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At least 19 recordsLinked to original sources

PubMed1987

Flurothyl seizure thresholds in mice treated neonatally with a single injection of monosodium glutamate (MSG): evaluation of experimental parameters in flurothyl seizure testing.

Monosodium glutamate (MSG) administration to neonatal rodents produces convulsions and results in numerous biochemical and behavioral deficits. These studies were undertaken to determine if neonatal administration of MSG produced permanent alterations in seizure susceptibility, since previous investigations were inconclusive. A flurothyl ether seizure screening technique was used to evaluate seizure susceptibility in adult mice that received neonatal injections of MSG (4 mg/g and 1 mg/g). MSG treatment resulted in significant reductions in whole brain weight but did not alter seizure threshold. A naloxone (5 mg/kg) challenge was also ineffective in altering the seizure thresholds of either control of MSG-treated mice. Flurothyl ether produced hypothermia which was correlated with the duration of flurothyl exposure; however, the relationship of hypothermia to seizure induction was unclear. Flurothyl seizure testing proved to be a rapid and reliable technique with which to evaluate seizure susceptibility.

Animals↗

PubMed1998

Decreased brainstem seizure thresholds and facilitated seizure propagation in mice exposed to repeated flurothyl-induced generalized forebrain seizures.

We recently have described a novel model of epileptogenesis utilizing the inhalant chemoconvulsant, flurothyl (Applegate et al., 1997; Samoriski and Applegate, 1997). The hallmark feature of this model is a change in behavioral seizure phenotype from a forebrain seizure, observed during the initial flurothyl exposures, to a brainstem seizure, elicited by flurothyl, after a 28-day stimulation free incubation period. In this study, we sought to establish the basis for this change in behavioral seizure response. To this end, we examined the effects of exposure to this paradigm on the generalized brainstem seizure threshold and on the propagation of forebrain seizures onto the brainstem seizure substrate. Ten mice were given flurothyl-induced generalized forebrain seizures on 8 consecutive days (induction phase). The other ten mice were not exposed to the flurothyl induction paradigm and served as controls. Minimal corneal electroconvulsive shock (mECS--20 mA) was used to assay whether there was any change in the animals' generalized brainstem seizure thresholds at 3, 14 and 28 days following the last flurothyl seizure trial. Mice that were exposed to flurothyl exhibited a progressive increase in the percentage of animals having a mECS-induced brainstem seizure when tested at 3 (40%), 14 (70%) and 28 (90%) days following the last flurothyl seizure. Control mice rarely had a brainstem seizure at any of the three time points tested, mostly forebrain seizures were observed. These results suggest that there is a significant progressive lowering of the brainstem seizure threshold, during the incubation phase of the flurothyl paradigm, which is coincident with the previously reported time course of change in the behavioral seizure phenotype observed using this flurothyl model (Applegate et al., 1997; Samoriski and Applegate, 1997). Following mECS testing, mice were implanted with bipolar electrodes and kindled from the olfactory bulb (OB). Mice exposed to the flurothyl paradigm demonstrated significantly faster kindling rates, longer afterdischarge durations. and longer durations of and latencies to stage 5 seizures compared to controls. Furthermore, animals exposed to the flurothyl protocol demonstrated an increase in the expression of brainstem seizures after focally-elicited OB afterdischarges. These results suggest that there is an increased interaction between the forebrain and brainstem seizure systems after exposure to this model of epileptogenesis. Together, results indicate that the change in behavioral seizure phenotype observed following exposure to our flurothyl paradigm are promoted by both decreases in brainstem seizure thresholds and facilitated forebrain seizure propagation onto the brainstem seizure system.

Animals↗

PubMed1978

Repeated exposure of rats to the convulsant agent flurothyl enhances 5-hydroxytryptamine- and dopamine-mediated behavioural responses.

