Abstract Submandibular secretory responses to electrical stimulation of the parasympathetic innervation at variable frequencies were measured in anaesthetized rats. Selective blockade by pirenzepine and by methoctramine occurred at doses (50 and of 300 nmol kg −1, i.v., respectively) that did not inhibit the responses to exogenous acetylcholine. In the presence of methoctramine, the nerve-evoked fluid responses were increased by 100% at 1 Hz independently of the total number of impulses (10–300), suggesting that M2 receptor activation inhibits transmitter release. The magnitude of the increase was inversely related to frequency of stimulation. The protein concentrations in the fluid responses were not significantly affected by methoctramine. Pirenzepine had an inhibitory effect on the fluid secretory responses, which was dependent of frequency, as well as of number of impulses, suggesting that M1 receptor activation facilitates transmitter release. At 10 Hz given intermittently (for 1 s at 10-s intervals), pirenzepine reduced the fluid response by 25%. The protein release was substantially and significantly reduced by pirenzepine independent of frequency but only during long periods of stimulation (300 impulses). It is concluded that muscarinic M1 receptor activation normally has a facilitatory effect on transmitter release, and that the facilitation occurs during short, intense stimulation. Muscarinic M1 receptors are, however, likely to regulate protein secretion by other mechanisms. Muscarinic M2 receptors, on the other hand, normally inhibit cholinergic transmission at low frequencies. Similar to findings in the alimentary tract of several species, stimulation in bursts at high frequencies is a more efficient stimulation pattern than continuous low frequency stimulation. This pattern of stimulation thus takes advantage of transient facilitation and avoids the inhibition at less intense neuronal activity.