Coronaridine congeners induce anticonvulsant activity in rodents by hippocampal mechanisms involving mainly potentiation of GABAA receptors.

ABSTRACT

The coronaridine congeners catharanthine and 18-methoxycoronaridine (18-MC) display sedative, anxiolytic, and antidepressant properties by acting on mechanisms involving GABAergic and/or monoaminergic transmissions. Here, we expanded their pharmacological properties by studying their anticonvulsant activity in male and female mice using the pentylenetetrazole (PTZ)-induced seizure test. To determine potential neurochemical mechanisms, the effect of congeners on monoamine content and kainic acid (KA)-induced epileptiform discharge was studied in the hippocampus. The behavioral results showed that coronaridine congeners induce acute anticonvulsant activity in a dose-dependent but sex-independent manner. Repeated treatment with a subthreshold dose (20 mg/kg) of each congener produced anticonvulsant activity in a sex-independent manner, but was significantly higher in male mice when compared to its acute effect. Using a behaviourally relevant regimen, we found that PTZ increased dopamine metabolites and serotonin tissue content. Coronaridine congeners, which induced distinct effects on monoamines, blunted the effect of PTZ instead of potentiating it, suggesting the existence of another mechanism in their anticonvulsant activity. The electrophysiological results indicated that both congeners inhibit KA-induced epileptiform discharges in hippocampal slices. A key aspect of this study is that the activity of both congeners was observed only in the presence of GABA, supporting the notion that hippocampal GABAAR potentiation plays an important role. Our study showed that coronaridine congeners induce acute anticonvulsant activity in a sex-independent manner. However, a comparatively higher susceptibility was observed in male mice after repeated treatment. The underlying hippocampal mechanisms mainly involve GABAAR potentiation, whereas monoamines play a minor role in the anticonvulsive action.