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PubMed1979

Catecholamines and convulsions.

Severe depletion of brain noradrenaline and separately of brain dopamine was induced in rats by intracerebral injection of the selective neurotoxin 6-hydroxydopamine, and the susceptibility of the treated animals to various seizure-inducing manipulations was examined. A significant potentiation of the seizures induced both by Metrazol and by electroconvulsive shock was found in animals depleted of brain noradrenaline, but no alteration was seen after depletion of brain dopamine on either measure. The catecholaminergic drug cocaine also induced seizures, but these were found not to depend on either brain noradrenaline or dopamine as they continued to occur in the virtual absence of either catecholamine. It is concluded that cocaine induces seizures by a non-specific toxic mechanism and that noradrenaline, but not dopamine, is involved in reducing the suceptibility of the central nervous system to the several distinct forms of seizure induction examined.

Animals↗

PubMed1977

Differential effects of cortical speading depression on epileptic foci induced by various convulsants.

Interaction between epileptic foci and spreading depression (SD) was studied in the cerebral cortex of rats anesthetized with Nembutal. At comparable discharge rates, picrotoxin and penicillin caused complete and partial SD blockade respectively, strychnine and Metrazol were ineffective and Aldactone facilitated SD. Conversely, the duration of SD-induced blockade of epileptic activity was maximal for Aldactone and minimal for picrotoxin. Treatment of the picrotoxin focus with tetrodotoxin (10(-4)M) reduced the discharge rate and reinstated SD propagation into the focus. [K+]e measured with ion-selective K+ electrodes 1 mm below the cortical surface increased to 8 mM in penicillin foci blocking SD and remained below 5 mM in Aldactone foci. It is concluded that the differential effect of various convulsants on SD propagation depends on the potassium concentration in the depth of the focus rather than on the discharge rate or on the mechanism of the the epileptogenic effect.

Animals↗

PubMed1989

Anticonvulsant profile of the progesterone metabolite 5 alpha-pregnan-3 alpha-ol-20-one.

5 alpha-Pregnan-3 alpha-ol-20-one (3 alpha-OH-DHP) is a naturally occurring metabolite of progesterone that can modulate brain excitability through a specific steroid recognition site on the GABA/benzodiazepine receptor-chloride ionophore complex. The anticonvulsant properties of 3 alpha-OH-DHP were determined using standardized anticonvulsant screening tests in mice. This steroid was found to be effective against metrazol-, (+)-bicuculline- and picrotoxin-induced seizures. The steroid has maximum potency against (+)-bicuculline-induced convulsions and no activity against maximal electroshock and strychnine-induced seizures. These findings support the hypothesis that therapeutically useful anticonvulsant steroids active at the putative steroid recognition site associated with the GABA/benzodiazepine receptor-chloride ionophore complex can be identified.

Animals↗

PubMed1982

A novel pyrazoloquinoline that interacts with brain benzodiazepine receptors: characterization of some in vitro and in vivo properties of CGS 9896.

The novel pyrazoloquinoline, CGS, 9896, was a potent inhibitor of specific [3H]-flunitrazepam binding in several brain regions with subnanomolar KI values. The inhibition of [3H] propyl beta-carboline-3-carboxylate ([3H]-PCC-) binding by CGS 9896 was enhanced by gamma-aminobutyric acid (GABA) but not by chloride ion. GABA enhancement of CGS 9896 inhibition of [3H]-PCC binding predicts this compound has benzodiazepine (BZD) agonist-type activity. Behavioral studies support this prediction. CGS 9896 was found to protect mice against bicuculline and metrazol induced seizure at doses that did not induce ataxia or sedation. CGS 9896 may represent a class of compounds with potential therapeutic value. The high affinity of this non-BZD compound suggests that CGS 9896 may also be of value as a high affinity ligand for the continued study of BZD receptors.

Animals↗

PubMed1987

Ontogenetic development of convulsant action of Ro 5-3663 in the rat.

Motor seizures were induced by Ro 5-3663 in 156 male albino rats aged 7,12,18,25, and 90 days. Both minimal and maximal seizures could be elicited in 18-day-old and older animals, whereas only maximal seizures were induced in the two youngest groups. ECoG changes were studied in other 21 young rats. First changes induced by Ro 5-3663 were formed by isolated sharp waves in 7- and 12-day-old rats and by episodes of rhythmic activity in older animals. An imperfect form of this rhythmic activity could be seen even in 12-day-old rats. Ictal ECoG activity exhibited an increase in frequency of individual graphoelements, in generalization and in synchronization of activity among different cortical regions with maturation. Correlation between motor and ECoG phenomena was poor in 7-day-old rats and ameliorated with age but it never reached perfection. The actions of Ro 5-3663 are identical with those induced by metrazol but they differ from those elicited by bicuculline or 3-mercaptopropionic acid.

