Baclofen causes a concentration-dependent inhibition of spontaneous firing, hyperpolarization and resistance decrease in locus coeruleus (LC) neurons recorded intracellularly in a brain slice preparation. The (-) isomer is active while the (+) isomer has little or no activity which indicates that the baclofen effect is stereoselective. Baclofen action on LC neurons is a direct postsynaptic effect since it remains in low Ca2+, high Mg2+ media. Baclofen actions on LC neurons are resistant to the GABAA antagonist bicuculline. The baclofen-induced hyperpolarization reverses at the K+ equilibrium potential, as estimated by the reversal potential of the post-stimulus hyperpolarization which follows an evoked train of action potentials. When the K+ concentration in the superfusion media is increased, the reversal potential for the baclofen-induced hyperpolarization shifts linearly with a slope of 61 mV per 10-fold change as predicted by the Nernst equation for a pure K+ conductance. The baclofen-induced K+ conductance increase is prevented by addition of the K+-channel blocker Ba2+ to the external media. Taken together, these data suggest that baclofen directly hyperpolarizes LC neurons by activation of GABAB receptors which leads to an increase in K+ conductance.