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PubMed1996

Correlated responses to selection in FAST and SLOW mice: effects of ethanol on ataxia, temperature, sedation, and withdrawal.

A replicated bidirectional selective breeding program has produced lines of mice that differ in locomotor response to ethanol (EtOH). FAST mice were bred for high locomotor activation, whereas SLOW mice were bred for low or depressed locomotor activity in response to 2.0 g/kg of EtOH. We tested FAST and SLOW mice for differences in sensitivity to the incoordinating (1.5 to 2.5 g/kg), hypothermic (3.0 g/kg), and sedative (4.0 g/kg) effects of EtOH, and for differences in sensitivity to withdrawal after acute and chronic EtOH exposure. SLOW mice were more ataxic in a grid test and developed greater tolerance than FAST mice at 2.0 g/kg of EtOH, were more hypothermic than FAST mice, and were more sensitive to the sedative effects of EtOH than FAST mice, as measured by latency to and duration of loss of righting reflex, and by blood ethanol concentrations at regain of the righting reflex. FAST mice had more severe withdrawal seizures after chronic exposure, but did not differ from SLOW mice in withdrawal severity after an acute injection of EtOH. These data suggest that FAST mice are generally more sensitive to central nervous system excitation, and SLOW mice are generally more sensitive to central nervous system sedation by EtOH, and further suggest genetic overlap with respect to genes that mediate locomotor responses to EtOH and genes determining sensitivity to EtOH-induced ataxia, hypothermia, sedation, and withdrawal severity after chronic exposure. Our current observations are in contrast to observations made earlier in selection, in which few line differences in sensitivity to EtOH effects other than locomotor activity were found. Thus, it seems that continued selection for differences in locomotor response to EtOH has produced genetically correlated differences in other EtOH responses.

Alcohol Drinking↗

PubMed2001

Neurotensin levels in specific brain regions and hypnotic sensitivity to ethanol and pentobarbital as a function of time after haloperidol administration in selectively bred rat lines.

Evidence indicates that sensitivity to ethanol is a good predictor of the development of alcoholism. Thus, identification of neuronal processes that regulate ethanol sensitivity has been the subject of much recent research. The present studies were designed to further test the hypothesis that neurotensinergic processes mediate, in part, hypnotic sensitivity to ethanol. Single doses of haloperidol were administered to lines of rats [selectively bred for high and low sensitivity (HAS and LAS, respectively) to hypnotic effects of ethanol] to produce increases in neurotensin (NT) levels in brain regions. At 20 h after administration, haloperidol produced dose-dependent increases in NT immunoreactivity levels in nucleus accumbens (NA) and caudate putamen (CP) in both HAS and LAS lines. Levels of NT in NA and CP returned to control values at 48 h after 4 mg/kg haloperidol. These studies used two measures of hypnotic sensitivity to ethanol: duration of loss of righting reflex (sleep time) and blood ethanol concentration at regain of righting reflex (BECRR). At 20 h, but not 48 h, after haloperidol treatment, both HAS and LAS rats displayed increases in ethanol-induced sleep time with concomitant decreases in BECRR. Pentobarbital-induced sleep time was not increased 20 h after administration of 4 mg/kg haloperidol; however, hypnotic sensitivity to both pentobarbital and ethanol was increased by acute (30-min) pretreatment with 1 mg/kg. These results suggest that NT levels in NA, acting via NT receptors, enhance hypnotic sensitivity to ethanol, but not pentobarbital.

Alcoholic Intoxication↗

PubMedDate not supplied

Body temperature and ethanol pharmacokinetics in temperature-challenged mice.

