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PubMed2000

Altered solution structure of alcoholic medium of potentized Nux vomica underlies its antialcoholic effect.

Nux vomica 30c, 200c and 1000c were administered orally to three batches of albino mice for three days. Six hours after the last dose on the third day the mice were injected i.p. with ethanol 4g/kg body wt. They lost their righting reflex and lay motionless apparently sleeping due to alcohol. Mice treated with three potencies of Nux vomica regained their righting reflex more quickly than the corresponding untreated controls. Each of the three batches of mice was tested twice for ethanol sedation, once with a potency of Nux vomica and another time with a placebo control. The time interval between drug treatment and control was 10 days. NMR spectra of Nux 30, Nux 200, Nux 1000, alcohol 30, alcohol 30 (unagitated) and 90% alcohol showed significant difference from each other with respect to the spin-lattice relaxation time (T1) of the deuterium nuclei. This gives a measurable physical basis of the effective high potencies of Nux vomica.

Administration, Oral↗

PubMed2004

Reduced hypothermic and hypnotic responses to ethanol in PACAP-deficient mice.

Using pituitary adenylate cyclase-activating polypeptide (PACAP)-deficient mice, we investigated whether PACAP is involved in the intoxicating effects of ethanol. The structure of PACAP is highly conserved during evolution, and in Drosophila, loss-of-function mutations in a PACAP-like neuropeptide gene, amnesiac, result in impairment of memory retention and increased sensitivity to ethanol. In mice, PACAP deficiency is associated with impaired memory performance and hippocampal long-term potentiation (LTP), however, sensitivity to ethanol has not been well investigated. Here, we addressed this issue in our recently developed PACAP-deficient mice. Sleep time (duration of the loss of righting reflex) was markedly shortened in PACAP-deficient mice compared with wild-type, although latency to the loss of righting reflex was not different between the two groups. Ethanol-induced hypothermia in wild-type control mice was significantly reduced in PACAP-deficient mice. Blood ethanol levels were not different between the two groups, excluding the possibility of increased ethanol metabolism. Thus, in contrast to that in Drosophila, PACAP deficiency in mammals caused a reduced sensitivity to ethanol. However, in both cases, PACAP or amnesiac products are likely to play significant roles in modifying the intoxicating effects of ethanol.

Animals↗

PubMedDate not supplied

The behavioral teratogenic potential of fenbendazole: a medication for pinworm infestation.

Fenbendazole (FBZ) is a benzimidazole currently used for anthelmintic treatment of pinworm populations in numerous animal species although it is not currently approved for laboratory rodents in the U.S. It has received considerable interest for treating rodent populations due to its low toxicity, wide safety margin and apparent absence of gross teratogenic effects. The purpose of this study was to assess the behavioral teratogenic potential of FBZ. Pregnant rats were administered either FBZ-medicated feed at a therapeutic level or normal rat chow throughout pregnancy and gestation. FBZ had no effect on pregnancy indicators such as maternal weight gain or water consumption, number of pups born or pup birth weights. Offspring were examined in a variety of paradigms including righting reflex, negative geotaxis, running wheel activity, Morris water maze (MWM) performance and digging maze performance. FBZ offspring did show delayed righting reflex, some modest changes in locomotor activity in a running wheel and minor alterations in performance during the probe session of the MWM relative to controls. However, the effects of FBZ on behavior were subtle and many of the behaviors examined were unaffected. These results suggest that FBZ may be an effective and relatively safe anthelmintic treatment for use in breeding colonies.

Analysis of Variance↗

PubMed1976

Studies on the comparative pharmacology and selective toxicity of tricaine methanesulfonate: metabolism as a basis of the selective toxicity in poikilotherms.

