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baseline time alter KA (in min)

FIGURE 7 Quantification of the occurrence of discharges in the hippocampus and neocortex along with behavioral activity and motor seizures after intraperitoneal administration of 14mg/kg of kainic acid (KA). Duration of phenomena in seconds was recorded within each 5-minute interval and plotted as a histogram (means from eight rats are shown, standard error of the means were omitted for clarity). Occurrence of discharges prevailed over the occurrence of behavioral activity, especially motor seizures. This indicates significant dissociation of electroencephalographic and motor seizures after systemic KA.

baseline time alter KA (in min)

FIGURE 7 Quantification of the occurrence of discharges in the hippocampus and neocortex along with behavioral activity and motor seizures after intraperitoneal administration of 14mg/kg of kainic acid (KA). Duration of phenomena in seconds was recorded within each 5-minute interval and plotted as a histogram (means from eight rats are shown, standard error of the means were omitted for clarity). Occurrence of discharges prevailed over the occurrence of behavioral activity, especially motor seizures. This indicates significant dissociation of electroencephalographic and motor seizures after systemic KA.

ventromedial thalamic nuclei. There are no changes in the 2DG uptake in the substantia nigra pars reticulata (Albala et al., 1984). A study in paralyzed, ventilated rats showed significant increases in glucose metabolism only throughout the hippocampus (Evans and Meldrum, 1984). Neuropathology is age specific. After PN18 to 21, there is a significant cell loss after KA in the hippocampus associated with synaptic remodeling (Albala et al., 1984; Sperber et al., 1999b). Other areas of neuronal damage include pyriform and entorhinal cortex, medial, cortical, and lateral posterior nuclei of amygdala and thalamic nuclei (mediodorsal, paraventricular and parafascicular) (Ben-Ari et al., 1981b). In younger animals, only minimal nonspecific changes in limbic structures can be observed (Albala et al., 1984; Nitecka et al., 1984). For additional details, see Chapter 34.

Limitations

Doses of KA may be quite specific for the rat strain (see Table 3). Similarly, significant differences in the prevailing location and extent of KA seizure-induced damage have been described in adult rats of different strains: Thus hip-pocampal CA1 damage prevails in Wistar rats and either CA1 or CA3 damage prevails in Sprague-Dawley rats (Albala et al., 1984; Sperber, 1996b; Brandt et al., 2003). Additionally, the damage may be sex specific (Brandt et al., 2003). Immature 2-week-old rats are very resistant to a classic KA seizure-induced damage seen in adult rats (hilus of the dentate gyrus, CA3 pyramidal cells (Albala et al., 1984; Nitecka et al., 1984; Sperber, 1996a; Sperber et al., 1999b; Haas et al., 2001; Sperber and Moshe, 2001).

Insights into Human Disorders

KA is an agonist for the KA subtype of ionotropic glutamate receptor with highest density in the hippocampus, especially in the CA3 region, also in the amygdala, perirhi-nal and entorhinal cortex (Miller et al., 1990). These areas are preferentially affected after systemic administration of KA. Therefore KA serves as a valuable model of partial (focal) seizures with complex symptomatology and secondary generalization from the limbic focus (Ben-Ari, 1985; Engel, 2001) as well as a model of epileptogenesis after status epilepticus (Cavalheiro et al., 1982; Stafstrom et al., 1993). For these features, KA-induced seizures may be a valuable tool in assessment of the antiepileptic drug efficacy in complex partial seizures. Another glutamate analogue structurally related to KA, domoic acid, produced temporal lobe seizures in humans after ingestion of infested mussels (Cendes et al., 1995), providing an additional support for use of KA in modeling limbic seizures.

Quisqualic Acid/a-Amino-3-Hydroxy-5-Methyl-4-Isoxasole Propionic Acid

Methods of Generation

Quisqualic acid (QA) and amino-3-hydroxy-5-methyl-4-isoxasole propionic acid (AMPA) are almost exclusively used for ICV administrations in minute amounts. QA can be dissolved easily in tris(hydroxyymethyl)-aminomethane (TRIS) buffer and pH balanced to 7.4 (Thurber et al., 1994). The ICV dose for QA is 10|mg per minute of 2.94mg/ml solution. Schoepp and colleagues (1990) described convul-sant effects of QA after systemic administration in PN7 and PN11 rats. QA seizures can also be induced in mice (Jurson and Freed, 1990; Schwarz and Freed, 1986). The ICV dose for AMPA is 1 to 5 |g (Turski et al., 1981).

Defining Features

After a period of either hypoactivity (PN23) or agitation (older rats), QA administered unilaterally ICV produces contraversive circling throughout development (PN23 adult). Later the rats display facial clonus, salivation, and tail tonus. In the EEG, spikes, spikes and waves, and serrated waves can be recorded (Thurber et al., 1994). Histologic evaluation after 2 weeks revealed that QA caused massive neuronal loss in hippocampal CA2 and CA3 regions. There was also a cell loss in the hilus and CA1 region of both the injected and contralateral side, which indicates seizure-induced damage.

