Metrazol and combined photic-metrazol activated electroencephalography in epileptic, schizophrenic, psychoneurotic, and psychopathic patients.
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Electroencephalography↗
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Behavioral and physiological studies of seizures induced by systemic injection of metrazol in chickens.
The influence of systemically administered Metrazol on behavior, electroencephalogram and body temperature has been studied in young and adult chickens. Distinct convulsions were induced by 30--50 mg./kg. Metrazol administered intravenously in adults: they consisted of an initial excited state, a tonic convulsion accompanied with opisthotonos, and finally, convulsive movements. During recovery from these convulsions, three distinct behaviors were observed: violent peck-like movement, watchful state and finally panting behavior. All of the birds receiving higher intravenous doses (60--100 mg./kg.) exhibited vigorous convulsions immediately after injection and death occurred in 100% of the birds receiving these doses. An intraperitoneal injection of 75--100 mg./kg. Metrazol produced typical convulsions in young and adult chickens. At these doses, convulsions consisted of an initial excited state, a tonic convulsion accompanied with opisthotonos, and convulsive movements which involved clonic and tonic phases. The threshold for evoking typical convulsions with intraperitoneal injection ranges between 50 and 60 mg./kg. Metrazol in young chickens. The intravenous threshold doses for evoking high amplitude (1--2 mV.) in the EEG of adult chickens was 60 mg./kg. Metrazol. High intraperitoneal doses of Metrazol(75-100 mg./kg.) produced typical spikes with large amplitude which were synchronous in the two hemispheres in both young and adult chickens. There was a marked increase in body temperature within 10 minutes after injection in all cases of 50 mg./kg. intravenous dose: maximum increase (at 40 min.) was 1.5 degrees C. as compared with controls, however, it decreased rapidly with panting behavior. The highest does (100 mg./kg.) produced a maximum increase in body temperature of 3 degrees C. Discussion of epileptic seizure susceptibility to Metrazol in aves, in the light of phylogenesis, is discussed.
Animals↗
Metrazol potentiated after-discharges: dose-response relationships and effects of selective lesions.
In Experiment 1 the dose-response effects of pentylentetrazol (Metrazol) on photically evoked after-discharge (PhAD) parameters were examined. Metrazol potentiated PhAD activity by affecting all measured parameters - PhAD frequency, amplitude, burst duration and spindle composition - in particular PhAD burt duration and spindle composition. A mimimum effective dose of 10 mg/Kg of Metrazol was required for some statistically reliable potentiation. Metrazol dosage levels of 20 and 25 mg/Kg induced lengthy bouts of EEG spindling and spiking as well as near maximized PhAD component augmentation. In Experiment 2 stereotaxically oriented knife-cuts isolated the thalamus from cortical and/or midbrain and brainstem input. Such lesions did not block the capacity of Metrazol to potentiate PhADs, although the lesions altered evoked activity. These findings are discussed in terms of the current thought of Metrazol action and thalamic mechanisms in the control of after-discharge activity.
Animals↗
Influence of propranolol on rhythmic electrocorticographic activity induced by metrazol in rats.
Influence of propranolol (5 mg/kg i.p.) on rhythmic metrazol activity (RMA) was studied in 11 male albino rats with chronically implanted cortical as well as subcortical (thalamic ventrobasal complex and dorsal hippocampus) electrodes. Metrazol was injected subcutaneously at a low dose of 30 mg/kg. Another group of five rats was used to study the action of propranolol on spontaneously appearing episodes of rhythmic spikes as well as on vigilance. The incidence of both rhythmic metrazol activity and episodes was significantly increased by propranolol. The latency to the first burst of rhythmic metrazol activity and to the maximum of its incidence was significantly shortened by propranolol. Propranolol also increased the incidence of relaxed wakefulness and delayed the appearance of slow wave sleep. The facilitation of RMA and spontaneous episodes could not be explained only by the increased amount of relaxed wakefulness, i.e. the vigilance level necessary for these two phenomena, because these changes did not coincide in time. In two animals, the combination of propranolol and metrazol led to the appearance of ictal activity which was sometimes accompanied by partial clonic convulsions. This phenomenon was never seen after metrazol alone (30 mg/kg s.c.) in control recordings. Propranolol was found to potentiate the possible models of human absences--spontaneous episodes, RMA and minimal clonic seizures.
