Somatostatin was applied to rat cortical neurons grown in dispersed cell culture while electrophysiological effects were monitored with intracellular recordings. The effects of somatostatin were predominantly excitatory, but they varied and were dose dependent. Somatostatin at concentrations between 100 pM and 1 microM depolarized 30 of 87 neurons, often with a concomitant increase in spontaneous action potentials and a small increase in membrane input resistance. Somatostatin also increased the frequency of synaptic activity coming into the recorded neuron in 45 of 78 recordings, an effect which was seen even in the absence of direct effects. In six of nine neurons, somatostatin decreased the amplitude of large ongoing inhibitory synaptic potentials, concomitant with an increase in membrane input resistance. Somatostatin occasionally caused inhibition of neuronal activity, an effect predominantly associated with the application of higher concentrations. The unpredictability of the response of an individual neuron to somatostatin is partially explained by three phenomena: a marked tachyphylaxis, an inverted U-shaped dose response curve for membrane depolarization, and qualitatively different responses depending on the concentration of somatostatin. These findings show that somatostatin is predominantly an excitatory agent when applied to cortical neurons, but it may cause several different changes in membrane properties. The dose response data suggest a considerable complexity of the actions of somatostatin at a cellular level.