Trimipramine is a tricyclic antidepressant which has only weak effects on noradrenergic systems. Its mechanism of action is not understood, but its clinical effectiveness has been proven over a period of 20 years. In the present investigation, trimipramine was shown to have no effect on noradrenaline (NA)-stimulated adenylate cyclase activity after either acute or once daily application for 28 days. There was no change in the KD or Bmax of [3H]DHA binding, demonstrating a lack of effect on beta-adrenergic receptors. However, it did exert effects on the cortical noradrenergic projection of the locus coeruleus and these effects were opposite to those described for typical antidepressants. In acute experiments, systemic injections of trimipramine potently activated locus coeruleus neurons and produced a reduction in the depressant action of noradrenaline administered iontophoretically to neurons in the cingulate cortex. After 4 weeks' treatment with a daily injection of 30 mg/kg i.p. trimipramine, cingulate cortical neurons became supersensitive to the action of iontophoretically applied noradrenaline. Although it is unknown whether these effects are related to the therapeutic efficacy of trimipramine, the results demonstrate that the down-regulation of central noradrenergic sensitivity in the rat is not a prerequisite for clinical efficacy of antidepressants in man.