Animals↗
Involvement of central cholinoceptors in Metrazol-induced convulsions.
Atropine sulphate (10 mg/kg IP) afforded 90% protection against clonic convulsions induced by standard doses of metrazol (80 mg/kg SC) in mice, whereas atropine methonitrate (10 mg/kg IP) did not offer any protection. Furthermore, physostigmine (1 mg/kg IP) caused recurrence of convulsions in atropinzed metrazol-treated mice and converted the subconvulsive dose of metrazol (40 mg/kg SC) into a 100% convulsive dose. However, neostigmine (1 mg/kg IP) did not antagonize the protection afforded by atropine sulphate against metrazol. The results of the study suggest an involvement of central cholinergic mechanisms in metrazol-induced convulsions.
Animals↗
Controlled demonstration of metrazol kindling.
Convulsive responses elicited in rats by intraperitoneal injections of metrazol were intensified following a seriew of metrazol injections administered once every three days. However, neither handling alone nor placebo injections increased the susceptibility of control rats to metrazol-induced convulsive symptoms. Thus, although increases in the susceptibility to metrazol seizures following periodic placebo injections have been reported by others, such increases do not appear to be a critical factor in metrazol kindling.
Animals↗
Principal cells in lateral geniculate: effects of metrazol on capacity to after-discharge.
The effect of metrazol on the capacity of dorsal lateral geniculate nucleus (dLGN) principal (P) cells to repetitively burst (after-discharge) following visual system stimulation was examined in P cells which differed in terms of response patterns to visual stimulation (latency of initial spike, extent of repetitive bursting, and on- or off-type responding cells). Twenty-seven P cells were examined in as many subjects. Metrazol augmented repetitive bursting irrespective of the type of P cell as long as repetitive bursting was present in the pre-metrazol period. P cells that displayed only a single initial burst to photic stimulation did not exhibit after-discharge bursting during the metrazol challenge. In all but one cell metrazol enhanced baseline firing rate. These results are discussed in terms of the putative nature of inhibition in the rat dLGN.
Action Potentials↗
Immunohistochemistry of c-fos in Mouse Brain During Postnatal Development: Basal Levels and Changing Response to Metrazol and Kainate Injection.
Levels and cellular distribution of FOS, the product of c-fos (onco)gene, were studied by immunohistochemistry during the development of mouse brain at rest and after the administration of convulsants. Basal FOS immunoreactivity became detectable only after postnatal day 20 (P20). Metrazol and kainate at the appropriate doses induced convulsions at all ages but, in both cases, FOS accumulated in limbic areas (particularly in the dentate gyrus) only after a certain age: P20 for kainate and P30 for Metrazol. Surprisingly, considering the different molecular targets of Metrazol and kainate, respectively, and the different type of convulsions elicited, the cell groups in the limbic areas in which FOS increased were the same in the two cases. These results suggest that both drugs produced FOS increase by finally activating the same circuit. During ontogeny, the ability to accumulate FOS, which appears after P20, could be the sign of the attained maturity of signal transduction mechanisms in the cells of the hippocampal formation; endogenous signals originating from the activity of the nervous system increase the basal FOS levels and exogenous signals (i.e. like those given, probably locally, by kainate) further increase these levels. Metrazol manifests its capability to induce FOS accumulation only at later ages. We suggest that this occurs because the Metrazol target is probably distant from the hippocampal region and thus the maturity of a nerve pathway(s) is also required for c-fos induction.
Journal Article↗
Influence of phenobarbital on ECoG phenomena induced by metrazol in rats during ontogenesis.
