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At least 271 records · Page 15Linked to original sources

PubMed2003

Early developmental neurotoxicity of a PCB/organochlorine mixture in rodents after gestational and lactational exposure.

The developmental and neurobehavioral effects of gestational and lactational exposure to a mixture of 14 polychlorinated biphenyls (PCBs) and 11 organochlorine pesticides was examined and compared against the commercial PCB mixture Aroclor 1254. The mixture was based on blood levels reported in Canadian populations living in the Great Lakes/St. Lawrence basin. Pregnant Sprague-Dawley rats were dosed orally with 0.013, 0.13, 1.3, or 13 mg/kg of the chemical mixture or 15 mg/kg of Aroclor 1254 from gestation day (GD) 1 to postnatal day (PND) 23. The highest mixture dose decreased maternal gestation and lactation body weight, and produced high mortality rates (80% overall) and reductions in offspring weight that persisted to adulthood. Aroclor 1254 produced smaller but persistent decreases in offspring weight without affecting maternal weight or offspring mortality. Aroclor 1254 and 13 mg/kg of the mixture produced comparable decreases in maternal and offspring serum T4 levels and comparable alterations to maternal thyroid morphology. Aroclor 1254 delayed the righting reflex and ear opening, accelerated eye opening, and reduced grip strength at PNDs 10-14. The mixture at 13 mg/kg delayed negative geotaxis in addition to delaying righting reflex and ear opening and reducing grip strength but had no effect on eye opening. Lower mixture doses (0.13 and 1.3 mg/kg) also delayed ear opening but affected no other parameters. Developmental exposure to the chemical mixture was found to be more toxic than exposure to Aroclor 1254 and produced a different profile of effects on early neurodevelopment. This PCB/organochlorine pesticide mixture affects mortality, growth, thyroid function, and neurobehavioral development in rodents.

Administration, Oral↗

PubMed1978

Increased penetration of barbital through the bloodbrain barrier in the rat after pretreatment with probenecid.

Some weak organic acids are eliminated from the brain by an acid transport system. The question arose is this system also used to transport drugs out of the brain? In that case probenecid pretreatment (100 mg/kg subcutaneously) should influence the induction time of a slightly lipid soluble barbiturate (barbital) which penetrates into the brain slowly, more than the induction time of a very lipid soluble barbiturate (hexobarbital). In the first experiment barbital (200 mg/kg) was given intraperitoneally and in the second experiment barbital (150 mg/kg) was infused intravenously during 10 min. In both experiments loss of righting reflex occurred more rapidly after pretreatment with probenecid compared with pretreatment with saline. Only in the second experiment did probenecid significantly increase the time during which the righting reflex was lost. In the next experiment hexobarbital was infused intravenously at a rate of 0.25 mg/kg/sec. until a burst suppression which lasted 1 sec. or more was seen in a concomitant EEG-record. When this "silent second" occurred the infusion was stopped and the ensuing anaesthesia times recorded. Probenecid had no effect on the induction when studied with this method, but the ensuing anaesthesia times were increased. The hypothesis of an acid transport system out of the brain was thus not refuted by these experimental results. Studies of brain concentrations of barbital also supported this finding. After 200 mg/kg intraperitoneally the concentration of barbital in the brain was higher after pretreatment with probenecid as compared to saline pretreated controls i.e. at times corresponding to the induction times in the in vivo experiments. No difference was found in the serum levels of barbital.

Anesthesia↗

PubMed1988

Myoclonic seizures in the mouse induced by alphaxalone and related steroid anaesthetics.

The anaesthetic steroids alphaxalone. 5 beta-alphaxalone and pregnanolone each caused myoclonic jerks in mice in a dose-related manner between 4 and 16 mg kg-1 i.v. There was no loss of righting reflex at these doses. The veterinary product Saffan, which contains alphaxalone and alphadalone, also caused myoclonic jerks at 2 mg kg-1 i.v., and a loss of righting reflex at doses of 4 mg kg-1 and above. These effects appear to be unrelated to the wide spectrum of potencies at the GABAA receptor complex of the three individual steroids as potentiators of muscimol, or as attenuators of picrotoxin.

