The present study was designed to determine the relationship between the discharge of noradrenergic locus coeruleus (LC) neurons and norepinephrine release in the medial prefrontal cortex, a target of LC projections. The LC was electrically stimulated at varying frequencies and patterns for 20 min and extracellular norepinephrine levels were measured in the medial prefrontal cortex of halothane-anesthetized rats using in vivo microdialysis. Electrical stimulation of the LC at 3-10 Hz with an evenly spaced pattern of pulses (tonic stimulation) increased cortical norepinephrine levels in a frequency-dependent manner, with 5- and 10-Hz stimulation increasing norepinephrine levels by 49 +/- 3% and 66 +/- 20%, respectively. The LC was also stimulated with bursts of pulses designed to deliver physiologically relevant phasic stimulation using the same number of stimuli in a 20-min period as delivered by tonic stimulation at 3 Hz. Results revealed that norepinephrine levels were significantly higher with phasic stimulation compared to tonic stimulation. The present findings indicate that both frequency and pattern of LC discharge are determinants of norepinephrine terminal release. Additionally, bursts of LC activity, similar to those that occur in behaving animals, may be more effective in increasing terminal norepinephrine release on a per spike basis than tonic increases in activity.