Effect of phenobarbital (PhB, 20 and/or 40 mg/kg) on epileptic ECoG phenomena induced by metrazol was studied in acute experiments in rats aged 7, 12, 18, 25 and 90 days. Fractionated administration of metrazol (20 mg/kg i.p. each 300 s) was used to quantify the effects of PhB. First signs of metrazol action (sharp elements and/or rhythmic metrazol activity) were not reliably influenced by PhB. On the contrary, the latency of the first EEG seizures as well as of the first generalized EEG seizures was prolonged and thus a dose necessary for their elicitation was increased in all age groups. These differences reached statistical significance in 12-, 18- and 25-day-old rats. A lack of effect of PhB against the rhythmic metrazol activity supports the adequacy of this activity as a model of human absences. Differences between the development of antiepileptic and hypnotic effects of PhB (described earlier) suggest two different mechanisms of action.
Aging↗
Influence of a new antiepileptic drug ORG 6370 on metrazol-induced seizures in rats during ontogenesis.
The anticonvulsant action of a new antiepileptic drug ORG 6370 (Organon International B.V.) was studied in 217 male albino rats aged 7, 12, 18, 25 and 90 days. Epileptic phenomena induced by a subcutaneous injection of a 100 mg/kg dose of metrazol (isolated myoclonic jerk, minimal metrazol seizures and major, generalized tonic-clonic metrazol seizures) were used as a model. ORG 6370 did not influence myoclonic jerks or minimal metrazol seizures in those age groups where they were regularly elicited. In 12-day-old rats pretreatment with ORG 6370 led to the appearance of minimal metrazol seizures, a phenomenon rarely seen under control conditions. Major seizures were suppressed only in adult rats with a 20 mg/kg dose; on the other hand, ORG 6370 exhibited a selective action against the tonic phase of major seizures at all stages of development. The profile of action of ORG 6370 is almost the same as that of phenytoin.
Animals↗
Metrazol-produced impairment of passive avoidance retention specifically antagonized by anti-petit mal drugs.
In a single session, naive female 250-g Wistar rats were trained to remain for 3 min on a platform located above an electrifiable grid. During training, animals were shocked (4 mA) after they stepped down. Retention of the step-down avoidance was tested 24 h later in rats treated SC 30 min before the session with saline or a subconvulsive dose of metrazol (40 mg/kg). During the retention test no shock was delivered. The latency to step down and the time on the grid were recorded. The metrazol rats significantly failed to retain the avoidance task. Groups of six rats per dose were trained and 24 h later pretreated, 5 min before metrazol, with an IP injection of the following antiepileptics (dose range in mg/kg): Ethosuximide (20--320); trimethadione (20--320); clonazepam (0.04--0.63); sodium valproate (20--320); carbamazepine (1.25--20); phenobarbital (5--80); or diphenylhydantoin (5--80); or high dose of haloperidol (0.16) and amphetamine (0.63). Only ethosuximide, trimethadione, and clonazepam significantly increased the latency to step down and significantly shortened the time on the grid. Sodium valproate only shortened the time spent on the grid. The results suggest that only anti-petit mal drugs antagonize the retention impairment of passive avoidance produced by metrazol.
Animals↗
Effect of metrazol on the discharge characteristics of muscle spindle afferents from the hind limb of the rat.
The nature of altered fusimotor discharge induced by subconvulsive doses of Metrazol has been investigated in deeply anaesthetized rats. Large amplitude stretching (ramp and hold or sinusoidal) of the appropriate muscle during the course of drug action shows Metrazol to have a predominant gamma d effect on primaries, and an exclusive gamma s effect on secondaries in both plantar and dorsiflexors of ankle and toes. Small amplitude stretches revealed gamma s activity which large amplitude stretching failed to show. Experiments with convulsive doses of Metrazol show that this elevated spindle discharge precedes development of electromyographic activity. It is suggested that fusimotor activity must be considered when analysing the mechanisms of Metrazol-induced seizures in non-paralysed animals.
Animals↗
Metrazol impairs conditioned aversion produced by LiCl: a time dependent effect.
The effects of 40 mg/kg Metrazol on a conditioned saccharin aversion produced by LiCl were studied in two experiments. In Experiment 1, it was found that Metrazol administered 10 min before or after LiCl did not impair conditioned aversion to saccharin. In Experiment 2, Metrazol was given 2 min before, 9 or 3 min after the administration of LiCl. Under these conditions, impairment did occur. It was concluded that Metrazol may impair conditioned taste aversion in a time-dependent manner. The present findings are discussed in terms of their relationship to ECS as an interfering agent and retroactive and proactive effects on the CS and/or the UCS.