Anesthetics↗

PubMed1985

Kinetics of drug action in disease states XI: effect of nicotine on the pharmacodynamics and pharmacokinetics of phenobarbital and ethanol in rats.

The purpose of this investigation was to determine if the reported prolongation of barbiturate- and ethanol-induced sleeping times by nicotine in rodents are pharmacodynamic or pharmacokinetic interactions. Adult female rats were pretreated with nicotine, either 0.5 or 1.5 mg/kg ip acutely or 0.5 mg/kg ip daily for 6 d, whereas control animals received saline solution. Phenobarbital or ethanol was infused intravenously at a slow rate until the rats lost their righting reflex. Acute pretreatment with nicotine reduced significantly the serum, brain, and cerebrospinal fluid (CSF) concentrations of phenobarbital and ethanol, respectively, at the onset of the loss of the righting reflex. Chronic pretreatment with nicotine had no such potentiating effects, indicative of rapid development of tolerance to nicotine. Neither acute nor chronic pretreatment with nicotine had any apparent effect on the elimination kinetics of phenobarbital or ethanol, on biochemical indices of hepatic integrity and renal function, or on the permeability of the blood-CSF barrier to protein. Nicotine, unlike morphine, did not increase the nociceptive threshold (tail squeeze) of rats under the experimental conditions. It is concluded that acute, but not chronic, pretreatment with nicotine increases the sensitivity of rats to the hypnotic effects of phenobarbital and ethanol, respectively. These interactions are entirely pharmacodynamic and have no apparent pharmacokinetic component.

Animals↗

PubMedDate not supplied

An evaluation of the role of ethanol clearance rate in the differential response of long-sleep and short-sleep mice to ethanol.

Ethanol (ETOH) clearance rates were determined in Long-Sleep (LS) and Short-Sleep (SS) mice, which were selectively bred for differential soporific response to ETOH. Determination of blood ethanol levels at 45 min intervals following administration of 3.8 g/kg IP indicated that SS mice clear ETOH at a faster rate. Repeatedly sampled mice of each line cleared ETOH more slowly than those where samples were taken only once. A second experiment utilized pairs of LS and SS mice matched on body weight. These were treated with one of several doses of ETOH, and duration of loss of the righting reflex measured for one member of the pair. Blood ETOH levels were determined in samples taken from both members of the pair when the tested member regained the righting reflex. LS mice had small but consistently higher blood ETOH levels in these pairs. The magnitude of the differences between the LS and SS mice in these experiments indicate that clearance rate differences can account for only a small portion of the differences in behavioral responses of these mice to ETOH.

Animals↗

PubMedDate not supplied

The interaction of dopamine, cocaine, and cocaethylene with ethanol on central nervous system depression in mice.

The interactions between dopamine, cocaine, cocaethylene, and ethanol were studied in Swiss-Webster mice. The loss of the righting reflex (LORR) was used as a measure of CNS depression. Animals were injected intraperitoneally (IP) with ethanol (4.0 g/kg). which caused a LORR. Immediately upon regaining of the righting reflex, mice were injected intracerebroventricularly (ICV) with saline, dopamine (0.1, 0.5, or 1.0 mumol/kg), cocaine (1, 15, or 25 mumol/kg), or cocaethylene (1, 15, or 25 mumol/kg). In the presence of systemic ethanol, all three compounds produced CNS depression in a dose-dependent manner. The dopamine D2-receptor antagonist sulpiride and the D1-receptor antagonist fluphenazine were given acutely ICV with dopamine in the presence of systemic ethanol to examine whether these antagonists could block the return to the LORR produced by dopamine. Sulpiride, however, actually enhanced the interaction between ethanol and dopamine in a dose-dependent manner as measured by the LORR; fluphenazine neither blocked nor enhanced the effect of dopamine in the presence of systemic ethanol. In addition, these antagonists had no effect on cocaine- and cocaethylene-induced CNS depression in the presence of systemic ethanol. The results of this study showed that the neurotransmitter dopamine and both cocaine and cocaethylene can promote further CNS depression in the presence of systemic ethanol, and that dopamine was significantly more potent than cocaine and cocaethylene as measured by the return to the LORR.