1 Rats were convulsed once daily for 7 days by exposure to the inhalant convulsant agent, flurothyl (Indoklon, bis (2,2,2-trifluouroethyl)ether). Twenty four hours after the final convulsion the rats were injected with tranylcypromine (20 mg/kg) followed 30 min later by L-DOPA (50 mg/kg), a procedure which increases brain dopamine concentrations. The flurothyl-treated rats showed a greater locomotor activity response than rats that had not been convulsed.2 This enhanced response appears to be due to increased postsynaptic dopamine receptor sensitivity since flurothyl-treated rats also showed enhanced locomotor responses to methamphetamine (2 mg/kg) and apomorphine (2 mg/kg).3 Enhanced 5-hydroxytryptamine-induced activity responses following administration of tranylcypromine (20 mg/kg) and L-tryptophan (50 mg/kg) were also seen 24 h after the last of 10 daily flurothyl-induced convulsions.4 The increased 5-hydroxytryptamine response also appears to be due to increased postsynaptic sensitivity since the flurothyl-treated rats showed increased hyperactivity following administration of tranylcypromine (20 mg/kg) and the suggested 5-hydroxytryptamine agonist, 5-methoxy N,N-dimethyltryptamine (2 mg/kg).5 No change in the brain concentration of 5-hydroxytryptamine, 5-hydroxyindoleacetic acid, tryptophan, dopamine or noradrenaline was observed 24 h after the last of 10 daily flurothyl-induced convulsions, compared to untreated rats. The rate of 5-hydroxytryptamine accumulation after tranylcypromine/L-tryptophan treatment and of dopamine and noradrenaline accumulation after tranylcypromine/L-DOPA treatment was similar in both groups.6 Repeated flurothyl convulsion has the same effects on these behavioural tests as repeated electroconvulsive shock. Since both treatments have been used successfully to treat depression, it is suggested that the mechanism of action of electroconvulsive therapy may be by increasing postsynaptic responses to the monoamine neurotransmitters.

Animals↗

PubMed1991

Effects of substantia nigra gamma-vinyl-GABA infusions on flurothyl seizures in adult rats.

There is evidence implicating the nigral gamma-aminobutyric acid (GABA) system in the control of seizures. Our previous studies have demonstrated that, in rat pups, intranigrally infused gamma-vinyl-GABA (GVG, 5-20 micrograms) strongly suppresses flurothyl-induced tonic but not clonic seizures. Furthermore, nigral infusions of bicuculline or muscimol abolish the anticonvulsant effect of GVG. In this study, we report that in adult rats bilateral infusions of GVG (20 micrograms) into the substantia nigra pars reticulata (SNR) significantly elevated the thresholds for both clonic and tonic seizures induced by flurothyl. Lower doses (5 and 10 micrograms) did not significantly protect adult rats against seizures, but there was a significant effect of GVG dose. Unilateral infusion of GVG (20 micrograms) in the SNR did not alter the thresholds for flurothyl-induced seizures. Intranigral infusions of bicuculline following pretreatment with GVG abolished the protective effect of GVG on flurothyl-induced seizures, indicating that the anticonvulsant effect of GVG is most likely mediated by the nigral GABAA receptor. Intranigral administration of muscimol after GVG pretreatment significantly suppressed flurothyl-induced seizures, but the combined effect of the two drugs was not as strong as that of GVG alone. The data suggest that GVG protects adult rats against flurothyl-induced seizures. In adults, however, the dose of GVG required to protect against both clonic and tonic seizures is higher than that needed in rat pup SNR.

Aminocaproates↗

PubMed1984

Differential effects of flurothyl- and electro-convulsive shock on sexual maturation and prolactin release in the rat.