Animals↗
Acute down-regulation of oxytocin and vasopressin mRNA levels following metrazole-induced seizure in the rat.
Following our recent demonstration of metrazole-induced immediate-early gene expression in the hypothalamic supraoptic nucleus (SON), we have now performed a mRNA and transcription analysis to determine the consequences of metrazole treatment for neurohypophyseal peptide gene expression in male rats. Levels of hypothalamic vasopressin (VP) and oxytocin (OT) mRNA were significantly reduced at 2 and 4 h after metrazole (50 mg/kg, i.p.), whereas pro-dynorphin mRNA was significantly elevated at 2 h. No changes in mRNA levels were found at 8, 24 or 48 h after treatment. Another convulsant (kainic acid, 8 mg/kg, i.p.) elicited similar effects on VP and OT mRNAs at 2 h. Specific analysis of the SON, following metrazole, revealed an equivalent effect on VP and OT mRNA levels but a nuclear run-on assay did not detect any change in SON VP gene transcription at 0.5, 1 and 2 h after treatment. The results provide evidence of a novel mechanism which may provide an additional level of control in the regulation of neuropeptide gene expression.
Animals↗
Anti-metrazol action of R 57720 during postnatal development in rats.
The effects of an experimental antiepileptic drug R 57720 (Janssen Pharmaceutica) on metrazol-induced seizures were studied in rats aged 7, 12, 18, 25 and 90 days. R 57720 exhibited a marked dose-dependent anticonvulsant effect against major, generalized tonic-clonic seizures in all the age groups studied. Similar action on minimal metrazol seizures (mMS) was present in rats aged 18 days and more. In the two youngest groups where metrazol did not induce mMS under control conditions, the combination of the 5- and 10-mg/kg doses of R 57720 and metrazol led to the appearance of mMS, whereas mMS failed to appear after the highest dose of R 57720 used (20 mg/kg).
Aging↗
Influence of cinromide on metrazol--induced seizures during ontogenesis in rats.
The effects of cinromide on two types of metrazol-induced seizures were studied in 236 male rats aged 7, 12, 18, 25 and 90 days. Cinromide was administered intraperitoneally in a dose of 25 or 50 mg.kg-1 30 min before a subcutaneous injection of metrazol. Major, i.e. generalized tonic-clonic seizures could be elicited by metrazol in all age groups. Cinromide was efficient against this type of seizures at all developmental stages, but its action in 7- and especially in 12-day-old rat pups was less marked than in older animals. Minimal metrazol seizures (predominantly clonic) could be reliably elicited since the age of 18 days. Cinromide was also able to suppress this type of seizures, but in adult rats the dose of 75 mg.kg-1 had to be administered because even the 50 mg.kg-1 dose was not sufficient. Quantitative changes of the antimetrazol action of cinromide were demonstrated during maturation in rats.
Aging↗
Influence of ethosuximide on metrazol-induced seizures during ontogenesis in rats.
Effects of metrazol (pentylenetetrazole and ethosuximide were studied in male albino rats aged 7, 12, 18 and 90 days. The 18-day-old rats exhibited the highest sensitivity to metrazol. CD50s in the remaining three age groups were nearly the same. Ethosuximide was reliably effective against metrazol only in adult rats; in young animals it did not significantly change CD50s. Metrazol induced in ethosuximide-pretreated young rats either modified (long-lasting minimal seizures in 18-day-old animals) or new seizure patterns (minimal seizures in 7- and 12-day-old rats).
Aging↗
Anti-metrazol effects of nitrazepam during ontogenesis in the rat.
Anti-metrazol effect of nitrazepam was studied in male rats aged 7, 12, 18 and 90 days. Nitrazepam protected all age groups against seizures elicited by metrazol (80 mg/kg s.c.); the 50%-protective dose decreased from 165.7 micrograms/kg in adult rats to 70.2 micrograms/kg in 7-day-old animals. The sensitivity of 7-day-old and adult rats to metrazol is nearly the same, so that we may conclude that nitrazepam exhibits higher anti-metrazol potency in 7-day-old rats than in adult ones.
Age Factors↗