Animals↗

PubMed2004

Role of neuroactive steroid allopregnanolone in antipsychotic-like action of olanzapine in rodents.

Olanzapine increases brain allopregnanolone (ALLO) levels sufficiently to modulate neuronal activity by allosterically regulating GABAA receptors. Recently, we reported the antipsychotic-like profile of ALLO in rodents. The present study examined the hypothesis that olanzapine-induced elevation of endogenous neurosteroid ALLO is vital for its neuroleptic-like action. The conditioned avoidance response (CAR) and apomorphine-induced climbing behavioral paradigms were used in rodents. Administration of ALLO (1 microg, intracerebroventricular (i.c.v.)) or neurosteroidogenic agents such as the mitochondrial diazepam binding inhibitor receptor agonist, FGIN 1-27 (0.5 microg, i.c.v.) or the ALLO precursor, progesterone (10 mg/kg, i.p.) significantly potentiated olanzapine-induced blockade of CAR and apomorphine-induced climbing. In contrast, these agents failed to alter the antipsychotic-like effect of risperidone and haloperidol. On the other hand, inhibition of the endogenous biosynthesis of neurosteroids by the 3beta-hydroxysteroid dehydrogenase inhibitor, trilostane (30 mg/kg, i.p.), the 3alpha-hydroxysteroid oxidoreductase inhibitor, indomethacin (5 mg/kg, i.p.), or the GABAA receptor antagonist bicuculline (1 mg/kg, i.p.) and dehydroepiandrosterone sulfate (DHEAS) (1 mg/kg, i.p.) blocked the effect of olanzapine, but not of risperidone and haloperidol. Socially isolated animals, known to exhibit decreased brain ALLO and GABAA receptor functions, displayed a shortening in the muscimol-induced loss of righting reflex and an increased susceptibility to apomorphine-induced climbing. Administration of olanzapine, but not of haloperidol and risperidone, normalized the duration of muscimol-elicited loss of righting reflex. Although all three antipsychotics proved capable of antagonizing the apomorphine-induced climbing, a dose almost five times higher of olanzapine was required in socially isolated animals. The data obtained suggest that enhancement of the GABAergic tone plays a key role in the antipsychotic-like effect exerted by olanzapine in rodents, likely as a consequence of augmented levels of neuroactive steroids, in particular ALLO, in the brain. The present findings provide the first specific behavioral evidence in support of the hypothesis that neuroactive steroid ALLO- mediated GABAergic modulation is essential for the antipsychotic-like action of olanzapine.

Animals↗

PubMed1988

Effect of intravenously-administered putative and potential antagonists of ethanol on sleep time in ethanol-narcotized mice.

Groups of male CD-1 mice (n = 12/group) were injected intraperitoneally (IP) with 5 g ethanol/kg of body weight. After loss of righting reflex, they were given vehicle or one of 2-3 doses of reputed or potential antagonists of ethanol intravenously (IV). Sleep time was measured from loss to return of righting reflex. Mean sleep time (MST) was increased significantly (P less than 0.05) by a large dose of dl-amphetamine (24 mg/kg) and by 4-aminopyridine (1, 5 mg/kg). Significant (P less than 0.01) increases were also produced by small and large doses of aminophylline (25, 100 mg/kg) and by yohimbine (1, 5 mg/kg). MST was not altered significantly by small and medium doses of dl-amphetamine (6, 12 mg/kg), a medium dose of aminophylline (50 mg/kg), or by any doses of naloxone, thyrotropin-releasing hormone, propranolol, physostigmine, doxapram, or Ro 15-4513. When Ro 15-4513 was given IP 15 minutes before ethanol (n = 6/group), onset and duration of narcosis were not altered. None of the compounds tested was an effective IV antidote for deep ethanol narcosis because of drug side effects, toxicity, prolongation of MST, or insufficient shortening of MST.

4-Aminopyridine↗

PubMed2003

Characterization of the pharmacokinetic and pharmacodynamic interaction between gamma-hydroxybutyrate and ethanol in the rat.

