Galanin exerts an inhibitory effect on locus coeruleus (LC) neurons via a postsynaptic, as yet unidentified galanin receptor. Using an in vitro intracellular recording technique the effect of two galanin receptor agonists on LC neurons was investigated. Bath application of [Sar(1), D-Ala(12)]gal(1-16)-NH(2) (AR-M961), an agonist both at galanin R1 and R2 (GALR1, GALR2) receptors, evoked a reversible membrane hyperpolarization and inhibition of spike discharge in all LC neurons tested (n=42). The action of AR-M961 was blocked by tetraethylammonium chloride. Hyperpolarizing responses induced by AR-M961 were retained in the presence of tetrodotoxin and high Mg(2+)/low Ca(2+) media. The selective GALR2 agonist Gal(2-11)-NH(2) (AR-M1896) only caused inhibition of spike discharge and a slight hyperpolarization in 26 of 34 LC neurons tested, and was on a molar basis much weaker than AR-M961. These results suggest that it mainly is the GALR1 receptor that mediates hyperpolarization of LC neurons.