATA heliox antagonized potentiation of GABA-activated 36Cl-uptake by ethanol, flunitrazepam and pentobarbital in LS mouse brain preparations, but did not alter GABA-activated 36Cl- uptake per se. In contrast to its antagonist effect versus other allosteric modulators, pressure did not antagonize these behavioral or in vitro effects induced by the neuroactive steroid, 3alpha-hydroxy-5beta-pregnan-20-one (3alpha,5beta-P). These findings add to evidence that pressure directly and selectively antagonizes drug effects mediated through allosteric coupling pathways. The results fit predictions, and thus support the hypothesis that allosteric coupling pathways in GABA(A) receptors represent initial sites of action for ethanol. Collectively, the results suggest that there may be common physicochemical and underlying structural characteristics that define ethanol sensitive regions of receptor proteins and/or their associated membranes that can be identified by pressure within (e.g., GABA(A)) and possibly across (e.g., GABA(A), NMDA, 5HT3) receptors.

Allosteric Regulation↗
PubMed1999

Glutamate uptake in mice bred for ethanol withdrawal severity.

RATIONALE: Withdrawal seizure-prone and withdrawal seizure-resistant mice were selectively bred to exhibit differences in handling-induced convulsion severity during ethanol withdrawal. The glutamatergic system has been implicated in seizure activity as well as ethanol withdrawal symptoms. OBJECTIVE: This study assessed L-[3H]glutamate uptake into hippocampal synaptosomes prepared from withdrawal seizure-prone and- resistant mice. METHODS: Glutamate uptake was characterized following repeated handling-induced convulsions, during acute intoxication, and during peak withdrawal following chronic ethanol exposure. RESULTS: Hippocampal synaptosomal L-[3H]glutamate uptake did not differ between convulsion- and ethanol-naive withdrawal seizure-prone and- resistant mice. Furthermore, exposure to convulsions or to a hypnotic dose of ethanol (4 g/kg) did not alter L-[3H]glutamate uptake. However, withdrawal from 72 h of ethanol exposure significantly increased L-[3H]glutamate uptake in both mouse lines as compared to their respective ethanol-naive controls. CONCLUSIONS: These data suggest that glutamate uptake is influenced by chronic ethanol exposure similarly in both withdrawal seizure-prone and- resistant mice. The observed increases in glutamate uptake during withdrawal may be associated with compensatory mechanisms triggered by chronic intoxication and are independent of the selected differences for withdrawal severity.

Alcoholic Intoxication↗
PubMed1999

Different levels of Fos immunoreactivity after repeated handling and injection stress in two inbred strains of mice.

Expression of Fos and Fos-related antigens was immunohistochemically analyzed in DBA/2J and C57BL/6J inbred mice in response to acute or repeated handling and injection stress. Both strains showed a strong induction of Fos and Fos-related antigens in discrete areas of hypothalamus, amygdala, neocortex, septum, and thalamus 2 h after an acute intraperitoneal injection of normal saline. To habituate animals to this procedure, mice were subjected to repeated handling and injections during 2 weeks preceding the experiment. This procedure led to complete habituation of the immediate early gene response to injection stress in stress-responsive brain areas of C57BL/6J mice, such that no significant difference was found between expression of these proteins in brains of saline-injected animals after repeated stress vs. control animals. In contrast, many brain areas of saline-injected DBA/2J mice still showed elevated Fos and Fos-related antigen expression after repeated injections. These results indicate that identical habituation procedures do not necessarily lead to identical levels of gene expression in brains of inbred strains of mice. In turn, they suggest that genetic components for some behavioral and pharmacological traits identified using inbred strains could be related to different rates of habituation to experimental procedures.

Animals↗
PubMed1999

Chronic ethanol differentially alters susceptibility to chemically induced convulsions in withdrawal seizure-prone and -resistant mice.

Withdrawal seizure-prone (WSP) and withdrawal seizure-resistant (WSR) mice were selectively bred to have severe (WSP) or mild (WSR) handling-induced convulsions after chronic ethanol inhalation. The purpose of the present experiments was to determine whether seizure susceptibility differences between WSP and WSR mice during ethanol withdrawal were specific to agents acting at gamma-aminobutyric acidA or excitatory amino acid (EAA) receptors. Male WSP and WSR mice were exposed to ethanol vapor or air for 24 or 72 h. During peak withdrawal (i.e., between 6.5 and 8 h after removal from the inhalation chambers), separate groups of animals were administered pentylenetetrazol, (+)bicuculline, N-methyl-D-aspartate, kainic acid, or strychnine via timed tail vein infusion. Withdrawal from ethanol significantly increased sensitivity to pentylenetetrazol and (+)bicuculline versus air-exposed WSP and WSR mice. In contrast, sensitivity to N-methyl-D-aspartate-induced convulsions was significantly decreased in the ethanol-exposed WSR and unchanged in the ethanol-exposed WSP mice. Sensitivity to kainic acid was significantly increased in both ethanol-exposed WSR and WSP mice, although the magnitude of change in sensitivity was greater in the ethanol-withdrawing WSP line. Interestingly, sensitivity to strychnine was decreased similarly in the ethanol-exposed WSP and WSR mice, compared with their respective air-exposed animals. These results suggest that chronic ethanol increased sensitivity to convulsants active at gamma-aminobutyric acidA receptors similarly in WSP and WSR mice, but differentially changed sensitivity to convulsants active at EAA receptors in the lines. This supports a role for EAA systems in determining genetic susceptibility to alcohol withdrawal.

Administration, Inhalation↗
PubMed1997

Rewarding effect of the neuroactive steroid 3 alpha-hydroxy-5 alpha-pregnan-20-one in mice.