Tricaine methanesulfonate, administered at a dose of 150 mg/kg i.p., produced a flaccid paralysis and loss of the righting reflex in a number of poikilothermic species including the frog. Leopard frogs (Rana pipiens) given 150 mg/kg i.p. regained the righting reflex at 113 +/- 28 (S.D.) minutes after injection. A similar dose administered i.p. to mice produced no apparent pharmacological response. The biological half-life (T1/2) of tricaine in frogs (R. pipiens) was about 70 minutes at temperatures of 23 and 37.5 degrees C; at 7 degrees C the T1/2 was 309 minutes. In contrast, in the mouse the drug was metabolized so rapidly that 5 minutes after i.p. administration of 5 mg of tricaine methanesulfonate (250 mg/kg) none of the unchanged drug could be recovered from the animal. It was, however, recovered quantitatively as Bratton-Marshall reacting metabolites, including m-aminobenzoic acid. Incubations of tricaine with serum from bullfrogs, mice and humans indicated that the drug was metabolized to m-aminobenzoic acid with an apparent Km of 3 X 10(-3) M for the reaction. The Vmax for incubations of the drug with bullfrog and human serum was 40 nmol/min/ml of serum, whereas in mouse serum it was 93 nmol/min/ml of serum. In vitro studies with liver homogenates showed that mouse liver metabolized tricaine 39 times more rapidly than frog liver. We conclude, therefore, that the liver is the major site of tricaine hydrolysis in mammals and that the selective toxicity of tricaine for poikilotherms is a consequence of their slower rate of hepatic biotransformation of tricaine.

Aminobenzoates↗

PubMed1996

Synergistic behavioral interaction between ethanol and clonidine in rats: role of alpha-2 adrenoceptors.

Activation of central alpha-2 adrenoceptor leads to a sleep-like state. The present study investigated the effect of ethanol on the loss of the righting reflex (LORR) and hypotension evoked by clonidine in Sprague-Dawley rats. Clonidine at 30 micrograms/kg had no effect on righting reflex, but a higher dose (60 micrograms/kg) elicited variable LORR that averaged 6.5 +/- 4.1 min. Similarly, 0.5 g/kg of ethanol elicited little effect (0.17 +/- 0.17 min), but a higher dose (1 g/kg) produced 2.5 +/- 1.1 min of LORR. Ethanol (0.5 g/kg), combined with the lower dose of clonidine, still had little effect on LORR, but when combined with the higher dose of clonidine the LORR (34.8 +/- 6.5 min) became significantly (P < .01) greater than the sum of the individual effects. Similarly, rats that received a combination of the higher dose (1 g/kg) of ethanol and lower dose (30 micrograms/kg) of clonidine exhibited significantly (P < .01) greater LORR (18.6 +/- 2.5 min) than the sum of individual effects. These findings suggest a synergistic interaction that is dose-related. The alpha-2 adrenoceptor antagonist yohimbine (1 mg/kg), or a mixed antagonist of imidazoline and alpha-2 adrenoceptors, idazoxan (60 micrograms/kg), counteracted the synergistic interaction between ethanol and clonidine on LORR; yohimbine was more effective than idazoxan, but the difference was not significant. Ethanol counteracted the hypotensive effect of clonidine and significantly (P < .05) increased blood pressure to levels higher than preclonidine and corresponding control values. Therefore, the synergistic interaction on LORR cannot be accounted for by an enhanced hypotensive response to clonidine. Furthermore, idazoxan counteracted the hypotensive response to clonidine more effectively than did yohimbine. Taken together, the findings suggest: 1) ethanol differentially influences the sedative (synergistic interaction) and hypotensive (antagonistic interaction) effects of clonidine; 2) the synergistic behavioral interaction is dose-related and involves, at least in part, central alpha-2 adrenoceptors; and 3) the hypotensive effect of clonidine is primarily mediated via imidazoline receptors.

Adrenergic alpha-Agonists↗

PubMed1991

Effect of CGS 19755, a competitive N-methyl-D-aspartate antagonist, on general anesthetic potency.

CGS 19755 is a competitive N-methyl-D-aspartate (NMDA) receptor antagonist which penetrates the blood-brain barrier. The effect of pretreatment with subanesthetic doses of CGS 19755 on general anesthetic potency was determined in mice. Mice were pretreated with saline or CGS 19755 by intraperitoneal (IP) administration 30 min before IP administration of an anesthetic dose of ethanol or pentobarbital or measurement of the volatile anesthetic minimum alveolar concentration (MAC). CGS 19755 increased the duration of ethanol- and pentobarbital-induced loss of righting reflex in a dose-dependent manner. The highest dose of CGS 19755 tested, 50 mg/kg, increased duration of loss of righting reflex by about four- and twofold for ethanol and pentobarbital, respectively. CGS 19755 also decreased the MAC for halothane. However, CGS 19755 pretreatment had no effect on the MAC for diethyl ether. These results suggest that the potency of certain general anesthetic agents can be increased by antagonism of brain NMDA receptors.

