Various lithium (Li(+)) compounds have been proven to be effective in the therapy of bipolar affective disorder, but their mechanism of pharmacological action is not clearly defined. In our present in vivo electrophysiological study we tested the action of microiontophoretically applied Li(+) and NE on the maintained firing activity of prefrontal cortical neurons of the rat. Target cells were located in the prelimbic cortical projection region (PrL) of the ascending norepinephrinergic pathway. Our data, collected from single unit activity of 59 PrL neurons, demonstrate that lithium can (1) suppress maintained discharge activity, or (2) antagonize both the inhibitory and excitatory modulation of firing activity elicited by NE. These effects of Li(+) were not replicable with GABA-initiated inhibition or glutamate analogue-initiated excitation of discharge activity. Our findings suggest that the action of Li(+) mainly targets the NE-coupled receptor mechanisms and, therefore, it may play an important role in stabilizing the modulation of discharge activity in the PFC caused by different extracellular levels of NE.