We examined the effects of somatostatin (SST) on neurons in the thalamic reticular nucleus (RT) using whole-cell patch-clamp techniques applied to visualized neurons in rat thalamic slices. SST, acting via sst 5 receptors and pertussis toxin-sensitive G-proteins, activated an inwardly rectifying K + (GIRK) current in 20 of 28 recorded cells to increase input conductance 15 ± 3% above control and inhibited N-type Ca 2+ currents in 17 of 24 neurons via voltage-dependent mechanisms. SST reversibly depressed evoked EPSCs (eEPSCs) to 37 ± 8% of control without altering their kinetics. SST-mediated inhibition of eEPSCs showed short-term relief from block during 25 Hz stimulus trains. SST also reduced the frequency (33 ± 8%) but not the amplitude of miniature EPSCs (mEPSCs). These data indicate that SST mediates presynaptic inhibition of glutamate release onto RT neurons. In current-clamp recordings, SST preferentially inhibited burst discharges mediated by near-threshold corticothalamic EPSPs and intracellularly applied depolarizing currents. SST had powerful effects on in vitro intrathalamic rhythms, which included a shortening of the duration and a reduction in spike count within each oscillatory event. Furthermore, there was a paradoxical increase in the synchrony of epileptiform oscillations, likely mediated by a suppression of the responses to weak synaptic inputs in RT. We conclude that SST suppresses discharges in RT neurons, via presynaptic inhibition of glutamate release and postsynaptic activation of GIRK channels, leading to the dampening of both spindle-like and epileptiform thalamic network oscillations. SST may act as an important endogenous regulator of physiological and pathological thalamocortical network activities.