DOPAMINERGIC MEDIATION OF THE DISCRIMINATIVE STIMULUS EFFECTS OF BUPROPION IN RATS

Bupropion is a novel, non-tricyclic antidepressant with a primary phar macological action of monoamine uptake inhibition. The drug resembles a psychostimulant in terms of its neurochemical and behavioural profil es in vivo, but it does not reliably produce stimulant-like effects in humans at clinically prescribed doses. Bupropion binds with modest se lectivity to the dopamine transporter, but its behavioural effects hav e often been attributed to its inhibition of norepinephrine uptake. Th is experiment examines monoaminergic involvement in the discriminative stimulus effects of bupropion. Rats were trained to press one lever w hen injected IP with bupropion (17.0 mg/kg), and another lever when in jected with saline. In substitution tests, dose-response curves were o btained for several monoamine uptake inhibitors. Nine of ten dopamine uptake blockers fully substituted fbr bupropion; the exception, indatr aline (LU 19-005), partially substituted (71% bupropion-appropriate re sponding). Serotonin and norepinephrine uptake blockers (zimelidine an d nisoxetine, respectively) produced negligible or limited substitutio n, and the anti-muscarinic dopamine uptake blocker benztropine produce d limited partial substitution. A series of dopamine D-1-like and D-2- like receptor agonists were also tested: only the D-2-like agonist RU 24213 fully substituted; three other D-2-like agonists and four D-1-li ke agonists partially substituted (50% < drug responding < 80%). Antag onism of the discriminative effects of bupropion was obtained with a D -1- and a D-2-like dopamine antagonist. The results demonstrate strong similarities with those obtained using other dopamine uptake inhibito rs as training drugs, and support the view that the behavioural effect s of bupropion are primarily mediated by dopaminergic mechanisms.