The relationships between ambient temperature, body temperature, ethanol pharmacokinetics and behavioral sensitivity to ethanol were examined in C57BL/6 mice. Mice were injected intraperitoneally with 3.6 or 2.0 g/kg ethanol. Exposure to increasing ambient temperatures of 4-34 degrees C immediately after ethanol injection resulted in a significant increase in body temperature, ethanol elimination rate and brain:blood ethanol concentration ratios in 3.6 g/kg ethanol-injected mice, but not in mice injected with 2.0 g/kg ethanol. As the mean body temperature increased from 26.0 to 38.2 degrees C in the 3.6 g/kg mice, there was a 50% increase in ethanol elimination rate. Delayed (30 min) exposure to increasing ambient temperatures following injection of 3.6 g/kg ethanol resulted in a significant increase in ethanol elimination rate, a marked increase in the duration of loss of righting reflex and a decrease in ethanol concentration at the regain of righting reflex. The results indicate that temperature-induced changes in the absorption, distribution and elimination of ethanol do not appear to mediate the effects of temperature on behavioral sensitivity to ethanol in C57 mice.

Animals↗

PubMed1992

Ketamine/xylazine/butorphanol: a new anesthetic combination for rabbits.

Ketamine is often used in combination with tranquilizers to produce surgical anesthesia in rabbits. While generally effective, there is considerable variation in the depth and duration of anesthesia achieved with ketamine combinations. Butorphanol is a mixed agonist-antagonist opioid that is widely used in a variety of other species. In this study, the commonly used ketamine (35 mg/kg)/xylazine (5 mg/kg) combination is compared with ketamine (35 mg/kg)/xylazine (5 mg/kg)/butorphanol (0.1 mg/kg). Rabbits were anesthetized on consecutive weeks with one of the two regimens. Physiologic parameters including heart rate, respiratory rate, blood pressure and arterial blood gases (pH, PO2, PCO2) were measured throughout anesthesia. Loss of palpebral, pedal and righting reflexes were recorded and reflexes were subsequently evaluated. The addition of butorphanol prolonged reflex loss to 140% (X = 68 min +/- 20 SEM) of control for palpebral reflex; 506% (X = 52 min +/- 18 SEM) of control for pedal reflex; and 159% (X = 128 min +/- 21 SEM) of control for righting reflex. Addition of butorphanol to ketamine/xylazine resulted in mild alterations in the physiologic changes traditionally associated with this combination. Butorphanol can be safely added to the ketamine/xylazine combination in rabbits and results in moderate increases in the duration of reflex loss.

Anesthesia↗

PubMed1988

Nitrogen dioxide exposure alters neonatal development.

Nitrogen dioxide (NO2) is one of the commonly encountered environmental contaminants. Experiments were carried out to test for neonatal behavioral alterations associated with prenatal NO2 exposure. Pregnant CD-1 mice were exposed in environmental chambers to 0, 22, or 45 ppm of NO2 in air from gestation day 7 to 18. The gas-air flow was set at 450 ml/min. Food and water were available at all times. The dams were allowed to deliver and neonatal behavioral development of the pups was studied. Nitrogen dioxide exposure did not affect the number of live pups born/litter; however, it significantly decreased their birth weight. Prenatal NO2 exposure at both levels significantly altered the righting reflex and aerial righting score of the pups on postnatal days 1 and 12, respectively. Prenatal NO2 exposure did not affect negative geotaxis and activity scores of pups on postnatal day 10 and 28, respectively. The data suggest that maternal NO2 exposure at low levels can affect neuromuscular coordination and thus produce deficits in the functional capability of the offspring.

Animals↗

PubMed1994

Effects of prenatal exposure to 50 Hz magnetic fields on development in mice: II. Postnatal development and behavior.

To investigate the potential of magnetic fields to act as a behavioral teratogen, pregnant CD1 mice were exposed or sham-exposed for all of gestation to a 50 Hz/20 mT magnetic field. Maturation of offspring was assessed using a range of standard developmental indices (eye opening, pinna detachment, hair coat, tooth eruption, sexual maturity, and weight) and simple reflexive behaviors (air righting, surface righting, forepaw grasp, cliff avoidance, and negative geotaxis). Activity and coordination levels were explored in juvenile and adult mice using an open field arena, a head-dip board, an accelerating Rotarod, and a residential activity wheel. All assessments were carried out without knowledge of exposure condition. Results from 168 sham-exposed mice from 21 litters and from 184 exposed mice from 23 litters were compared using survival analysis techniques and multivariate regression methods. Three possible field-dependent effects were found: Exposed animals performed the air righting reflex earlier (P < 0.01); exposed males (but not females) were significantly lighter in weight (P = 0.008) at 30 days of age; and exposed animals remained on a Rota-rod for less time as juveniles (P = 0.03). Some of these results have not been reported in other studies and may reflect spurious statistical significance, although some effect of magnetic field exposure cannot be ruled out. Overall, these results suggest that prenatal exposure to a 50 Hz magnetic field does not engender any gross impairments in the postnatal development or behavior of mice. This does not preclude such exposure affecting more subtle aspects of behavior.

