MUSCARINIC MODULATION OF SYNAPTIC TRANSMISSION IN SLICES OF THE RAT VENTRAL STRIATUM IS DEPENDENT ON THE FREQUENCY OF AFFERENT STIMULATION

Extracellular, intracellular and tight-seal patch-clamp recordings in ventral striatal slices were used to investigate whether the effective ness of muscarinic neuromodulation of fast synaptic transmission may b e dependent on the frequency of afferent stimulation. In all neurons t ested, EPSPs were reversibly attenuated by muscarine or carbachol. Thi s action was completely antagonized by atropine or pirenzepine. Severa l observations indicated a presynaptic site of action. In extracellula r recordings, carbachol reduced the monosynaptic population spike but not the non-synaptic compound action potential. The acetylcholinestera se inhibitors eserine and pyridostigmine also induced an atropine-sens itive reduction of the EPSP. When the rate of afferent stimulation was increased, control EPSPs or EPSCs exhibited a decline in peak amplitu de until reaching a steady-state value. Muscarinic modulation of stead y-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 GABA(A) and GABA(B)-receptor/channel antagonists picrotoxin and 2-hydr oxy-saclofen, the opiate receptor antagonist naloxone and atropine fai led to alter the shape of the frequency-response curve. These results show that both exogenous and endogenous muscarinic receptor agonists a re capable of activating a presynaptic mechanism by which fast excitat ory inputs to the ventral striatum are depressed. The depressive effec t is clearly stronger at lower rates of afferent stimulation than at h igh rates. This frequency-dependent attenuation of excitatory synaptic inputs exemplifies a new type of activity-dependent neuromodulation i n central neural circuits.