The effects of single and repeated seizures on luteinizing hormone (LH), follicle stimulating hormone (FSH) and prolactin secretion and on the onset of sexual maturation in rats are described. In addition, the influence of convulsions generated electrically (electroconvulsive shock, ECS) and chemically (using flurothyl) are compared. Repeated flurothyl convulsions and ECS (one daily convulsion from age 24 days) significantly delay vaginal opening in female rats. The incidence of first ovulation at maturation is reduced to 20% compared with 70-100% for untreated groups. Body and adrenal weights in immature rats are not modified by flurothyl convulsions. Repeated ECS does not influence adrenal weight although somatic growth is inhibited. In an effort to clarify the mechanism of action of convulsions on puberty onset, we examined acute changes in LH, FSH and prolactin secretion and the surge response of LH/FSH to gonadal steroid priming. A single flurothyl convulsion potently inhibits prolactin secretion. In contrast, an ECS acutely stimulates prolactin release in male and female rats. Convulsive seizures do not consistently alter tonic gonadotropin output. However, both flurothyl convulsions and ECS attenuate estradiol benzoate/progesterone-induced LH and FSH surges in ovariectomized rats though this is apparently not mediated by dopamine/prolactin since bromocriptine treatment delays sexual maturation without preventing ovulation at first estrus. Similarly, bromocriptine does not disrupt LH/FSH surges induced by gonadal steroid treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1997

An indirect method for absorption rate estimation: flurothyl-induced seizures.

This paper develops a method to estimate a minimal amount of flurothyl necessary to induce the seizures (the seizure threshold). A simple mathematical model is proposed which permits one to determine the drug absorption rate from the amount which has been administered and from the measured latency to onset of seizure. Experimental animal (rats) were exposed to a continuous intake of flurothyl in two different situations: either being alone in the airtight chamber or sharing it in a pair. In the latter case, we assume that the two rats uniformly share the infused drug. Our calculations estimate that approximately 20 microliters of flurothyl is necessary to induce twitches, whereas 25 microliters of flurothyl is the dose required for the induction of clonic seizures. The model can be used to estimate the threshold amounts of any drug producing obvious behavioral changes irrespective of the route of administration.

Absorption↗

PubMed1975

Retrograde enhancement of memory by mild flurothyl treatment in the chick.

Strong flurothyl treatment (1.7% v/v for 8 min) produces retrograde amnesia in chicks when administered as long as 24 hr after one-trial avoidance training with a strongly aversive stimulus. Mild flurothyl treatment (0.2% v/v for 8 min) produced retrograde enhancement when administered as long as 16 min after similar training with a moderately aversive stimulus. The moderate training followed by mild flurothyl treatment enhanced 24-hr retention to the level found after strong training alone. Enhanced retention persisted for at least 72 hr; nonspecific performance effects faded within 48 hr. The predominant dose-dependent and time-dependent enhancement effect of mild flurothyl treatment is interpreted as improved memory consolidation.

Amnesia↗

PubMedDate not supplied

Functional observational battery comparing effects of ethanol, 1,1,1-trichloroethane, ether, and flurothyl.

Several recent reports have demonstrated that acute solvent exposure in animals produces a profile of neurobehavioral effects similar to that of classical CNS depressant drugs such as the barbiturates and ethanol. The present investigation further delineated the behavioral pharmacology of three solvents [1,1,1-trichloroethane (TCE), ether, and flurothyl] using a functional observational battery (FOB) composed of 21 qualitative and quantitative measures of behavior. The profiles of acute effects produced by TCE and ether were similar to one another and similar to the profile of effects produced by the IP administration of ethanol. This profile of depressant effects included changes in posture, decreased arousal, disturbances in gait, decreased forelimb grip strength, increased landing foot splay, and impaired psychomotor coordination. Flurothyl exposure also produced dose-related effects on many of the measures in the FOB; however, unlike the depressant vapors, flurothyl did not affect measures of muscle tone and equilibrium such as forelimb grip strength and landing foot splay, or measures of sensorimotor reactivity, including the touch response and tail pinch response. In addition, flurothyl produced handling-induced convulsions in some mice. Recovery from the acute effects of these vapors was rapid and began within minutes of removal from the exposure chamber. These results provide further evidence that exposure to certain solvents produces a profile of reversible effects qualitatively similar to that produced by depressant drugs and alcohol, and that the FOB can be used to compare and contrast profiles of depressant and excitatory effects of inhalants.

