EFFECTS OF THE PUTATIVE ANTIDEPRESSANT, ABT-200, ON THE CLEARANCE OF EXOGENOUS NOREPINEPHRINE IN RAT CEREBELLUM

ABT 200 methylenedioxy-1'-naphthalenyl-methyl]-pyrrolidine methanesulf onate] is a potent alpha(2)-adrenoceptor antagonist (Ki = 1.2 nM) with modest norepinephrine uptake-blocking activity (IC50 = 841 nM) that i s currently under clinical evaluation as an antidepressant. The effect s of ABT 200, nomifensine (an inhibitor of catecholamine uptake), and rauwolscine (a selective alpha(2)-adrenoceptor antagonist) on the clea rance of exogenous norepinephrine in the cerebellum of urethane-anesth etized rats was investigated using a vivo electrochemistry. Chronoampe rometric recordings were continuously made at 5 Hz using Nafron-coated , single carbon fiber electrodes. When a calibrated amount of norepine phrine was pressure-ejected at 5-min intervals from a micropipette adj acent (290-330 mu M) to the electrode, transient and reproducible nore pinephrine signals were detected. In response to systemic ABT 200 (30 mg/kg i.p.) or nomifensine (30 mg/kg i.p.), the signals increased in b oth amplitude and time course, indicating significant inhibition of th e norepinephrine transporter. A lower dose (15 mg/kg i.p.) of either A BT 200 or nomifensine had no effect in this paradigm. Local applicatio n of ABT 200 (400 mu M) or nomifensine (400 mu M) prior to pressure-ej ection of norepinephrine also significantly increased the amplitude an d time course of the norepinephrine signals. In contrast, systemic adm inistration of rauwolscine (30 mg/kg i.p.) or vehicle solution, and lo cal application of vehicle solution, had no effect on the norepinephri ne signals. These data indicate that at the higher dose evaluated,both ABT 200 and nomifensine inhibit cerebellar norepinephrine uptake in v ivo. (C) 1995 Wiley-Liss, Inc.