INTRACEREBROVENTRICULAR PERTUSSIS TOXIN ENHANCES SENSITIVITY TO CHEMICAL CONVULSANTS AND DECREASES THE PROTECTIVE EFFICACY OF CARBAMAZEPINE IN MICE

Abstract

The effects of pretreatment with pertussis toxin on pentylenetetrazole-, bicuculline-, aminophylline- and pilocarpine-induced seizures were investigated in mice. In animals treated intracerebroventricularly with pertussis toxin (0.5μg animal⁻¹120h prior to testing), the CD₅₀(convulsive dose in 50%) values were considerably decreased in comparison with the CD₅₀in sham-treated animals. CD₅₀values of pentylenetetrazole, bicuculline, pilocarpine and aminophylline were calculated to be 39.9, 2.0, 262 and 141mgkg⁻¹, whereas they were calculated to be 57.7, 2.7, 324 and 230mgkg⁻¹in sham-treated animals. The observations suggest that the enhanced sensitivity to a number of chemical convulsants irrespective of their mode of action possibly results from a functional suppression of inhibitory transmission at receptors coupled to pertussis toxin sensitive G proteins, rather than a direct action on G protein linked excitatory neurotransmission.

Pertussis toxin significantly decreased the protective action of carbamazepine, increasing its ED₅₀(effective dose in 50%) from 14.8 to 20.1mgkg⁻¹in a maximal electroshock convulsive test. It influenced the ED₅₀of neither diphenylhydantoin nor diazepam. The diminution of carbamazepine's efficacy might result from a summation effect of adenosine receptor antagonist properties of the drug and a suppression of transmission at adenosine receptors coupled to G proteins sensitive to pertussis toxin.

Pertussis toxin pretreatment remained without any significant influence on the total plasma levels of carbamazepine, diphenylhydantoin and diazepam. This may lead to the conclusion that the interaction between pertussis toxin and carbamazepine does not seem to be of a pharmacokinetic nature and occurs probably at neuronal level.