Animals↗

PubMed1987

Mutual interactions between repeated flurothyl convulsions and electrical kindling.

The interactions between repeated flurothyl seizures and electrical kindling induced from the neocortex or the amygdala were investigated. Three consecutive flurothyl-induced convulsions enhanced the rate of development of subsequent electrical kindling from the neocortex. Similarly multiple (more than 15) generalized kindled seizures, induced from either the neocortex or the amygdala, reduced the latency of onset of flurothyl seizures with repeated exposures producing a 'kindling-like' effect for flurothyl. These results indicate that eventually seizures will beget seizures independently of the site of origination of the seizures.

Amygdala↗

PubMed1998

Regional analysis of the spatial patterns of Fos induction in brain following flurothyl kindling.

We have recently demonstrated that eight, daily flurothyl-induced generalized clonic seizures, followed by a four week stimulus-free interval, results in a long-lasting reduction in generalized seizure threshold and a change in the type of seizure expressed in response to flurothyl from clonic to tonic. There is a progressive increase in the probability that a mouse will express a tonic seizure during the four week interval, suggesting that prior flurothyl seizures initiate a proepileptogenic process that requires time to develop. In this study, the immunohistochemical detection of the c-fos protein (Fos) was used to evaluate whether seizure-induced epileptogenesis resulted in regional differences in the degree of neuronal activation. Fos immunoreactivity was examined 1.5 h following either a single generalized seizure, the last of eight consecutive daily seizures or a retest seizure evoked two weeks after the last of eight seizures. In each condition, generalized seizure behaviours were elicited in C57BL/6 mice using flurothyl and classified as either "forebrain" (face and forelimb clonus) or "brainstem" (running/bouncing, treading, tonic extension). The spatial distribution of Fos induction was compared on the basis of the seizure phenotype and the seizure history. The predominant differences in Fos distribution were found to be related to the type of seizure expressed regardless of the seizure history. Furthermore, the different motor components that make up a "brainstem" seizure could not be distinguished by the pattern of Fos labelling suggesting that multiple convulsive behaviours are mediated by one anatomical system. Finally, Fos induction in the ventromedial hypothalamic nucleus preceded and predicted the change in seizure type from "forebrain" to "brainstem". These data support the concept that separate anatomical systems mediate the expression of the two generalized seizure phenotypes. In addition, the ventromedial nucleus of the hypothalamus may be a point of interaction between the systems and may play a role in seizure-induced neural reorganization.

Animals↗

PubMed1995

Barbiturate-reversible reduction of water diffusion coefficient in flurothyl-induced status epilepticus in rats.

Rat brains (n = 17) with flurothyl-induced status epilepticus (SE) have been imaged with a gradient-echo diffusion-weighted imaging sequence at 2.0 T. The apparent water diffusion coefficient (ADC) decreased during seizure discharges. The magnitude of the ADC reduction correlated well with the duration of flurothyl exposure. A 17% reduction in the water ADC compared with preseizure condition was observed in rats with the longest flurothyl exposure time. In 13 rats, pentobarbital was used to arrest the electrographic seizure activity. ADC values began to return to normal a few minutes after the injection. In four rats with no pentobarbital administration, ADC values remained depressed up to 1 h after seizure onset. The results suggest that diffusion-weighted MR imaging may be useful for mapping recent intense seizure activity in human patients with medically intractable epilepsy.

Animals↗

PubMed1976

Memory performance after flurothyl treatment in rainbow trout.

