PD134308 and PD135158 are highly selective CCK-B receptor antagonists and were used to investigate the role of CCK-B receptors in aversive responding in rodent and primate models of anxiety. Both PD134308 and PD135158 were as effective as diazepam to antagonise aversive behaviour in the mouse light/dark discrimination test, in the rat social interaction and elevated X-maze tests, and in a marmoset 'human threat' model. However, the CCK-B antagonists were much more potent than diazepam and their effects were recorded over an extensive dose range. Furthermore, even at high doses, sedation or muscle relaxation was not observed and anxiogenesis was absent after withdrawal from a subchronic treatment. In contrast, withdrawal from drugs of abuse, diazepam, alcohol, cocaine and nicotine was associated with a withdrawal anxiogenesis that was completely prevented by PD134308 and PD135158. It is concluded that CCK-B receptors are involved in aversive-anxiety responding and that CCK-B receptor antagonists may provide a novel and improved approach to the treatment of anxiety and withdrawal from drugs of abuse.