Anesthetics↗

PubMed2002

Ethanol-induced activation and rapid development of tolerance may have some underlying genes in common.

Ethanol exerts biphasic effects on behavior, stimulant at low doses and depressant at higher doses. In the present study we used two mouse genetic models to investigate the relationships among activating and depressant responses to alcohol. The first model was a panel of nine isogenic genotypes. FAST and SLOW mice, selectively bred for high and low ethanol-induced motor activation, respectively, were used as a second model. We used loss of righting reflex to assess initial sensitivity and acute functional tolerance to a hypnotic dose of ethanol (3 g/kg, 20% v/v). Blood ethanol concentration at the onset of loss of righting reflex was used as an estimate of initial sensitivity, while the difference between concentration values at the recovery and loss of righting represented an acute functional tolerance score. Mean initial sensitivity and acute functional tolerance values of the nine strains were correlated with a previously obtained measure of ethanol-induced locomotor activation. Activation correlated significantly with both initial sensitivity (rg = 0.80; P < 0.05) and acute functional tolerance (rg = 0.77; P < 0.05). Thus, inbred genotypes that were activated more by a low dose of ethanol were also more sensitive to and developed more acute tolerance to a high dose. FAST mice had initial sensitivity values similar to those of SLOW mice, but developed more pronounced tolerance, indicating that ethanol-induced activation and acute functional tolerance may be regulated by some common genetic mechanisms. In summary, these results supported a genetic association between ethanol-induced activation and rapid development of tolerance.

Animals↗

PubMed1988

Strategy to assess the role of (inter)active metabolites in pharmacodynamic studies in-vivo: a model study with heptabarbital.

The purpose of this investigation was to develop a universal experimental strategy by which the role of (inter)active metabolites in in-vivo pharmacodynamic studies can be examined. Heptabarbital was chosen as a model drug and several pharmacokinetic variables which may affect in-vivo concentration-pharmacological response relationships were examined. Adult female rats received an i.v. infusion of the drug at one of three different rates (0.225-1.50 mg min-1) until the animals lost their righting reflex (after 11 +/- 1 to 88 +/- 8 min of infusion). The serum concentration of the drug at onset of loss of righting reflex (LRR) increased slightly with increasing infusion rate. The drug concentrations in brain tissue and cerebrospinal fluid (CSF), (mean +/- s.d.: 67 +/- 5 mg kg-1 and 24 +/- 4 mg L-1, respectively, for the lowest infusion rate) were not affected by the infusion rate. The possible contribution of (inter)active metabolites to the pharmacological response of heptabarbital was determined by administration of different i.v. bolus doses (14.1-22.5 mg) resulting in widely differing sleeping-times (7 +/- 3 to 119 +/- 20 min). The concentrations of heptabarbital in serum, brain tissue and CSF at offset of LRR (mean +/- s.d.: 77 +/- 8 mg L-1, 76 +/- 7 mg kg-1 and 29 +/- 5 mg L-1, respectively, for the highest dose) were not affected by the administered dose.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed2000

Potency of propofol, thiopentone and ketamine at various endpoints in New Zealand White rabbits.

Effective plasma concentrations of propofol, thiopentone and ketamine were determined at different endpoints in a study with randomized, crossover design in nine New Zealand White rabbits. A continuous infusion was used (30 ml/h) with concentrations of 10 mg/ml for propofol, 25 mg/ml for thiopentone and 20 mg/ml for ketamine. The endpoints were loss of the righting reflex, loss of purposeful reactions to tail clamping (as an example of a peripheral pain stimulus) or to intranostril insufflation of ammonia vapour (as an example of a central reflex stimulus), and the recovery of these reflexes and reactions. According to the ED50 values the potency ratios of propofol, thiopentone and ketamine were at the loss of righting reflex 1:1.8:1.2, at the loss of reaction to ammonia vapour 1:1.5:1.6, and at the loss of reaction to tail clamping 1:1.5:3.9, respectively. Recovery was significantly faster after propofol than after thiopentone and ketamine. Measuring the effective plasma concentrations of intravenous anaesthetics provides a method of relating dose to effect, but there still remains a variable gap between plasma concentration and effect.