Fingerling rainbow trout (N = 436) were trained in one trial with brief electric shock (2.0 V/cm) to suppress their spontaneous upstream swimming into a quiet well. Memory retention one day later was not influenced by the temperature at which they had been acclimated, trained and tested (10 degrees C, 15 degrees C or 20 degrees C). When exposed 4 min after training for 2 min, to a flurothyl solution (10, 25, 50, 100 or 200 mul/l) trout convulsed and overturned. The onset of overturn was concentration- and temperature-dependent. Flurothyl altered the one-day retention of avoidance behavior; low concentrations enhanced, whereas high concentrations impaired. Memory-enhancing low concentrations of flurothyl, applied after post-training amnesic treatment with carbon dioxide, reversed the carbon dioxide amnesia.

Animals↗

PubMed1985

Unidirectional interaction between flurothyl seizures and amygdala kindling.

In this report, the interaction between flurothyl convulsions and electrical kindling of the amygdala was investigated. Three flurothyl convulsions decreased the afterdischarge threshold of the amygdala and enhanced the rate of development of electrical kindling without affecting the intensity of postictal refractoriness. On the other hand, 3 generalized kindled convulsions did not alter the flurothyl convulsive threshold. The data suggest that the influence of generalized convulsions on future seizure susceptibility may depend on the agents used to induce the convulsions.

Amygdala↗

PubMed1996

Flurothyl seizure susceptibility in rats following prenatal methylazoxymethanol treatment.

Methylazoxymethanol acetate (MAMac) is a potent teratogenic agent which can produce ectopic cell placement in developing rat brains. In the present study, we evaluated (i) whether prenatal exposure to MAMac results in a lowered seizure threshold to flurothyl and (ii) if there is a correlation between the number of ectopic cells in MAMac-exposed hippocampus and flurothyl-induced seizure latency. In 60 day old (P60) rats exposed to MAMac in utero, the latencies to myoclonic jerk (173 +/- 2.3 s) and forelimb clonus (215 +/- 4.6 s) were significantly shorter than those of controls (200 +/- 6.9 s and 238 +/- 8.8 s, respectively). MAMac also increased the proportion of flurothyl-treated rats that progressed from bilateral forelimb clonus to generalized tonic-clonic seizures (control: 33%; MAMac: 91%). Shorter seizure latencies were associated with an increased number of ectopic pyramidal cells in region CA1/CA2. These results suggest seizure susceptibility is enhanced in an animal model (MAMac) characterized by abnormal neuronal migration.

Animals↗

PubMedDate not supplied

Developing genetically epilepsy-prone rats have an abnormal seizure response to flurothyl.

Development of clonic-tonic flurothyl-induced seizures was examined in both normal and genetically epilepsy-prone rats (GEPRs). At each age, from 10 to 30 days, clonus occurred at significantly shorter latencies in GEPRs than in normal rats. The latency to onset of clonic seizures did not change with age, however, in either GEPRs or normal rats. A different pattern of response was observed in the progression to tonic seizures. As normal animals matured, the latency to tonic seizures became longer and, by day 30, the duration of flurothyl exposure necessary to induce tonus was almost 70% greater in normal rats than in the GEPRs. In contrast, in GEPRs, tonic extension occurred immediately following the onset of clonus throughout development. A subset of GEPRs failed to have audiogenic seizures in a 40-day posttest. These animals had a flurothyl response identical to their audiogenic-susceptible litter mates. These data suggest that (a) a protective mechanism which develops against tonic seizures in normal rats fails to mature in the GEPR, and (b) seizure inducing gene-linked neural abnormalities occur in the GEPR independent of pathologies underlying audiogenic seizures.

Acoustic Stimulation↗

PubMed1995

Effects of MK-801 and phenytoin on flurothyl-induced seizures during development.

