The central, but not the peripheral, administration of thyrotropin releasing hormone (TRH) elicited an increase in the gastrointestinal (GI) motor activity in anesthetized rabbits. This effect did not appear to be mediated via the pituitary-thyroid axis and it was relatively independent of the degree of basal motor activity in the Gl tract. Intravenous administration of either atropine or ganglionic blocking agents antagonized this phenomenon. Bilateral vagal transection prevented the TRH-induced stimulation of Gl motor activity, but neither spinal transection nor i.v. guanethidine had any effect. When injected into the lateral ventricles, 3rd ventricle of cisterna magna, TRH always elicited its Gl effects. Central cholinergic mechanisms appear to be involved because both atropine methyl bromide and atropine sulfate given i.c.v. antagonized the Gl effects. Intravenous injection of phenoxybenzamine also inhibited the TRH effect. TRH stimulates neural pathways within the central nervous system to activate efferent vagal fibers leading to a generalized increase in the motor activity of the Gl tract.