Animals↗

PubMedDate not supplied

Potential of neurotoxicity after a single oral dose of 4-bromo-, 4-chloro-, 4-fluoro- or 4-iodoaniline in rats.

The potential for neurotoxicity after a single oral dose of four halogenated aniline derivatives--4-bromoaniline (4-BA), 4-chloroaniline (4-CA), 4- fluoroaniline (4-FA) and 4-iodoaniline (4-IA)--was given to rats was investigated at or near the lethal dosage level. Hindlimb paralysis was found in the 4-BA, 4-CA and 4-FA groups on clinical observation, with the maximum incidence of 100% in the 4-BA and 4-FA groups and 66.7% in the 4-CA group. Detailed clinical observations with functional tests identified the following effects: reduced response of hindlimb extensor thrust, gait abnormality in the open field and decreased grip strength in the fore- or hindlimbs in the 4-BA, 4-CA and 4-FA groups; decreased number of supported rearing episodes in the open field in the 4-BA and 4-CA groups; abnormal landing in the aerial righting reflex in the 4-BA and 4-FA groups; and prolonged surface righting reflex in the 4-BA group. Spongy change in the white matter of the spinal cord and brainstem and nerve fibre degeneration in the peripheral nerves were found in all haloaniline-treated groups. The central and peripheral nervous systems were most severely affected in the 4-BA group and the lesions in the 4-IA group were limited in grade. This study demonstrates that a bolus dose of 4-haloanilines to rats induces a neurotoxicity similar in character to that evoked by the parent aniline. The decreasing order of neurotoxic potential appears to be 4-BA >> 4-FA > or = 4-CA >> 4-IA when comparing at or near the lethal dosage level.

Administration, Oral↗

PubMed1987

Deleterious effects of adrenocorticotrophic hormone administration during late pregnancy upon offspring somatic, neurological, and sexual development in mice.

The influence of administration of adrenocorticotrophic hormone (ACTH) during days 12-17 of pregnancy upon somatic, neurological, and neuromuscular development of offspring in mice was studied. The effects upon the onset of puberty in female offspring was also examined. Litters from mice given the higher of two doses of ACTH (1 IU/day or 8 IU/day) showed lower body weights at birth and weaning than controls. This treatment also increased pre- and postnatal mortality rates, although not significantly. Litters from mice treated with either dose of ACTH showed retarded development of the forelimb and hindlimb grasp reflexes, the body righting reflex, the auditory startle response, and eye opening. Although ear opening was delayed in litters from ACTH-treated mice, results did not achieve statistical significance. Study of female offspring housed in small groups revealed that one indicator of puberty, vaginal opening, was delayed in female offspring of ACTH-treated mice. Experiments were conducted to identify factors mediating this syndrome: ACTH did not depress maternal food intake or alter the length of pregnancy, therefore fetal undernutrition or premature birth can be excluded as mediating factors. All litters were fostered to untreated mice to control for postnatal factors influencing development. As ACTH cannot cross the placenta, the syndrome is likely to result from in utero exposure to abnormally high concentrations of glucocorticosteroids of maternal origin. It is concluded that such alterations to the fetal environment can exert a deleterious influence upon somatic, neurological, and sexual development, and that hormones of the maternal pituitary-adrenocortical axis may naturally act to regulate general development of the fetus.

Adrenocorticotropic Hormone↗

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↗

PubMed1984

Long term alterations in the excitability of the flexion reflex produced by peripheral tissue injury in the chronic decerebrate rat.