Anesthetics, Intravenous↗

PubMed1982

High-affinity choline uptake in the hippocampus: its relationship to the physiological state produced by administration of barbiturates and other treatments.

Choline uptake in hippocampal synaptosomes was not inhibited by pentobarbital administration when rats were decapitated immediately upon loss of the righting reflex (3-4 min) even though it was inhibited at later times post-injection, when the rats were still unable to right themselves. Choline uptake was increased when the animals were decapitated at convulsion after an injection of picrotoxin, high doses of bicuculline, or one of the convulsant barbiturates. However, another convulsant barbiturate, as well as strychnine and lower doses of bicuculline, did not increase choline uptake even though the animals also convulsed. Thus loss of righting reflex or convulsion is not directly correlated with changes in choline uptake. At 7 min after injection, levels of pentobarbital in the hippocampus (and other brain regions) were correlated with the degree of inhibition of choline uptake up to about 50% inhibition; however, greater inhibition could not be achieved with much higher brain levels of the drug. Although hippocampal uptake was partially inhibited at 1 h after septal lesions, 3 h after the lesion the inhibition was no longer apparent. Inhibition was almost complete 10-12 days after the lesion. These results suggest that other factors in addition to impulse flow influence choline uptake.

Animals↗

PubMed2004

Fluoxetine and norfluoxetine stereospecifically facilitate pentobarbital sedation by increasing neurosteroids.

Mice housed in social isolation exhibit a decreased response to gamma-aminobutyric acid-mimetic drugs [i.e., pentobarbital (PTB)] associated with a down-regulation of telencephalic allopregnanolone (Allo) levels. In these mice, the PTB-induced loss of righting reflex is greatly reduced. Fluoxetine (FLX) and norfluoxetine (NFLX) stereospecifically reverse the effect of social isolation on the PTB-induced loss of righting reflex and on the decrease of telencephalic Allo content. The S-isomers of FLX and NFLX are 2- and 7-fold more potent, respectively, than their respective R-isomers. The EC(50)s of FLX and NFLX required to normalize brain Allo content and PTB action are 10-50 times lower than the IC(50)s required for selective serotonin reuptake inhibitor activity. We conclude that normalization of PTB action elicited by the S-isomers of FLX and NFLX is related to the reversal of the down-regulation of brain Allo content and is independent of selective serotonin reuptake inhibitor activity.

Animals↗

PubMed1991

Observation of the development of tolerance to and physical dependence on barbital by cortical evoked potential in rats.

To observe the dispositional and functional tolerance to and physical dependence on barbital, the influence of repeated administration of the drug on serum barbital levels, coordinative motion, body weight, and cortical evoked potential was assessed. Rats administered the first dose of barbital showed marked impairment of gross behavior and then loss of the righting reflex. While they were repeatedly treated with barbital for a 4-week period, the CNS depression became weaker and weaker, and loss of the righting reflex was no longer observed. Serum barbital levels after administration of barbital tended to decrease by the 28th day of repeated drug administration. Coordinative motion was markedly impaired after administration of the first dose, but gradually recovered during the repeated administration period. Barbital at 100 mg/kg, i.p., prolonged the latent time of the evoked potential in normal untreated rats but not in tolerant rats. During the withdrawal period, no particular change was observed in the animals' gross behavior. However, body weight loss and shortening of the latent time of the evoked potential were observed at 60 to 72 hours of withdrawal. These results suggest that cortical evoked potential can serve as a useful method for observing tolerance to and physical dependence on barbital.

Animals↗

PubMed1988

Kinetics of drug action in disease states. XXV. Effect of experimental hypovolemia on the pharmacodynamics and pharmacokinetics of desmethyldiazepam.

