Comparison of the actions of trimethadione and chlordiazepoxide in animal models of anxiety and benzodiazepine receptor binding.

Trimethadione was compared with chlordiazepoxide for anti-anxiety activity in two behavioral tests known to predict the anxiolytic action of drugs. In the drug-discrimination test, male hooded rats were trained to discriminate the anxiogenic action of pentylenetetrazol from saline by responding for food reinforcement on one of two levers after treatment with pentylenetetrazol (1450 mumol/kg) and on the other lever after injection of saline. Pretreatment with either chlordiazepoxide (2.8-33 mumol kg) or trimethadione (559-2236 mumol/kg) prior to the injection of pentylenetetrazol, produced a dose-dependent antagonism of the anxiogenic stimulus. In the other test, male Wistar rats were trained to respond for milk reinforcement in a conflict procedure in which some of the reinforced responses resulted in the delivery of footshock. Treatment of these rats with chlordiazepoxide (17-67 mumol/kg) or trimethadione (1118-2236 mumol/kg) antagonized the footshock-induced suppression of responding. In a receptor binding study, trimethadione failed to inhibit flunitrazepam binding. These data suggest that trimethadione is an effective anxiolytic agent whose action does not directly involve benzodiazepine receptors.