Electrophysiological experiments using intracellular recording techniques and extracellular pharmacologic applications have been performed on mouse spinal neurons and pituitary cells grown in tissue culture and on molluscan central neurons. The research has focussed on the mechanisms or how endogenous and exogenous ligands alter neuronal excitability. We have found that endogenous amino acids, peptides, purines and pyrimidines and exogenous benxodiazepines and barbiturates can all produce transmitter-like effects on cultured neurons. We have also found that certain pharmacological agents can have direct effects on non-synaptic membranes. We have applied "fluctuation" analysis to the transmitter-like actions and find that both endogeous and exogenous agents act in a similar manner to open ion channels. We have begun to characterize other forms of chemical excitability revealed by pharmacological applications of these substances. One insight we plan to pursue is the notion that the pharmacologic actions of some drugs may be mediated through receptors for endogenous ligands.