Chronic decerebrate rats have been prepared by the aspiration of all the cranial contents rostral to the mesencephalon. With careful nursing, body temperature control and orogastric tube feeding the rats survive for up to 4 months. The decerebrate rats have intact brain stem and spinal reflexes including locomotion, righting reflexes and grooming. Mild noxious cutaneous thermal and mechanical stimuli of an intensity which does not produce tissue damage evokes flexion withdrawal reflexes, vocalization, orientation to the site of the injury and generalized escape or attack responses, from the animals. These effects are transient and only occur during the application of the stimulus. The rats do not exhibit stress reactions, aggression or vocalization when handled before or after application of such noxious stimuli. The production of localized tissue injury by thermal or chemical means results in long term alterations (up to 6 weeks) in the thresholds and excitability of the flexor reflex, both ipsilateral and contralateral, to the site of the injury. It is proposed that the reduction in the flexor reflex threshold is analogous to the hyperalgesia and allodynia that follows tissue injury in man and that the long term alterations in the flexor reflex in the chronic decerebrate rat provide a model for the study of chronic pain, without the ethical problems associated with such studies in intact animals.

Afferent Pathways↗

PubMedDate not supplied

Developmental alterations of ethanol sensitivity in selectively bred high and low alcohol sensitive rats.

Initial sensitivity and acute tolerance to ethanol have been implicated as risk factors in the development of alcoholism in humans. These behaviors were investigated in rats selectively bred for differences in hypnotic sensitivity following their first dose of ethanol in two different experiments. In Experiment 1, developmental profiles of the association between initial sensitivity and acute tolerance induced by a single exposure to ethanol were examined using male and female high, low, and control alcohol sensitive (HAS, LAS, and CAS) rats. Dose-response curves were constructed for duration of the loss of the righting reflex and for blood ethanol concentration (BEC) at the regain of the righting reflex. Animals were tested with a single ethanol dose ranging from 1.5 to 5.0 g/kg at either 15, 25, 40, 70, 120, or 180 days of age (DOA). For each group, acute tolerance to ethanol was estimated by the slope of the regression line using dose of ethanol and mean BEC at regain. In general, all rat lines showed an increase in hypnotic sensitivity to ethanol with age. To a large degree, the lower sensitivity observed in 15 and 25 DOA HAS and LAS rats was associated with an increase in the development of acute ethanol tolerance relative to older rats. Divergence of the LAS and CAS lines was evident by 25 DOA and remained stable with advancing age. However, HAS rats did not differ significantly from CAS rats until 40 DOA, after which the magnitude of the difference continued to increase with age. In Experiment 2, rats were treated with alcohol at 25, 70, or 180 DOA. Rats at 70 or 180 DOA required less ethanol to disrupt their motor coordination on a rotating dowel (rotarod). Blood ethanol levels were determined at the loss and subsequent regain of the ability to negotiate the rotarod. Total duration of inability to negotiate the rotarod also was recorded. HAS rats were less able to remain on a rotarod while under the influence of alcohol relative to LAS and CAS rats regardless of age. However, no evidence of acute tolerance was observed in this experiment and, in fact, there was evidence of reverse tolerance in that all animals had lower BEC values at regain of ability than they did at loss.

Age Factors↗

PubMed1978

Primitive reflex profile. A pilot study.

Seven primitive reflexes used by physical and occupational therapists in evaluating children with cerebral palsy were each graded on a 0 to 4+ scale to constitute a Primitive Reflex Profile. The reflexes studied were the asymmetrical tonic neck reflex, the symmetrical tonic neck reflex, the tonic labyrinthine reflex, the positive support reflex, the derotational righting reflex, the Moro reflex, and the Galant reflex. The Primitive Reflex Profile was studied in 53 cerebral palsied patients to assess both the feasibility of its administration and its usefulness in discriminating functional levels of ambulation. The Primitive Reflex Profile was administered by at least two members of a team consisting of four pediatric developmentalists and two physical therapists. In using this instrument, the extreme functional groups were clearly defined and showed the expected overlap with the intermediate classification.