Animals↗

PubMed1978

Increase in vivo of unesterified fatty acids, prostaglandin F2 alpha but not thromboxane B2 in rat brain during drug induced convulsions.

The amount of free arachidonic acid and prostaglandin F2 alpha in rat cerebral hemispheres was increased following convulsions induced by carbachol and metrazol. The level of thromboxane B2 was not affected and prostaglandin endoperoxides could only be "trapped" after a very short convulsive period. Unesterified fatty acid levels at 2 minutes post-mortem were decreased by 50% in the cerebral hemispheres of phenytoin treated rats. Under the same conditions, phenobarbital and diazepam had little effect on the levels of free fatty acids in rat brain.

Animals↗

PubMed1979

Some properties of brain specific benzodiazepine receptors: new evidence for multiple receptors.

Several new lines of evidence suggest the existence of two or more distinct types of benzodiazepine receptors, in contrast to earlier results suggesting the presence of only one class of receptors. Appropriate thermoinactivation experiments indicate two receptors with different thermostabilities. Several triazolopyridazines, with some of the pharmacological properties of anxiolytics have recently been shown to displace 3H-diazepam and 3H-flunitrazepam with Ki values in the 6 to 100 nanomolar range. These new substances are active in conflict tests in rats and monkeys and prevent metrazol induced seizures in vivo, but strikingly lack the ataxia and sedative properties of the benzodiazepines. Hill analyses of dose-response curves for some of these substances yields Hill coefficients in the range of 0.4--0.6, suggesting that these compounds may be able to discriminate between several types of benzodiazepine receptors.

Amino Acids↗

PubMed1981

Pharmacologic analysis of sodium valproate-induced suppression of secondary components of visual evoked potentials in albino rats.

Sodium Valproate (VPA) administered to rats in a dose of 10 or 200 mg/kg IP suppressed the slow negative wave (SNW) and photically-induced afterdischarge (SAD) of VEP (when they were present) within 15-30 min. The recovery of VEP amplitude began at 3 hr. This effect was antagonized by subconvulsive doses of convulsant benzodiazepine RO 5-3663 (2 mg/kg) and metrazol (15 mg/kg) but not by picrotoxin (2 mg/kg) and naloxone (10 mg/kg). The SNW suppression may be attributed to a disinhibitory action of a system located presynaptically on recurrent collaterals of the output neurons, or nerve terminals of inhibitory interneurons or both. Alternative conjecture suggests that VPA depolarizes the dendritic tree masking thereby somatic inhibition produced by recurrent circuits.

Animals↗

PubMed1981

Ketamine: convulsant or anti-convulsant?

Ketamine hydrochloride in doses producing narcotic-cataleptic effects (50--100 mg/kg, IP) reduced the intensity of picrotoxin convulsions and eliminated seizures caused by metrazol administration. Subcataleptic doses (5--20 mg/kg) increased the duration of mitigated convulsive symptoms (abortive grand mal fits, jerks) especially those evoked by picrotoxin. Narcotic-cateleptic doses of ketamine considerably increased the duration of the period of single and multiple jerks produced by picrotoxin administration. Both convulsants transformed 1--2 Hz "ketamine complexes" into 2--4 Hz Wave spike discharges which appeared in a quasi-periodic fashion alternating with periods of relatively suppressed electrocortical activity. Electroencephalographic grand mal patterns were typically dissociated from behavioral manifestations under 50--100 mg/kg of ketamine, followed by a short period of postictal depression and a rapid recovery of preseizure electrographic patterns. Findings suggest that mechanisms involved in seizure alleviation may be responsible for sustaining mitigated convulsive phenomena. Neuro-chemical processes underlying antiepileptic ketamine potency remain unknown.

Animals↗

PubMed1981

Pharmacologic analysis of the postictal immobility syndrome in the rat.

Postictal immobility (IP) following chemically (pictrotoxin, metrazol) and electrically-induced (maximal electroshock, MES) convulsions has behavioral features close to neuroleptic-type catalepsy. EEG, monitored postictally, showed that catalepsy is accompanied by a variety of EEG patterns. Cataleptic behavior extended beyond the period of "postictal EEG depression". During PI rats had vivid righting and corneal reflexes. Like haloperidol-pretreated rats they were able to maintain uncomfortable postures on the vertical grid or horizontal bar; although signs of rigidity were noticed, the rats would fail to remain self-supporting when placed across metal bookends ("bridge" test). All rats reacted to the tail-pinch immediately when the seizure would halt. However, 10-15 min later when PI was minimal or not detectable, animals became totally unresponsive to pressure applied to the tail ("delayed analgesia"). Examination of VEP recovery after MES showed that the secondary slow negativity and sensory after discharge were well developed irrespective of the score of the tail-pinch test. Pharmacological profile of PI suggests that the endogenous opiate system might contribute to this syndrome. Similar to morphine-induced catalepsy/catatonia: (1) PI is insensitive to atropine and scopolamine; (2) neither haloperidol nor alpha-methyl-p-tyrosine was able to potentiate it; (3) PI is reduced by apomorphine, naloxone, and physostigmine. Also, drugs acting via GABA system (gamma-vinyl GABA, diazepam, sodium valproate) reduce PI intensity. It is hypothesized that PI system (1) is controlled by GABA carrying fibers and (2) uses neuropeptide with neuroleptic properties.

