A possible interaction of immunomodulator muramyl dipeptide (MDP) with 5-HT4 and 5-HT1A receptors was investigated. The activation of 5-HT4 receptors releases acetylcholine from nerve terminals, thereby contracting the guinea-pig distal ileum. The whole ileum segments were therefore cut and placed into the bath. The preparations were contracted by 5-HT (10 nM-3.2 microM); these contractions were totally abolished in the presence of atropine (1 microM) and significantly attenuated in the presence of SDZ-205,557 (320 nM). The 5-HT evoked contractions remained unchanged in the presence of MDP (5, 50 or 500 nM). MDP (l0 nM-3.2 microM) could not directly contract the preparations. In further experiments, the possible interaction of MDP with 5-HT1A receptors was investigated. The activation of 5-HT1A receptors inhibits the release of acetylcholine from nerve terminals, thereby decreasing the height of electrically evoked neurogenic twitches of guinea-pig ileum. The whole ileum segments were cut, placed into the bath and stimulated electrically. Selective 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) decreased the height of twitches and this effect was significantly attenuated in the presence of 5-HT antagonist metergoline (1 microM). The effect of 8-OH-DPAT remained unchanged in the presence of MDP (5, 50 or 500 nM). MDP (10 nM-3.2 microM) did not exert any direct effect on the preparations. These results suggest that MDP interacts with neither 5-HT4 nor 5-HT1A receptors.