The antidepressant tianeptine is associated with a small but significant incidence of gastrointestinal (GI) side effects, including nausea and constipation. Since the site of action of tianeptine is not clear, we looked for an ability of this drug to directly interfere with GI motility. The effects of tianeptine were studied in rat isolated stomach and colon preparations, in which neuronally mediated (predominantly cholinergic) contractions were evoked by electrical field stimulation. Tianeptine concentration dependently inhibited these contractions in both stomach (0.3-10microM; n=2-5) and colon (1-10microM; n=3-6). This activity was likely to be prejunctional, since contractions evoked by carbachol were unaffected by tianeptine 1microM. Further, the inhibitory activity of tianeptine was unaffected by inhibitors of 5-hydroxytryptamine and noradrenaline re-uptake, adenosine metabolism, nitric oxide synthesis and tryptophan dehydroxylase. Thus, our experiments demonstrate a pathway by which tianeptine affects GI functions and this could explain the side effects observed. It is not known if the mechanism of this activity is also related in any way to the therapeutic action of tianeptine within the CNS.