Limitations

Blood-brain barrier permeability is an obstacle for systemic use of QA/AMPA in older animals.

Insights into Human Disorders

QA and AMPA act as agonists at the AMPA subtype of ionotropic glutamate receptors expressed especially in the hippocampal CA3 region and in the amygdala (Insel et al., 1990). Thus seizures after systemic administration may arise from these structures. However, the usefulness of these two drugs administered systemically for screening purposes is limited by their cost and very poor penetration to the brain.

W-methyl-D-aspartic acid (NMDA)

Methods of Generation

NMDA dissolves well in normal saline up to 50mg/ml. Seizures are usually induced intracerebrally administered, 2 to 10nmol (Ishimoto et al., 2000; Lees, 1995) administered NMDA because of poor blood-brain barrier permeability. However, appropriate doses of NMDA(>100mg/kg) administered systemically will induce seizures even in mature animals with a fully developed blood-brain barrier. In mice, CD50 is around 110mg/kg administered IP (Budziszewska et al., 1998), whereas in rats, it is estimated between 150 to 200mg/kg IP (Mares and Velisek, 1992). In immature rats, doses required for seizure induction are much lower than in adults (Schoepp et al., 1990; Mares and Velisek, 1992) (for developmental CD50, see Figure 8). Seizures occur within 15 to 45 minutes, depending on the dose.

Defining Features

The first symptom is increased locomotor activity, especially in prepubertal and adult rats. Wild running is the most prominent feature. If rats are allowed enough space, they run the "8"-shaped trajectory. After the period of hyperactivity, automatisms occur at all developmental stages. These usually start with tail flicking beginning at the tip and continuing sigmoidally to the trunk. Sometimes biting of fore-limbs or hindlimbs occurs. In rats younger than 3 weeks of age, NMDA induces a special seizure pattern consisting of hyperflexion of the head, body, and tail while the rat is lying on its side. These seizures are termed emprosthotonic. Additionally, NMDA induces tonic-clonic but not clonic seizures throughout development. The tonic phase of tonic-clonic seizures may not be developed. However, in this model, clonus regularly precedes tonus, which is indicative of imminent death (Maress and Velissek, 1992). (For further

Clonic Convulsion Rats

FIGURE 8 CD50 values for tonic-clonic seizures induced by i.p. administration of N-methyl-D-aspartic acid (NMDA) during postnatal development in Wistar rats (according to Mares and Velisek, 1992). Tonic-clonic seizures were the only seizure occurring throughout development after systemic administration of NMDA. CD50 for postnal day 60 (PN60: young adult) rats was estimated due to few experimental groups used for this age.

FIGURE 8 CD50 values for tonic-clonic seizures induced by i.p. administration of N-methyl-D-aspartic acid (NMDA) during postnatal development in Wistar rats (according to Mares and Velisek, 1992). Tonic-clonic seizures were the only seizure occurring throughout development after systemic administration of NMDA. CD50 for postnal day 60 (PN60: young adult) rats was estimated due to few experimental groups used for this age.

details, see Chapter 48.) The EEG pattern is nonspecific. Long periods of EEG suppression occur in cortical and hip-pocampal recordings (Figure 9). During these almost iso-electric recordings, various behaviors can be observed, including hyperactivity and tonic-clonic seizures. Later, serrated EEG waves may occur (Kabova et al., 1999). Frequently, chaotic activity in the EEG appears between motor seizures. Although intracerebrally administered NMDA induces severe neuronal damage (Lees, 1995; McDonald et al., 1988) in adult rats, no overt neuronal damage is found after seizures induced by systemic NMDA in young rats (Kabova et al., 1999; Stafstrom and Sasaki-Adams, 2003). Systemic administration of NMDA in rats induces c-fos expression, especially in the piriform cortex and dentate gyrus of the hippocampus, irrespective of seizure occurrence (Morgan and Linnoila, 1991).

Limitations

Follow-up studies after NMDA-induced emprosthotonus are quite restricted by the very low survival rates. Administration of the NMDA receptor antagonist ketamine (50 mg/kg IP) after a defined (15-30 minutes) period of seizure duration may help to increase survival.