It has been reported that hypovolemia secondary to extensive blood loss alters the functionality of the central nervous system and is associated with changes in the dose requirements or intensity of action of various central nervous system depressants, including a benzodiazepine. To investigate the mechanism(s) of this effect, the influence of experimental hypovolemia on the pharmacodynamics, receptor binding and pharmacokinetics of a benzodiazepine drug was determined. Adult male Sprague-Dawley rats were made hypovolemic by removal of about 30% of their blood over 30 min. An i.v. infusion of desmethyldiazepam (DDZP) was started 30 min later and continued until the animals lost their righting reflex. Compared to results obtained with normal controls, the hypovolemic rats required about one-half the dose of DDZP to produce loss of righting reflex and had significantly lower DDZP concentrations in serum and cerebrospinal fluid at that time. This effect of substantial blood removal could not be reversed by prompt return of the removed blood to the animals. Experimental hypovolemia had no apparent effect on the in vitro binding of tritiated diazepam to benzodiazepine receptor sites in the cerebral cortex of rats. The plasma clearance of DDZP was decreased significantly and the biological half-life was increased in hypovolemic rats compared to normal animals when both received a 30-mg/kg dose by i.v. infusion over 10 min. It is concluded that acute hemorrhagic hypovolemia increases the sensitivity of the central nervous system to the depressant effect of DDZP and decreases the body clearance of that drug in rats. Thus, the pharmacodynamics as well as the pharmacokinetics of a benzodiazepine are altered by hypovolemia.

Animals↗

PubMed2003

Behavioural changes induced by early and long-term gravito-inertial force modification in the rat.

The study concerns rats conceived, born and raised in a hypergravity environment (HG: 2 g) for 3 months using a centrifuge. They were then exposed to terrestrial gravity (1 g) and submitted to behavioural tests investigating their spontaneous locomotor activity (open-field), their posture (support surface), and their vestibular function (air-righting reflex). Performances were compared to age-matched control rats housed at 1 g for the same time period. Results showed static and dynamic behavioural deficits as early as the rats were exposed to normal gravity. They exhibited strongly increased motor activity in open-field, with longer travelled distances and more scattered trajectories; in addition, the HG rats displayed more numerous rearings than controls did. They showed postural changes characterized by an enlarged support surface and they did not succeed in the air-righting reflex, due to increased time-delay for head righting. None of these changes were permanent. Indeed, for all tests, the HG rats tested after 3 weeks spent in normal terrestrial gravity exhibited behaviours similar to those of the controls. HG-induced changes in the functional properties of the vestibular system may explain the deficits showed by the HG rats once exposed to normal gravity. The adaptation process to 1 g leading to the appearance of normal behaviour takes about 3 weeks. It likely implicates a central re-evaluation of the sensory inputs and an updating of the motor commands.

Adaptation, Physiological↗

PubMed1983

Murine auto- and cross-tolerance to volatile anaesthetics.

Auto-tolerance and cross-tolerance to halothane, isoflurane and enflurane were tested on 36 mice divided into three equal groups. Each group was first exposed to increasing concentrations of either of the three anesthetics on 13 occasions. The concentration at which each mouse lost its righting reflex during successive exposures in a rotating cage was noted. Cross-tolerance was assessed by comparing the number of mice which had lost their righting reflexes during their first exposure to a given anaesthetic agent to the number which lost it after having been exposed to another anaesthetic. All animals developed auto-tolerance to halothane, isoflurane and enflurane. Cross-tolerance was noted only between mice exposed to isoflurane and enflurane and between mice exposed to halothane and subsequently anaesthetized with isoflurane, but not vice versa.

Animals↗

PubMed1995

Effects of dietary alpha-linolenic acid deficiency on neuromuscular and cognitive functions in mice.

