Phencyclidine (PCP) was examined for its ability to modulate histamine release from rat brain slices labeled with L-[3H]histidine. PCP failed to mimic but completely reversed the autoinhibitory effect of histamine at H3-receptors with an apparent Ki value of 13 +/- 3 microM. A direct interaction of PCP with H3-autoreceptors rather than PCP or sigma receptor sites was confirmed by binding studies. PCP inhibited the binding of [3H](R)alpha-methylhistamine to H3-receptor sites in rat cerebral membranes with a Ki value of 25 +/- 2 microM. It is concluded that PCP is a H3-receptor antagonist of moderate potency.