ABT 200 [(RR,SS)-3-phenyl-l-~l',2',3',4'-tetrahydro-5',6'-methylenedioxy-1'-naphthalenyl-methyl]-pyrrolidine methanesulfonate] is a potent alpha2-adrenoceptor antagonist (Ki = 1.2 nM) with modest norepinephrine uptake-blocking activity (ICs0 = 841 nM) that is currently under clinical evaluation as an antidepressant. The effects of ABT 200, nomifensine (an inhibitor of catecholamine uptake), and rauwolscine (a selective alpha2-adrenoceptor antagonist) on the clearance of exogenous norepinephrine in the cerebellum of urethane-anesthetized rats was investigated using a vivo electrochemistry. Chronoamperometric recordings were continuously made at 5 Hz using Nafion-coated, single carbon fiber electrodes. When a calibrated amount of norepinephrine was pressure-ejected at 5-min intervals from a micropipette adjacent (290-330 pM) to the electrode, transient and reproducible norepinephrine signals were detected. In response to systemic ABT 200 (30 mgkg i.p.) or nomifensine (30 mgkg i.p.1, the signals increased in both amplitude and time course, indicating significant inhibition of the norepinephrine transporter. A lower dose (15 mgkg i.p.) of either ABT 200 or nomifensine had no effect in this paradigm. Local application of ABT 200 (400 yM) or nomifensine (400 yM) prior to pressure-ejection of norepinephrine also significantly increased the amplitude and time course of the norepinephrine signals. In contrast, systemic administration of rauwolscine (30 mgkg i.p.) or vehicle solution, and local application of vehicle solution, had no effect on the norepinephrine signals. These data indicate that at the higher dose evaluated,both ABT 200 and nomifensine inhibit cerebellar norepinephrine uptake in vivo. o 1995 Wiley-Liss, Inc.