Insights into Human Disorders

NMDA is a prototype agonist at the NMDA subtype of the ionotropic glutamate receptor. These receptors are prominently expressed in the hippocampal CA1, dentate gyrus, and striatum (Insel et al., 1990). Based on the specific motor pattern of hyperflexion, significant age specificity (Maress and Velissek, 1992), resistance to pharmacotherapy (Kabova et al., 1999; Velisek and Mares, 1995), and long-term learning impairments (Stafstrom and

FIGURE 9 Electrocorticogram and stereo electroencephalographs (EEG) recording in a postnatal day 18 (PN18) Wistar rat before and after intraperitoneal administration of N-methyl-D-aspartate (NMDA). Top traces: baseline recordings before NMDA administration. Bottom traces: EEG suppression, which developed after systemic NMDA administration. During these periods of EEG suppression, different associated motor behaviors or seizures were recorded from motionlessness to emprostho-tonus and tonic-clonic seizures. RF, right frontal (sensorimotor) cortex; RO, right occipital (visual) cortex; LF, left frontal cortex; LO, left occipital cortex; RHi, right hippocampus.

FIGURE 9 Electrocorticogram and stereo electroencephalographs (EEG) recording in a postnatal day 18 (PN18) Wistar rat before and after intraperitoneal administration of N-methyl-D-aspartate (NMDA). Top traces: baseline recordings before NMDA administration. Bottom traces: EEG suppression, which developed after systemic NMDA administration. During these periods of EEG suppression, different associated motor behaviors or seizures were recorded from motionlessness to emprostho-tonus and tonic-clonic seizures. RF, right frontal (sensorimotor) cortex; RO, right occipital (visual) cortex; LF, left frontal cortex; LO, left occipital cortex; RHi, right hippocampus.

Sasaki-Adams, 2003), we believe that NMDA-induced emprosthotonic seizures in the immature rats are one of the closest models currently available for the West syndrome, although with some reservations (Lado and Moshé, 2002; Stafstrom and Holmes, 2002). NMDA seizures have been previously proposed as a model of refractory seizures (Loscher, 1997). NMDA induces only a tonic-clonic seizure pattern, and this seizure type in various chemically induced models is significantly suppressed by NMDA receptor antagonists; therefore we further propose that the tonic-clonic seizure pattern uses NMDA receptor neurotransmission for its expression (Velfsek and Mares, 1990, 1992; Velfsek et al., 1989, 1990 1991, 1997).

Other Drugs (Homocysteine, Homocysteic Acid)

Methods of Generation

Homocysteine seizures can be induced in rats and in mice (Blennow et al., 1979). Homocysteine can be dissolved in normal saline and effective dose ranges between 6 and 16mmol/kg in rats (Kubova et al., 1995). D,L-homocysteic acid can be also dissolved in saline; however, the pH needs to be adjusted by alkalinization. CD50 for PN7-25 rats are between 1.5 and 12.5mmol/kg (Folbergrova et al., 2000; Mares et al., 1997).

Defining Features

D,L-homocysteic acid induces seizures similar to NMDA during development. A special feature of D,L-homocysteic acid and both its stereoisomers is the occurrence of barrel rotations in PN12 rats (Mares et al., 1997). Homocysteine induces different seizures. The first sign is decreased locomotion; then clonic seizures may occur. Younger rats may display a status of clonic seizures. Flexion (emprostoho-tonic) seizures develop later but regularly in rats younger than PN15 and only rarely in older age groups. Tonic-clonic seizures can be observed in all age groups. The efficacy of homocysteine increases with age (Kubova et al., 1995). In the EEG, slow waves (young rats), spikes, and spike and wave patterns occur (in prepubertal and older rats). All these phenomena have very poor electroclinical correlation, which slightly improves with age. Metabolic studies show early (1 hour after ICV infusion) decreases in glucose and glycogen and increases in lactate in the cerebral cortex and late (24 hours after administration) increases in glucose and glyco-gen (Folbergrova et al., 2000).

Limitations

The profile of action is practically the same as with NMDA seizures, including EEG patterns (Mares et al., 2004). All the mechanisms of action of homocysteine remain to be elucidated. Because of high mortality after systemic homocysteic acid administration in developing rats (similar to NMDA), investigators may use ICV administration, which induces long-lasting but not lethal tonic-clonic seizures (Folbergrova et al., 2000).

Insights into Human Disorders

Both homocysteine and homocysteic acid are related to the EAA system. Although L-homocysteic acid is an agonist at the NMDA subtype of the ionotropic glutamate receptor, homocysteine has broader nonspecific agonistic features on the EAA receptors. Homocysteic acid can be used instead of NMDA for flexion (emprosthotonic) seizures.

Acetylcholine (ACh)-Related Substances

The cholinergic system has been practically explored for seizure induction far before the experimental approach was used. Organophosphorus-based nerve gasses tabun, sarin, soman, cyclosarine, VX, and VR produce seizures on their way to lethal effects and mechanistically block acetylcholine (ACh) degradation in the synaptic cleft by inhibiting acetycholinesterase (Shih and McDonough, 1999). Experimentally, in addition to the use of nerve gasses, muscarinic receptor agonists are widely employed for induction of clonic seizures, especially of the long-lasting SE with neu-ropathologic consequences (Turski et al., 1989b). Issues of pilocarpine-induced seizures and SE are analyzed in detail in Chapter 35.

