CB1 cannabinoid receptors located at presynaptic sites suppress synaptic transmission in the rat brain. The aim of this work was to examine by single-unit extracellular techniques the effect of the synthetic cannabinoid receptor agonist WIN 55212-2 on KCl-evoked excitation of locus coeruleus neurons in rat brain slices. Short applications of KCl (30 mM) increased by 9-fold the firing rate of locus coeruleus cells. Perfusion with the GABAA receptor antagonist picrotoxin (100 μM) increased KCl-evoked effect, whereas NMDA and non-NMDA glutamate receptor antagonists (D-AP5 100 μM and CNQX 30 μM, respectively) were able to decrease KCl-evoked effect only in the presence of picrotoxin (100 μM). Bath application of WIN 55212-2 (10 μM) inhibited KCl-evoked effect; this inhibition was blocked by the CB1 receptor antagonist AM 251 (1 μM). However, a lower concentration of WIN 55212-2 (1 μM) did not significantly change KCl effect. In the presence of picrotoxin (100 μM), perfusion with D-AP5 (100 μM) or CNQX (30 μM) blocked WIN 55212-2-induced inhibition, although picrotoxin (100 μM) itself failed to affect cannabinoid effect. In conclusion, GABAergic and glutamatergic components are both involved in KCl-evoked excitation of LC neurons, although CB1 receptors only seem to inhibit the glutamatergic component of KCl effect in the locus coeruleus.