It has been reported that ethanol enhances the hypnotic effect of gamma-hydroxybutyrate (GHB). In order to clarify the nature of this interaction we studied the pharmacokinetics and pharmacodynamics of combinations of GHB and ethanol in rats. Intraperitoneal injections of the GHB precursor gamma-butyrolactone (300 mg/kg) together with ethanol (3000 mg/kg) (n = 4) resulted in a longer "sleeping time" than the sum of the individual times (n = 8). Pharmacokinetic analysis of GHB concentrations with a two-compartment model with Michaelis-Menten (M-M) elimination in rats receiving a bolus of GHB (400 mg/kg, i.v.) in addition to steady-state ethanol concentrations (300-3000 microg/ml) (n = 12) or saline (n = 15) showed no marked differences in the area under the curve. The nature of the pharmacodynamic interaction was studied using isobolographs and an interaction model for the loss of the startle and righting reflex and a reaction to a painful tail clamp in rats receiving combinations of steady state concentrations of ethanol (1000-3000 microg/ml) and GHB (200-1400 microg/ml). For the righting reflex, synergy was observed at high ethanol concentrations (>2000 microg/ml) and additivity at lower concentrations. For the startle reflex, it was antagonistic at ethanol concentrations below 1000 microg/ml, and additivity was seen at higher concentrations. For the tail clamp reaction, a slight but significant antagonism was found at all combined concentrations. It is concluded that ethanol prolongs the sleeping time induced by GHB in the rat, which may not be due to a pharmacokinetic interaction. Pharmacodynamic interactions between GHB and ethanol in the rat occur, and the nature varies with the reflex studied and the concentration of ethanol used.

4-Butyrolactone↗

PubMed2001

Coordinate regulation of xenobiotic and bile acid homeostasis by pregnane X receptor.

Identification and characterization of the pregnane X receptor (PXR) as a key regulator of cytochrome P450 3A (CYP3A) gene expression has led to an increased understanding of the molecular basis of many drug-drug interactions. Mice lacking PXR (PXR-KO) were used in the present study to delineate the role of PXR in regulating hepatomegaly and regulating the activity of CYP3A, organic anion transporting polypeptide-2 (Oatp2), and Cyp7a1 (cholesterol 7alpha-hydroxylase) gene products in vivo. Pregnenolone-16alpha-carbonitrile (PCN) produced hepatomegaly in the wild-type mice but not in the PXR-KO mice. PCN increased both the number of proliferating cell nuclear antigen immuno-positive nuclei and apparent cell size in the wild-type mice but not in the PXR-KO mice. To determine the role PXR plays in regulating CYP3A activity, 6beta-hydroxylation of testosterone and the duration of the loss of righting reflex following administration of the muscle-relaxant zoxazolamine were measured. PCN increased the level of testosterone 6beta-hydroxylation and decreased the duration of the loss of righting-reflex time following zoxazolamine administration in wild-type mice, but did not effect either of these parameters in PXR-KO mice. PCN increased the hepatic uptake of [(3)H]digoxin, an Oatp2 substrate, in wild-type mice but not in the PXR-KO mice. Similarly, PCN decreased bile acid excretion in wild-type mice but not in the PXR-KO mice. Taken together, these data demonstrate a pivotal role for PXR in the regulation of drug-induced hepatomegaly and in the metabolism (CYP3A), transport (Oatp2), biosynthesis (Cyp7a1), and excretion of xenobiotics and bile acids in vivo.

Animals↗

PubMed1993

The behavioral reactions of a snake and a turtle to abrupt decreases in gravity.

We report here on the behavioral reaction of two reptiles to abrupt decreases in gravity. One striped rat snake, Elaphe quadrivirgata, and three striped-neck pond turtles, Mauremys japonica, were exposed to microgravity on parabolic flight, during the filming of a documentary for the NHK television station in Japan. The video films revealed that the snake reflexively responded to the shift from hyper- to hypogravity by taking up a defensive posture--on the first parabola, the snake struck at itself. The turtles actively extended their limbs and hyper-extended their neck in microgravity, a posture which is identical to the displayed during their contact "righting reflex", when placed upside-down in normal gravity. The aggressive display of the snake was unexpected, although the righting response of the turtles was consistent with that shown by other vertebrates, including fish and mammals, exposed to microgravity. An implication of these observations is that the afferent signal for the righting reflex of vertebrates in normal gravity must be the unloading of ventral receptors in the sensory system, rather than the loading of dorsal receptors. These are the first behavioral records for any reptiles exposed to hypogravity.