Adolescent↗

PubMed1989

Comparison of anaesthetic and kinetic properties of thiobutabarbital, butabarbital and hexobarbital after intravenous threshold doses in the male rat.

Due to the exceptionally long duration of action of thiobutbarbital the anaesthetic properties of this barbiturate was reinvestigated with an intravenous threshold technique using butabarbital and hexobarbital as references. Adult male rats were used. The criterion of anaesthesia was a burst suppression in the EEG of 1 sec. or more (the "silent second" = SS). The dose which induced the criterion was used as a threshold. The barbiturates were infused with different rates to obtain dose rate curves. After induction of the threshold criterion the animals were either killed and different tissue concentrations were analyzed with a HPLC method or allowed to survive and duration of SS and duration of loss of righting reflex were recorded. With hexobarbital, duration of SS and of loss of righting reflex increased significantly with increasing dose rate. With increasing rates of thiobutabarbital and butabarbital there was in both cases a stepwise increase in duration of SS. At sacrifice, after induction of SS with slow rates brain concentrations of both thiobutabarbital and butabarbital were lower than values recorded after higher rates. The change between the two concentrations was abrupt and occurred at a rate of 20 mg/kg/min. with thiobutabarbital and at the rate of 1.25 mg/kg/min. with butabarbital. This phenomenon was the reverse of acute tolerance which was recorded with hexobarbital and can thus be denoted acute supersensitivity. A kinetic analysis of serum, muscle and fat indicated considerable differences between the barbiturates. As indicated by mortality figures the induction of acute supersensitivity could be potentially dangerous.

Anesthetics↗

PubMed1987

Barbiturates inhibit stress-induced analgesia.

The effect of pentobarbitone and thiopentone on stress-induced analgesia was studied in 40 male Sprague-Dawley rats. Antinociception was determined by measuring motor reaction threshold to the noxious pressure on the tail with the use of an "Analgesymeter." Stress was induced by placement of a clamp on the hind paw. The stress procedure was found to cause an increase in reaction threshold, which was partially suppressed by naloxone 0.5 mg X kg-1. Pentobarbitone in a subanaesthetic dose of 25 mg X kg-1, SC, almost completely abolished the stress-induced increase in the reaction threshold (an increase in reaction threshold from 329 +/- 33 g to 486 +/- 62 g in control group, and from 250 +/- 26 g to 273 +/- 35 g in pentobarbitone group, p less than 0.02 for the difference in the threshold changes). Thiopentone used in a dose of 25 mg X kg-1, IV, caused a loss of the righting reflex for 37 +/- 10 minutes; stress procedure applied ten minutes after regaining the righting reflex did not cause any increase in the reaction threshold (with an increase in the reaction threshold in control group from 355 +/- 50 g to 540 +/- 26 g, p less than 0.001 for the difference between the groups). The results suggest that the barbiturates in subanaesthetic doses inhibit stress-induced analgesia. Thiopentone used in an anaesthetic dose has the potential for inhibition of stress-induced analgesia in the period of recovery from anaesthesia.

Animals↗

PubMed1983

Increased responsiveness to ethanol with advancing age in rats.

Male CD strain rats of three different ages (young-5 months; middle-15 months; old-27 months) were tested for their responsiveness to doses of ethanol sufficient to produce hypothermia or hypnosis. Comparison dosages of ethanol across age groups were based upon the estimated equivalent dilution of the drug into the body water compartments of subjects. In the hypnosis study, there were no statistically significant differences among the groups with regard to the time elapsed until the righting reflex was lost or in total sleep time. However, old animals recovered the righting reflex in the presence of lower blood ethanol concentrations than those observed for young and middle animals, suggesting a greater sensitivity of target tissues to the hypnotic effects of ethanol in old rats. The responsiveness of old rats to the hypothermic effect of ethanol was greater than that of younger rats only when the experiment was conducted at an ambient room temperature of 10 degrees C.

Aging↗

PubMedDate not supplied

Absence of acute tolerance to ethanol hypnosis in F-344 and BN/BIRIJ rats.