We determined the effects of the N-methyl-D-aspartate (NMDA) receptor blocker MK-801 (0.05, 0.1, and 0.5 mg/kg intraperitoneally, i.p.) and phenytoin (PHT, 5, 10, and 20 mg/kg i.p.) on flurothyl-induced clonic and tonic-clonic seizures in 9-, 15-, 30-, and 60-day-old male rats. Both agents had seizure-, age-, and dose-specific effects. The highest dose of MK-801 was anticonvulsant against clonic flurothyl-induced seizures only in 9- and 60-day-old rats, but suppressed tonic-clonic seizures in all ages. The lowest dose of MK-801 (0.05 mg/kg) produced significant anticonvulsant effects only in 15 day old rats. PHT did not have any effect on clonic seizures throughout development. Both doses of PHT (10 and 20 mg/kg) were anticonvulsant against tonic-clonic seizures in adult rats but not in any other age group. The results indicate that NMDA receptors play an important role in tonic-clonic flurothyl-induced seizures throughout development (especially in 15-day-old rats) and that the anticonvulsant effects of PHT may vary at different stages of brain development.

Age Factors↗

PubMed1987

Pentobarbital-like discriminative stimulus properties of halothane, 1,1,1-trichloroethane, isoamyl nitrite, flurothyl and oxazepam in mice.

Volatile inhalants represent a diverse group of chemicals which pose a public health problem because of their abuse potential and neurobehavioral toxicity. Although relatively little is known about their pharmacology, they share certain pharmacological properties with classic central nervous system depressants. Drug discrimination procedures were used to compare the effects produced by pentobarbital (PB), oxazepam and several inhalants. Mice were trained to discriminate PB from saline injections in a two-lever operant task. Stimulus generalization was examined after 20-min inhalation exposures to halothane (500-8000 ppm), 1,1,1-trichloroethane (500-12000 ppm), isoamyl nitrite (150-1050 ppm), flurothyl (562-1300 ppm) and injections of oxazepam (0.1-20 mg/kg). Halothane, 1,1,1-trichloroethane and oxazepam produced discriminative stimulus effects similar to those produced by PB. Isoamyl nitrite and flurothyl, while decreasing rates of responding, were not consistently generalized from PB. Differences are apparent in the PB-like discriminative effects of inhalants. Toluene, as shown in a previous study, as well as halothane and 1,1,1-trichloroethane have PB-like discriminative effects which are also shared by oxazepam and may be another common effect of central nervous system depressants. Other chemicals, like isoamyl nitrite and flurothyl, are representative of qualitatively different classes of behaviorally active inhalants.

Administration, Inhalation↗

PubMed1990

The pattern of 72-kDa heat shock protein-like immunoreactivity in the rat brain following flurothyl-induced status epilepticus.

The inducible 72-kDa heat shock protein (HSP72) is a highly conserved stress protein that is expressed in CNS cells and may play a role in protection from neural injury. We used a monoclonal antibody to HSP72 and immunocytochemistry to localize HSP72 in the rat brain 24 h following either 30 or 60 min of flurothyl-induced status epilepticus. Sprague-Dawley rats were anesthetized with halothane, paralyzed, and ventilated, and remained normotensive and well oxygenated for the duration of the seizures. Seizure activity was quantified via analysis of the scalp EEG pattern. HSP72-like immunoreactivity (HSP72-LI) was induced in specific brain regions in a graded fashion that correlated, in part, with the duration and degree of seizure activity. Milder seizures produced HSP72-LI limited to layers 2 and 3 of frontoparietal cortex, dentate hilus cells, and CA3 pyramidal neurons. More extensive seizures led to HSP72-LI in layers 2, 3 and 5 of frontoparietal and visual cortex, dentate hilus cells, CA1 and CA3 pyramidal neurons, and certain thalamic and amygdaloid nuclei. These are similar to many, but not all, of the brain regions known to be injured with this model. No HSP72-LI was observed in sham-treated controls or flurothyl-treated animals whose seizures were controlled with pentobarbital. HSP72-LI thus localizes to certain regions of seizure-induced injury, and may provide a sensitive method of detecting neuronal 'stress' or injury relatively soon after status epilepticus. Whether or not HSP72 synthesis plays a protective role in the pathogenesis of seizures, or is only a marker for cell injury, remains to be determined.

Animals↗