Mice were fed a diet deficient in alpha-linolenic acid [18:3 (n-3)] or a control diet and the effect of this deficiency was assessed by behavioral and pharmacological measurements. Three weeks before mating female mice were fed a diet containing either peanut oil poor in alpha-linolenic acid (n-3)- or peanut+rapeseed oil rich in alpha-linolenic acid (n-3)+ = controls. Pups, aged 47 to 61 days, fed the same diet as their dams, were used for behavioral experiments. Muscular function and neuromuscular coordination assessed by the traction test, the elevated rotarod test and swimming endurance were unchanged by the (n-3)- deficiency. The level of anxiety assessed by the elevated plus-maze (anxiety protocol), the light-dark transition and the neophobia tests did not differ between (n-3)- and control (n-3)+ mice. Defensive behavior was not changed by the diet. The pentobarbital-induced loss of the righting reflex had the same duration in males, females, and controls as in (n-3) deficient mice; the latency to pentobarbital-induced loss of the righting reflex was significantly shorter in females than in males but did not differ according to the diet. Mice fed the (n-3)- deficient diet showed less efficient learning in the elevated plus-maze (learning protocol) and poorer understanding of the situation (or less motivation to escape) in the low rotarod test than mice fed the control (n-3)+ diet.

Animals↗

PubMed1989

Evaluation of anaesthetic potency of medetomidine-ketamine combination in rats, guinea-pigs and rabbits.

In many animal species ketamine hydrochloride is combined with xylazine, an alpha 2-adrenoceptor agonist, to achieve anaesthesia. The purpose of this study was to evaluate the anaesthetic efficacy of various dose combinations of another alpha-2-adrenoceptor agonist medetomidine and ketamine in rats, guinea pigs and rabbits. Both sexes of all three species in groups of five were used. In rats, dose combinations medetomidine/ketamine, both in mg/kg, used were 0.25/60, 1.0/60 and 0.5/70; in guinea pigs 0.5/40 and in rabbits 0.5/25 and 0.5/60. In rats and rabbits the righting reflex was lost within 2-3 min. In rats with doses 0.25/60 and 0.5/75 other reflexes disappeared, reappearing after 20-25 min and 60-70 min in males, the respective values being 120-140 min and 150-180 in females. The righting reflex reappeared after 130-135 and 160-190 min in males and 240 and greater than 300 min in females in the order above. In guinea pigs irrespective of route of ketamine administration all reflexes remained. In rabbits, a dose 0.5/25 caused disappearance of ear pinch reflex. We conclude that the medetomidine-ketamine combination can be used in rats and rabbits as an anaesthetic, and in guinea pigs only for immobilization.

Adrenergic alpha-Agonists↗

PubMed2003

The general anesthetic propofol increases brain N-arachidonylethanolamine (anandamide) content and inhibits fatty acid amide hydrolase.

1. Propofol (2,6-diisopropylphenol) is widely used as a general anesthetic and for the maintenance of long-term sedation. We have tested the hypothesis that propofol alters endocannabinoid brain content and that this effect contributes to its sedative properties. 2. A sedating dose of propofol in mice produced a significant increase in the whole-brain content of the endocannabinoid, N-arachidonylethanolamine (anandamide), when administered intraperitoneally in either Intralipid or emulphor-ethanol vehicles. 3. In vitro, propofol is a competitive inhibitor (IC(50) 52 micro M; 95% confidence interval 31, 87) of fatty acid amide hydrolase (FAAH), which catalyzes the degradation of anandamide. Within a series of propofol analogs, the critical structural determinants of FAAH inhibition and sedation were found to overlap. Other intravenous general anesthetics, including midazolam, ketamine, etomidate, and thiopental, do not affect FAAH activity at sedative-relevant concentrations. Thiopental, however, is a noncompetitive inhibitor of FAAH at a concentration of 2 mM. 4. Pretreatment of mice with the CB(1) receptor antagonist SR141716 (1 mg kg(-1), i.p.) significantly reduced the number of mice that lost their righting reflex in response to propofol. Pretreatment of mice with the CB(1) receptor agonist, Win 55212-2 (1 mg kg(-1), i.p.), significantly potentiated the loss of righting reflex produced by propofol. These data indicate that CB(1) receptor activity contributes to the sedative properties of propofol. 5. These data suggest that propofol activation of the endocannabinoid system, possibly via inhibition of anandamide catabolism, contributes to the sedative properties of propofol and that FAAH could be a novel target for anesthetic development.

Amidohydrolases↗