Behaviorally all these drugs induce akinesia, tremor, olfactory automatisms, wet-dog shakes, and clonic seizures, culminating in SE (Turski et al., 1983). These symptoms can be clearly observed only with pilocarpine because nerve gasses have extremely fast onset of seizures, consistent with their intended effects: Only in animals that do not develop seizures and thus do not die is it possible to record automatisms (Shih et al., 2003). In the EEG, the hippocampus is activated before the amygdala and cortex are, with prevailing high-voltage spiking. Neuropathologically, pilocarpine-induced SE produces an extensive and age-specific injury.

Pilocarpine

Methods of Generation

Systemic (IP) injection of pilocarpine, 300 to 400mg/kg, produces seizures in rats and mice (Turski et al., 1983). However, this very high dose has significant peripheral effects. Therefore concomitant treatment with a peripheral muscarinic antagonist (not crossing the blood-brain barrier), such as scopolamine methylbromide (1 mg/kg sub-Q), is necessary. To decrease pilocarpine doses (and thus peripheral effects), pretreatment with lithium chloride (LiCl, 3 mEq) may be used 24 hours before the pilocarpine dose of 30 to 60mg/kg. This paradigm significantly limits peripheral side effects (Jope et al., 1986). For detailed information on all aspects of pilocarpine-induced seizures, see Chapter 35.

Defining Features

Pilocarpine induces automatisms, WDS, and clonic seizures developing into SE as described previously. In the EEG, fast spikes occur in the hippocampus and spread to the cortex at all studied ages PN3 through adulthood (Caval-heiro et al., 1987). Metabolic studies determined the involvement of the hippocampus, dentate gyrus, globus pal-lidus, substantia nigra, ventrobasal and mediodorsal thalamus, pyriform, and visual and frontal cortex (Clifford et al., 1987). Features of the Li-pilocarpine model are very similar to those of pilocarpine (Turski et al., 1989a). Neuropatho-logic changes are age specific. In adult rats, the hippocampus is predominantly damaged (Turski et al., 1989a), but other areas (e.g., amygdala, pyridorm cortex, thalamic nuclei, and the substantia nigra pars reticulate) are also affected. In immature animals at PN11-21, some damage can be found in the hippocampus, thalamus, olfactory cortex, septum, and neocortex (Cavalheiro et al., 1987). However, in immature rats at the lower limit of this developmental interval (PN12), neuronal damage is found in thalamic nuclei (Kubova et al., 2001).

Limitations

Pilocarpine seizures are very persistent and long-lasting, and they result in severe neuropathologic damage that far exceeds the damage seen in human mesial temporal lobe sclerosis. The pilocarpine or Li-pilocaprine model has become very popular during the period of very limited (practically nonexistent) availability of KA, which until then had been a drug of choice for models of temporal lobe seizures with SE, resulting in spontaneous seizures and brain damage. The administration of a peripheral cholinergic antagonist further complicates the use of high doses of pilo-carpine for acute seizure induction. On the other hand, the low cost of pilocarpine compared with KA represents a significant advantage.

Insights into Human Disorders

Pilocarpine is an agonist of muscarinic ACh receptors expressed especially in the hippocampus, striatum, and cortex (Kuhar and Yamamura, 1976). Therefore its seizure-producing effect arises from the increased activation of these receptors. The pilocarpine model may be useful for testing of the drugs potentially effective against complex partial seizures.

Weapon-Grade Organophosphorus Compounds

Methods of Generation

All nerve agents (organophosphates) (Lotti, 2000; Spencer et al., 2000) can be dissolved in saline. Seizures were described after administration in rats and guinea pigs. All the drugs are extremely toxic (Lotti, 2000; Spencer et al., 2000); the median lethal dose (LD)50 ranges from 8 |mg /kg to 300 |g/kg, depending on the potency (from the lowest to the highest: tabun, cyclosarin, sarin, soman, VR, and VX; see Table 4) and on the experimental animals used. Administration is usually sub-Q (Shih et al., 1999). No data for immature rats are available.

Features

Convulsions begin as a tremor, twitching, and shivering, continuing to strong convulsions (Tuovinen, 2004) associated with loss of righting reflex (Shih et al., 1999). Cortical EEG displays fast spiking (Shih et al., 2003).

Limitations

These drugs are extremely toxic and dangerous for humans even in minimal doses. The popularity of this model is limited. There is no available detailed description of seizures and associated EEG.

TABLE 4 LD50 of Weapon-Grade Organophosphates

Nerve agent

LD50 rats (mg/kg sub-Q)"

LD50 guinea pigs (mg/kg sub-Q)'

Tabun

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