Microinfusion of calcium (Ca++)-free artificial cerebrospinal fluid onto locus coeruleus (LC) neurons in vivo potently increased their discharge rate, while response of these cells to a sensory stimulus was significantly reduced. These effects resulted in part from interference with the calcium-dependent potassium conductance in these neurons, as microinfusions of solutions having barium substituted for calcium partially mimicked the effects of Ca(++)-free infusions. In addition, microinfusion of control medium containing the Ca++ channel blocker, cadmium (2-20 mM), also mimicked the effect of the Ca(++)-free solution. This study presents an effective means by which extracellular concentrations of neuromodulatory ions can be manipulated in vivo. In addition, these results indicate that extracellular Ca++ potently modulates the spontaneous as well as evoked activity of central noradrenergic neurons in vivo.