The GABAA-receptor agonist neuroactive steroid 3 alpha-hydroxy-5 alpha-pregnan-20-one (3 alpha,5 alpha-P) has anxiolytic and locomotor stimulant effects and shares some subjective properties with benzodiazepines, barbiturates and ethanol, but there have been no studies of its reinforcing or rewarding effects. The present study examined the rewarding properties of 3 alpha,5 alpha-P using the conditioned place preference paradigm. Male DBA/2J mice received four pairings of a distinctive floor stimulus with 3 alpha,5 alpha-P (3.2, 10 or 17 mg/kg, IP) in an unbiased conditioning procedure. On alternate days a different distinctive floor was paired with vehicle. At the lowest dose (3.2 mg/kg), there was no difference between conditioning subgroups in preference for the drug-paired floor type, indicating an absence of place conditioning. However, a dose-dependent conditioned preference was evident at the higher doses as shown by the greater amount of time spent on the floor paired with 3 alpha,5 alpha-P. In addition, 3 alpha,5 alpha-P produced a dose-dependent increase in locomotor activity, which was significant following the 17 mg/kg dose. A control study showed no effect of the beta-cyclodextrin vehicle on place conditioning in the absence of neurosteroid. These results provide the first demonstration that 3 alpha,5 alpha-P, an endogenous modulator of GABAA receptor function, possesses rewarding properties using the conditioned place preference paradigm.

Animals↗
PubMed1997

Exploring alcohol withdrawal syndrome.

Alcohol withdrawal syndrome is characterized by hyperactivity of the nervous system. This hyperactivity represents the brain's attempt to function normally despite the inhibitory effect of chronic alcohol consumption. The syndrome manifests when alcohol consumption ceases. Experimental, clinical, and genetic research have linked the development of withdrawal to alterations in the sensitivity of neuronal communication systems. Early treatment of the syndrome is advised, because the symptom severity may increase with each subsequent episode.

Animals↗
PubMed1997

Genetic differences in behavioral sensitivity to a neuroactive steroid.

Recent work found that lower endogenous levels of the gamma-aminobutyric acid-agonist, neuroactive steroid 3alpha-hydroxy-5alpha-pregnan-20-one (3alpha,5alpha-THP) may be correlated with increased ethanol withdrawal severity in the selectively bred Withdrawal Seizure-Prone and -Resistant mice. The present studies were conducted to determine whether decreased sensitivity to 3alpha,5alpha-THP was correlated with ethanol withdrawal hyperexcitability in another genetic mouse model, namely the C57BL/6 (B6) and DBA/2 (D2) inbred strains. These strains also differ in ethanol withdrawal severity (D2 >> B6). B6 and D2 male mice were injected with 3alpha,5alpha-THP (0-10 mg/kg i.p.) 15 min before the timed tail vein infusion of pentylenetetrazol. B6 mice were more sensitive than D2 animals to the anticonvulsant effect of 3alpha,5alpha-THP. Subsequent studies measured sensitivity to several of the pharmacological effects of 3alpha,5alpha-THP. B6 and D2 male mice were injected with 3alpha,5alpha-THP (0-32 mg/kg) before testing for locomotor activation (total number of entries) and anxiolysis (percent open arm entries) on the elevated plus maze, muscle relaxation (impairment of forelimb grip strength), ataxia (impairment of Rotarod performance) and seizure susceptibility to pentylenetetrazol. B6 mice were more sensitive than D2 animals to the anxiolytic, locomotor stimulant and anticonvulsant effects of 3alpha,5alpha-THP. In contrast, D2 mice were more sensitive than B6 mice to 3alpha,5alpha-THP-induced muscle relaxation and ataxia. Plasma 3alpha,5alpha-THP levels did not differ in the B6 and D2 mice injected with this steroid, suggesting that the strain differences were not pharmacokinetic. Collectively, the results in selectively bred Withdrawal Seizure-Prone and -Resistant mice and B6 and D2 inbred strains suggest that genetic differences in neuroactive steroid sensitivity and biosynthesis may contribute to ethanol withdrawal severity.

Animals↗
PubMed1996

Effect of 12 atmospheres helium-oxygen on the response of mice to convulsant drugs.

The mechanism by which 12 atm abs of a helium-oxygen gas mixture (heliox) antagonizes behavioral effects of ethanol is unknown. Although the threshold for pressure-reversal of general anesthesia and expression of the high pressure neurologic syndrome (HPNS) is well above 12 atm abs in mice, the ethanol antagonism by 12 atm abs heliox could result from similar underlying excitatory effects. To investigate this possibility, the behavior of water-injected control mice and the latency to convulsions in drug-injected mice were determined in 1 atm abs air and 12 atm abs heliox. Four convulsant drugs were tested: picrotoxin (2 mg/kg), dl-allylglycine (300 mg/kg), isoniazid (300 mg/kg), and l-methionine-dl-sulfoximine (170 mg/kg). Responses were videotaped to observe behavior and to measure latency to the onset of myoclonus and clonus. Results indicated no observable excitatory effects of 12 atm abs in control mice. The latency to myoclonus was significantly reduced by pressure in allylglycine-treated mice but not in mice treated with the other convulsants. Latency to clonus was not significantly altered by pressure, relative to latency at 1 atm abs heliox, for any drug tested. In conclusion, the present findings indicate that exposure to 12 atm abs heliox is not proconvulsant and, thus, the findings do not support the hypothesis that 12 atm abs heliox antagonizes ethanol indirectly via an increase in central nervous system excitability.

Allylglycine↗