Aggression↗

PubMed1980

An evaluation of the selectivity of fenmetozole (DH-524) reversal of ethanol-induced changes in central nervous system function.

The selectivity and specificity of fenmetozole (DH-524) [2(3,4-dichlorophenoxy-methyl)2-imidazole HCl] as an antagonist of the actions of ethanol were examined. Fenmetozole (15--30 g/kg) reduced ethanol-induced impairment of the aerial righting reflex without changing blood or brain ethanol content, indicating that the antagonistic actions of fenmetozole were not de to change in the pharmacokinetics of ethanol. Since fenmetozole also reduced aerial righting reflex impairment due to phenobarbital, chlordiazepoxide, and halothane, this action of fenmetozole was not specific to ethanol. In mice, both the ethanol-induced increase in locomotor activity at 2.0 g/kg and the decrease caused by 4.0 g/kg were antagonized by fenmetozole. In addition, fenmetozole attenuated the ethanol-induced reduction in cerebellar cyclic guanosine monophosphate (cGMP) content, but the drug also significantly elevated cGMP levels in this tissue when given alone. Fenmetozole did not alter ethanol-induced increases in punished drinking in a conflict test, except at a high dose which alone decreased both punished and unpunished responding. Fenmetozole also failed to precipitate ethanol withdrawal-like reactions when given to physically-dependent, intoxicated rats. Thus, the antagonistic action of fenmetozole against ethanol would not seem to be related to a specific receptor interaction but rather may be the result of a physiological antagonism.

Acoustic Stimulation↗

PubMed1980

Diazepam under hyperbaric conditions in rats.

The effect of diazepam, expressed as loss of the righting reflex, in 60 adult rats compressed with oxygen/helium to 90 ATA was compared to 18 diazepam-treated rats at 1 ATA. A marked pressure reversal of the loss of righting reflex was found. Convulsions provoked by high helium pressure were prevented by diazepam and the symptoms of High Pressure Nervous Syndrome (HPNS) were reduced.

Anesthetics↗

PubMed1991

[Interaction of the hypnotic lormetazepam with central benzodiazepine receptor subtypes omega 1, omega 2 and omega 3].

To clarify the action of lormetazepam, 3-hydroxybenzodiazepine, on the benzodiazepine (BZ) receptor subtypes, effects of lormetazepam on motor performance in the traction test and hexobarbital-induced loss of righting reflex in mice and the binding to BZ receptor subtypes were investigated in comparison with those of other BZ hypnotics. Lormetazepam prolonged the duration of hexobarbital-induced loss of righting reflex. The minimal effective dose (1 mg/kg, p.o.) was higher than that of flunitrazepam, lower than those of diazepam and zopiclone, and the same as those of triazolam and brotizolam. Lormetazepam showed the ataxic effect at 10 mg/kg, p.o., but the separation between its effective doses for the hypnotic and ataxic effects was the largest among the hypnotics tested. In the displacement study on [3H]flumazenil binding to cerebellar and spinal cord membranes, lormetazepam bound with a higher affinity to omega 1 receptor (Ki = 10 nM) than to omega 2 receptor (Ki = 29 nM). The GABA-ratios of lormetazepam to omega 1 and omega 2 receptors were 3.9 and 4.0, respectively; and they were higher and lower than those of flunitrazepam to omega 1 and omega 2 receptors, respectively. In the displacement study on [3H] Ro5-4864 binding to kidney membranes, lormetazepam bound with a lower affinity to the omega 3 receptor (Ki = 213 nM) than flunitrazepam. Thus, lormetazepam was suggested to be a potent hypnotic with weaker ataxic effects than other BZ hypnotics, which may be due to its selective and potent agonistic action on central omega 1 receptors.

Animals↗

PubMed1997

The influence of nicardipine and ifenprodil on the brain free arachidonic acid level and behavior in hypoxia-exposed rats.

