Extracellular, intracellular and tight-seal patch-clamp recordings in ventral striatal slices were used to investigate whether the effectiveness of muscarinic neuromodulation of fast synaptic transmission may be dependent on the frequency of afferent stimulation. In all neurons tested, EPSPs were reversibly attenuated by muscarine or carbachol. This action was completely antagonized by atropine or pirenzepine. Several observations indicated a presynaptic site of action. In extracellular recordings, carbachol reduced the monosynaptic population spike but not the non-synaptic compound action potential. The acetylcholinesterase inhibitors eserine and pyridostigmine also induced an atropine-sensitive reduction of the EPSP. When the rate of afferent stimulation was increased, control EPSPs or EPSCs exhibited a decline in peak amplitude until reaching a steady-state value. Muscarinic modulation of steady-state EPSPs/EPSCs was significantly stronger in the range of lower frequencies (0.25-4 Hz) than at higher frequencies (8 and 12 Hz). The GABAA and GABAB-receptor/channel antagonists picrotoxin and 2-hydroxy-saclofen, the opiate receptor antagonist naloxone and atropine failed to alter the shape of the frequency-response curve. These results show that both exogenous and endogenous muscarinic receptor agonists are capable of activating a presynaptic mechanism by which fast excitatory inputs to the ventral striatum are depressed. The depressive effect is clearly stronger at lower rates of afferent stimulation than at high rates. This frequency-dependent attenuation of excitatory synaptic inputs exemplifies a new type of activity-dependent neuromodulation in central neural circuits.