PTZ seizure test

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). 

Interest in CNS diseases was the basis for an extensive programme directed to the discovery of novel anxiolytic agents at The R. W. Johnson Pharmaceutical Research Institute. Binding affinity determinations at the BZD site of the GABAa receptor and two in vivo assays, the Vogel test (anticonflict) and the PTZ seizure test (anticonvulsant), were employed to evaluate the potential anxiolytic activity of test compounds. 

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. 

A ter el at. (1984) documented the anticonvulsant properties of PBO and compared them with those of clinically established anti epileptic drugs. PBO administered inlrapcritoncally to mice exerted peak anti maximal electroshock activity and peak neurotoxicity at 5 and 7 hours, respectively. The median neuroluxic dose was I.69U mg kg"1. In the maximal electroshock seizure test I he median effective dose (HD j) was 457 mg kg"1 and the protective index (PI) was 3,69. In the subcutaneous pentylenetetrazol (PTZ) test the ED u was 443 mg kg 1 and PI was 3.81. PBO prevented seizure spread and elevated seizure threshold, and its PI compared favourably with those of clinically useful anticonvulsants,... 

Two pyrimidinyl compounds (71) and (72) and pyrazine (70) were evaluated. Of these, the 2-primidinyl compound (71) displayed slightly less binding affinity than (32) with better potency in the PTZ seizure assay and equivalent potency in the conflict test. 

It has become clear that drugs which are effective in protecting mice against PTZ are effective in absence seizures while those able to control the tonic response to maximal electroshock are effective in tonic-clonic seizure. Some drugs are effective in only one test and clinical condition whilst a few are active in both (Table 16.1). Experimental focal seizures are indicative of partial seizures. 

Another high affinity partial agonist for the BZD site of the GABAa receptor, compound (27), was as effective as diazepam in increasing the number of shocks taken in the Vogel assay and was similarly active in the Gel-ler-Cook conflict anxiety test. This compound also prevented PTZ-induced seizures in mice and was found to be a partial BZD agonist in vitro. No typical benzodiazepine-like side effects were observed for (27) [66]. 

Compounds (28), (29), and (30) are BZD receptor partial agonists which are anxiolytic in mice subjected to an operant punishment test and protect against PTZ-induced seizures in mice and rats [67], They cause minimum motor impairment in rodents and do not cause withdrawal in mice and squirrel monkeys. 

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