1. The effects of the calcium channel blockers, nicardipine and ifenprodil, on the brain free arachidonic acid level and learning ability in rats exposed to hypoxia were examined. 2. Adult rats were injected with 0.003; 0.01; 0.03; 0.1; 0.3 or 1.0 mg/kg of tested drugs i.p. Thirty min later the learning ability was tested in a passive avoidance task according to the step-through procedure. Immediately after the training trial, the animals were subjected to a period of oxygen deprivation hypoxia until the loss of the righting reflex. The retention trial was carried out 24 hr later. 3. The other groups of animals were pretreated with mentioned substances before hypoxia-exposure. Fifteen min after the loss of the righting reflex they were decapitated and brains were frozen in liquid nitrogen. The brain free arachidonic acid level was quantified by gas chromatography. 4. Both nicardipine and ifenprodil were effective in preventing a memory decline in hypoxia-exposed rats but did not prevent the accumulation of the brain free arachidonic acid in hypoxia-exposed rats. 5. The protective effects of both substances in behavioral studies during acute brain damage caused by hypoxia could not be explained by the prevention of the increase of the brain free arachidonic acid, but by some other mechanism.

Animals↗

PubMed1983

An evaluation of tribromoethanol (TBE) as an anaesthetic agent in the Mongolian gerbil (Meriones unguiculatus).

Mongolian gerbils injected i.p. with a 1.25% solution of tribromoethanol (TBE) quickly lost the righting reflex and showed good surgical anaesthesia, the duration of which was positively related to the dose administered. All levels (225-450 mg/kg bodyweight) of TBE injected s.c. resulted in loss of the righting reflex, though surgical anaesthesia was not attained. Following recovery from anaesthesia induced with 2.25% TBE i.p., or high doses of 1.25% TBE i.p., visceral adhesions and deaths occurred. To avoid these TBE-induced fatalities such extreme care must be taken during the preparation, storage and administration of the agent that it is not recommended as a suitable anaesthetic for general use in the gerbil.

Anesthesia, General↗

PubMed2002

Hypnotic activity of melatonin: involvement of semicarbazide hydrochloride, blocker of synthetic enzyme for GABA.

AIM: To assess the effect of semicarbazide hydrochloride (SCZ), the blocker of synthetic enzyme for GABA, on the hypnotic activity of melatonin. METHODS: Righting reflex method in mice and electroencephalography (EEG) in rats were used to determine effects of SCZ on sleep and hypnotic activity of melatonin. RESULTS: Melatonin displayed a marked hypnotic activity both in righting reflex experiment and EEG recording. SCZ had no influence on sleep parameters in mice and rats when it was used alone. However, it blocked the sleep-potentiation effect of melatonin in mice. SCZ also inhibited melatonin-induced increase in total sleep time, slow wave sleep time, and paradoxical sleep time, and prevented melatonin-induced decrease in awake time in rats. CONCLUSION: SCZ antagonized the hypnotic activity of melatonin. It is thought that the hypnotic activity of melatonin is mediated by GABAergic system.

Animals↗

PubMed1992

Effects of atipamezole, an alpha 2-adrenoceptor antagonist, on the anesthesia induced by barbiturates and medetomidine.

We studied the effects of atipamezole, an alpha 2-adrenoceptor antagonist, on hypnosis induced by medetomidine, an alpha 2-adrenoceptor agonist (1 mg/kg IP), and pentobarbital (40 mg/kg IP) by testing the righting reflex in the rat. The duration of antinociception was assessed with repeated pinch tests. Medetomidine-induced hypnosis and antinociception were inhibited by atipamezole at doses greater than 0.1 mg/kg. Atipamezole restored the righting reflex at a dose ratio that was 1:10 or more to that of medetomidine used to induce hypnosis. Subcutaneous atipamezole (1.5 mg/kg) increased the duration of hypnosis induced by pentobarbital (40 mg/kg) and pentobarbital + medetomidine (0.3 mg/kg). Hypnosis induced by methohexital (60 mg/kg IP) was also prolonged by atipamezole. The capacity of atipamezole to reverse the effects of medetomidine is also reduced in the presence of barbiturates. Thus, atipamezole should be used only at low doses to reverse a combination anesthesia induced by barbiturates and medetomidine.

Adrenergic alpha-Antagonists↗