We tested drugs acting at histamine H3 receptors in mice on the gastrointestinal transit of a charcoal meal in vivo and on neurogenic contractions of isolated ileal preparations. The agonist (R)-alpha-methylhistamine (100 micromol/kg) caused a maximum 25% reduction of gastrointestinal transit, an effect mimicked by immepip (100 micromol/kg) and antagonized by thioperamide (20 micromol/kg) or clobenpropit (20 micromol/kg). In the isolated ileum, (R)-alpha-methylhistamine (10-100 microM) caused a slight, thioperamide-insensitive, reduction (maximum 15%) of electrically evoked cholinergic contractions. In comparison, the alpha2-adrenoceptor agonist clonidine (0.1 micromol/kg) caused a 35.2% inhibition of the gastrointestinal transit and almost completely reduced (maximum 82% at 1 microM) the cholinergic contraction of the isolated ileum, both effects being antagonized by idazoxan (0.4 micromol/kg and 1 microM, respectively). These results suggest that histamine H3 receptors, located outside the myenteric plexus, mediate an inhibition of the gastrointestinal transit in vivo. Conversely, the presence of a2-adrenoceptors in the cholinergic nerve endings and their inhibitory role in the control of gastrointestinal propulsion is confirmed.