Male Fischer 344 (F-344) rats of three different ages (4, 13, and 25 months) and male Brown Norway (BN/BIRIJ) rats (4 months) were injected (IP) with a hypnotic dose of ethanol (3.0 g/kg, 10% w/v in saline). Half of the animals were decapitated and brains extracted immediately upon loss of the righting reflex (LRR), while the other half were allowed to reach recovery of the righting reflex (RRR), at which time brains were extracted. Brain alcohol analyses revealed significantly higher concentrations in young F-344 rats at both LRR and RRR, indicating less sensitivity of target tissue to ethanol hypnosis in the young of that strain. All age groups of the F-344 rats as well as the young BN/BIRIJ rats displayed lower brain concentrations of ethanol at RRR than at LRR, a finding opposite to that characteristic of acute tolerance. The relationship of LRR to RRR values did not differ among the age groups of F-344 rats. We conclude that the F-344 and BN/BIRIJ strains do not develop acute tolerance to ethanol hypnosis. The findings are consistent with the hypothesis that animals with low ethanol preferences, such as the F-344 and BN/BIRIJ strains, also have low capabilities to develop acute tolerance to ethanol hypnosis.

Aging↗

PubMed1994

Pharmacological profile of the novel putative anxiolytic agent 1-amino-5-bromouracil.

The newly synthesized compound, 1-amino-5-bromouracil (ABU, CAS 127984-93-4), showed unique anxiolytic activity in rats and mice. Its minimum effective dose was 10 mg/kg p.o. in the Geller type conflict test in rats, and it showed anxiolytic activity at a dose of 20 mg/kg i.p. in the Vogel type conflict test in mice. ABU also induced loss of the righting reflex in mice. The ED50, a dose level that induces loss of the righting reflex in 50% of mice, was 86.4 mg/kg p.o. On the other hand, ABU showed only weak activities both potentiating the drug-induced anesthesia and myorelaxing in comparison with diazepam. Furthermore ABU did not show an affinity for benzodiazepine receptor. Thus, the pharmacological profile of ABU is concluded to be different from that of diazepam.

Anesthetics↗

PubMed1997

Evaluation of five agents/methods for anesthesia of neonatal rats.

Although neonatal altricial rodents are frequently used in experimental projects in which they must undergo survival surgical procedures, there are few published guidelines for anesthetizing them. Many of the drugs and methods that are commonly used to anesthetize newborn rodents provide inadequate anesthesia or are associated with problems, such as excessively high mortality. A two-part study was undertaken with the intention of identifying agents or methods that can be used to provide humane, safe, and effective anesthesia for neonatal rats. In part I, 1- to 3-day-old rat pups were anesthetized with methoxyflurane or one of several injectable agents, or by induction of hypothermia (immersion in ice water). Times to loss of the righting reflex, surgical anesthesia (indicated by loss of the pedal reflex and failure to respond to a skin incision), and recovery of the righting reflex were measured, and heart rate, respiratory rate, and oxygen saturation were monitored. Ketamine (100 mg/kg of body weight, i.p.), pentobarbital (30 to 40 mg/kg, i.p.), and fentanyl-droperidol combination (0.16 mg of fentanyl and 8.0 micrograms of droperidol/g, i.p.) proved unsafe (> 50% mortality) and/or ineffective at inducing short-term surgical anesthesia. In contrast, methoxyflurane and hypothermia were safe and effective. On the basis of subjective observations that they struggled and vocalized less, pups placed in protective latex sleeves prior to immersion in ice water appeared to be less distressed than pups immersed unprotected. In part II of the study, it was possible to safely maintain 1- to 3-day-old pups at a surgical plane of anesthesia for 30 min with either methoxyflurane or hypothermia. Supplementation with pentobarbital (20 mg/kg, i.p.) offered no advantages but significantly prolonged time to recovery. Surviving pups in both studies grew at similar rates during the month after testing. It was concluded that methoxyflurane or hypothermia are good choices for short- or long-term anesthesia of neonatal rats, and that use of a protective sleeve appears to reduce distress associated with induction of profound hypothermia.

Anesthesia, General↗