A search was made in sympathetic ganglia of the bullfrog for a noncholinergic, nonaminergic transmitter that is released by a distinct group of preganglionic axons. These initiate a late slow excitatory postsynaptic potential which lasts for many minutes. The most promising candidate for the role of transmitter is a peptide that resembles luteinizing hormone-releasing hormone (LHRH; luliberin). The reasons are: (i) LHRH (1 muM) and some of its analogs cause a slow depolarization of ganglion cells. (ii) Radioimmunoassays established that 100-800 pg of a LHRH-like substance is contained in the lumbar chain of sympathetic ganglia. (iii) The LHRH-like material is specifically distributed in those spinal nerves that contain axons that initiate the slow noncholinergic synaptic responses. (iv) Five days after ipsilateral preganglionic axons are cut, 95% of the LHRH-like substance disappears from ganglia, while the LHRH immunoreactivity triples in the spinal nerves proximal to the cut region. (v) About 0.6% of the LHRH-like material within ganglia can be collected from the perfusate after 30 min of incubation in isotonic KC1; this release is Ca dependent. (vi) The candidate for transmitter has several chemical characteristics of a peptide and has a Mr near 1000.