Animals↗

PubMed1985

Drug discrimination and cross generalization between two methylxanthines.

Twenty-one rats were trained to discriminate 32 mg/kg caffeine from saline in a two-lever drug discrimination task (variable ratio) while another ten rats were trained to discriminate 56 mg/kg theophylline from saline. For each group, dose-effect curves (% drug-lever responses and overall response rate) were obtained for both caffeine and theophylline. Significant dose-related generalization of each training drug was found for both the caffeine- and theophylline-trained rats. Concomitant dose-related decreases in overall response rate also were apparent. Similar dose-related effects were seen with cross-generalization tests for various doses of the other xanthine. The nature of the training session preceding the test session was found to have an effect on discrimination performance at intermediate test doses. Drug appropriate responding was higher and overall response rate was lower after saline- than after drug-training days. Such data may suggest the possibility of short-term tolerance to caffeine's cue. That the discriminative cue was specific to the xanthines was shown by the lack of generalization seen after either amphetamine or metrazol.

Amphetamine↗

PubMed1985

Comparison of anticonvulsive properties of eboracin and phenytoin in mice.

The in vivo effects of phenytoin (diphenylhydantoin, Dilantin) and the experimental anticonvulsant, eboracin, a substituted indenopyrrole, were compared in mice. Pretreatment with varying dosages of either agent followed by challenge with the chemoconvulsant pentylenetetrazol (Metrazol) indicated that eboracin provided slightly less protection against seizures than phenytoin and was much less toxic. Intermediate doses of either agent led to a form of clonic status epilepticus which persisted for an average of 18 min in phenytoin-treated and 58 min in eboracin-treated mice. Pretreatment with higher or lower doses did not lead to these manifestations. Animals in which this syndrome had been induced should be of value in studies of the chemistry and physiology of the clonic state.

Animals↗

PubMed1988

Preclinical studies with pyrazolopyridine non-benzodiazepine anxiolytics: ICI 190,622.

Tracazolate is a pyrazolopyridine anxiolytic that enhances the binding of [3H]-flunitrazepam [( 3H]FLU) to brain tissue. The discovery that a metabolite of tracazolate, desbutyltracazolate, was a weak inhibitor of [3H]FLU binding led to the synthesis of a series of potent anxiolytics. From this series, ICI 190,622 emerged as a viable drug candidate, being a potent anxiolytic in rats and monkeys. This anxiolytic agent appears to produce only minimal sedation. Furthermore, ICI 190,622 appears less likely to potentiate the actions of ethanol than diazepam. ICI 190,622 is also a potent anticonvulsant (anti-metrazol ED50 = 1.1 mg/kg, PO) in rodents. Neurochemically, ICI 190,622 is similar to the benzodiazepine anxiolytics. In vitro, ICI 190,622 competitively inhibited [3H]FLU binding in cerebral cortex with an IC50 of 81 nM and was 4.3-fold more potent in the cerebellum (IC50 = 19 nM). This suggests a selectivity for the Type 1 benzodiazepine binding site. In contrast, diazepam showed similar affinities in both regions (cerebral cortex = 7 nM and cerebellum = 9 nM). Following oral administration, ICI 190,622 displaced [3H]FLU binding from cerebellar membranes more potently than diazepam (ED50 = 3 and 6 mg/kg, respectively, 1 hour after administration). Thus, ICI 190,622 should be an effective anxiolytic with significant advantages over benzodiazepines.

Animals↗

PubMed1988

Episodic barrel rotations induced by intrastriatal injection of quinolinic acid in rats. Inhibition by anticonvulsants.

