BEHAVIORAL AND BIOCHEMICAL EFFECTS OF THE ANTI-DEPRESSANT BUPROPION (WELLBUTRIN) - EVIDENCE FOR SELECTIVE BLOCKADE OF DOPAMINE UPTAKE INVIVO

Abstract

Bupropion (BW 323U; Wellbutrin) [(.+-.)-.alpha.-tert-butylamino-3-chloropropiophenone HCl], a novel compound with antidepressant effects in man, reduced immobility in an experimental-helplessness, forced-swimming-antidepressant test in rats, as did imipramine and amitriptyline. Higher doses elevated locomotor activity in an automated open field and produced stereotyped sniffing, which was contrasted with apomorphine. When bupropion or desmethylimipramine was given before intracisternal injections of 6-hydroxydopamine, bupropion produced a dose-related selective antagonism of the destruction of dopamine [DA] neurons; under the same conditions, desmethylimipramine produced a dose-related selective antagonism of the destruction of noradrenergic neurons. Studies in which the dose of bupropion and the dose of 6-hydroxydopamine were varied revealed that a dose-related selective antagonism of DA depletion by 6-hydroxydopamine occurred when doses up to, and including, 50 mg/kg i.p. of bupropion were administered. Some antagonism of norepinephrine [NE] depletion occurred at 100 mg/kg of bupropion i.p. Bupropion selectively reversed the DA depletion produced by .alpha.-methyl-m-tyrosine, apparently bupropion is a DA uptake inhibitor in vivo. The importance of DA systems for the behavioral effects of bupropion were studied. When the locomotor stimulant effects of bupropion were tested in rats with chronic destruction of DA neurons, produced by 6-hydroxydopamine, bupropion failed to elevate locomotor activity. Rats treated in experiments using 6-hydroxydopamine to produce relatively selective NE depletions responded to bupropion with locomotor activity, stimulation-like controls. Rats with similar depletions of DA or NE were tested for the ability of low doses of bupropion to reduce immobility in the experimental-helplessness, forced-swimming-antidepressant test. Prior destruction of DA neurons prevented activity of bupropion in this test. Bupropion is a selective DA uptake inhibitor in vivo, and dopaminergic systems play an important role in its CNS pharmacology.