Convulsive Threshold Tests

Tests for the convulsive threshold estimate whether a test substance induces changes in the probability of convulsions occurring either spontaneously or, more importantly, in association with other treatments. Although overt convulsions can usually be detected using the Irwin procedure, proconvulsant activity can occur in the absence of overt convul- 

Rats are administered ECS (rectangular current, 1.5 s, 200 Hz) via earclip electrodes connected to a constant current shock generator (Ugo Basile Type 7801). 

Animal nr. 1 is exposed to 30 mA of ECS. If animal nr. 1 does not convulse (tonic convulsions) within 5 seconds maximum, animal nr. 2 is exposed to 40 mA, with increases of 10 mA until the first tonic convulsion is observed. Once the first tonic convulsion is observed, the intensity of ECS is decreased by 5 mA for the next animal and then the intensity is decreased or increased by 5 mA from animal to animal depending on whether the animal convulses or not. The minimum intensity given is 5 mA and the maximum intensity given is 95 mA. 

The results are represented as the mean intensity administered and as percent change from control. The number of deaths is also recorded approximately 30 minutes after the animal has been tested for convulsions. 

A positive percent change indicates an anticonvulsant effect. A negative percent change indicates a proconvulsant effect. 

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The anticonvulsant activity of a drug may also be evaluated by measuring its ability to raise the convulsive threshold, i.e. the amount of applied current or infused PTZ required to just evoke a seizure. Comparison of the efficacy of drugs in the threshold and maximal seizure tests may distinguish between their abilities to raise seizure threshold or reduce seizure spread and development. 

The present Section describes basic protocols satisfying ICH S7A recommendations for core battery CNS studies. Included are protocols for measuring general behavioral signs induced by test substances (Irwin Test), effects on spontaneous locomotion (Activity Meter Test), effects on neuromuscular coordination (Rotarod Test), effects on the convulsive threshold (Electroconvulsive Shock (ECS) Threshold and PTZ Seizure Tests), interaction with hypnotics (Barbital Interaction Test) and effects on the pain threshold (Hot Plate Test). 

Fig. 3. Convulsive threshold in the Rat PTZ Test. Effects of Ro 15-4513 and diazepam (p.o.) on the latency to tonic convulsions induced by PTZ in the rat.

More elaborate procedures can be employed to assess whether drug withdrawal induces changes in fearfulness, pain sensitivity, convulsive threshold or even memory. On the other hand, it is frequently difficult to demonstrate effects on these parameters and the tests involved are particularly time-consuming. The procedure described below represents an initial screen which has been shown to be sensitive to several dependence-inducing drugs such as opioids and benzodiazepines (Goudie et al. 1993). 

The barbiturates are substituted pyrimidine derivatives with an ureide configuration (Fig. 20.4). They are lipophilic weak acids (pKa 7-8) that are weii distributed into brain (see Appendix A for the respective pKa values). Although many barbiturates dispiay sedative-hypnotic activity (see Chapter 19), oniy a few have antiseizure properties. Paradoxically, many barbiturates cause convulsions at larger doses. The barbiturates clinically useful as AEDs are phenobarbital, mephobarbital, and primidone (Fig. 20.8). In laboratory animals, phenobarbital is effective by several tests in nontoxic doses. It is active against electrically induced seizures (MES), and it elevates the threshold for pentylenetetrazole stimulation. The mechanism of antiseizure action for the barbiturates... 

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