Unilateral intrastriatal injection of quinolinic acid (2,3 pyridine dicarboxylate; QUIN) in the rat produces episodic barrel rotations and tonic-clonic forepaw movements, lasting for several hours. We investigated whether intraperitoneal posttreatment with anticonvulsants could abolish this phenomenon when it is already fully developed, and whether their potency ratio was similar in models of epilepsy. All 8 tested antiepileptics, namely carbamazepine, clonazepam, diazepam, diphenylhydantoin, ethosuximide, flunarizine, phenobarbital and sodium valproate decreased this behaviour in a dose-dependent way. Six other drugs with anticonvulsant properties were also effective: DL-2-amino-7-phosphonoheptanoic acid, desipramine, etomidate, ketamine, meprobamate and sabeluzole. The ED50-values for halving the frequency of the episodes of barrel rotation correlated well with published ED50-values for inhibition of tonic hindpaw extension in the maximal metrazol seizure test (rs = .95, p less than 0.001) and with the ED50-values for halving the duration of the forepaw clonus in the rat-kindling model (rs = .93, p less than 0.001). This quinolinic acid test allows visualization of the onset of action of anticonvulsants, with each animal as its own control. In order to assess whether this test is also sensitive to drugs influencing the symptoms of Huntington's disease, the effect of the dopamine antagonists haloperidol and pimozide, the acetylcholinesterase inhibitor physostigmine and the anticholinergics atropine and dexetimide were investigated as well. The experiments suggested that the barrel rotations and clonic forepaw movements, only 3-6 hours after intrastriatal injection of QUIN respond to anticonvulsants, but are not specifically sensitive to drugs used in the symptomatic treatment of Huntington's disease.

Animals↗

PubMed1992

Transient suppression of a secondary humoral response in rats is evoked by lithium-pilocarpine-induced limbic seizures.

Several experiments were designed to evaluate a secondary humoral response following limbic seizures. After baseline antigen binding capacity (ABC) had been determined for the primary response, a second subcutaneous injection of the antigen (human serum albumin) was accompanied by an injection of either lithium (3 mEq/kg)-pilocarpine (30 mg/kg) or one of two comparator treatments: metrazol (30 mg/kg) or cyclophosphamide (50 mg/kg); other rats served as drug controls. Only the groups that received the lithium-pilocarpine (status epilepticus) or cyclophosphamide (no seizure) displayed significant immunosuppression after 5 but not 10 days. The results support the hypothesis that seizure activity within the amygdaloid-hippocampal complex modulates immunocompetence through corticotropin mechanisms.

Adrenocorticotropic Hormone↗

PubMed1982

A screening method for substances potentially active on learning and memory.

A series of substances from different pharmacological classes was examined by two different tests for their activity on learning and memory. A concomitant evaluation was performed by use of a one-trial passive avoidance immediately followed by electroshock in mice and the pole-climbing test in rats. Only doses not producing changes in gross behavior (Irwin's test) were used. A facilitating action on all the considered parameters was observed for d-amphetamine, caffeine, L-glutamine, Mg pemoline, phosphorylserine, piracetam, strychnine, and tricyanoaminopropene. A worsening action was found for atropine, cycloheximide, diazepam, and morphine. Chlorpheniramine, diphenylhydantoin, GABA, imipramine, meclizine, mescaline, metrazol, and testosterone showed no or doubtful activity. Our results suggest that the parallel use of these relatively simple tests supplies information that is satisfactory for screening purposes and that has a high degree of predictability as substantiated by literature data.

Animals↗

PubMed1989

High-frequency components in epileptiform EEG.

We analyzed the spectral content of interictal and ictal EEG of rats treated with metrazol. Significant power was present in the EEG between 100 and 800 Hz ictally but not interictally. Since high-frequency activities appeared to accompany spiking episodes, a computer algorithm was developed to recognize rapid voltage fluctuations or high-frequency components in EEG. The algorithm turned out to be effective in the identification of seizure spikes. The significance of high frequencies in EEG spikes and the advantage of the spike selection algorithm are discussed.

Algorithms↗

PubMed1988

High-frequency discharge of dentate granule cells, but not long-term potentiation, induces c-fos protein.

Competence genes, such as c-fos, may play key roles in information storage in the nervous system by linking relatively brief extracellular signals to long-term changes in the neuron. In support of this idea we, and others, have shown that the c-fos protein occurs in adult mammalian neurons and that higher levels of the protein are induced in certain brain regions after kindled or metrazol-induced seizures in mice and rats, sensory stimulation and mechanical damage in spinal cord neurons, and after depolarization in PC12 cells. Here we report that a massive induction of c-fos protein is observed in dentate granule cells in four conditions that result in repetitive firing: localized seizure discharges; high frequency antidromic activation; orthodromic activation in the presence of iontophoresed bicuculline; and frequency potentiation. However, stimulation of the perforant path with high frequency trains that produced long-term potentiation at the perforant path-granule cell synapse did not reliably induce c-fos in the dentate gyrus. These findings suggest that c-fos induction can follow repetitive neuronal discharge but is not involved in long-term potentiation.

Action Potentials↗