Comparison of the effects of bupropion on nicotinic receptor-evoked [(3)H]dopamine release from rat striatal synaptosomes and slices.
Tobacco smoking is a nicotine addiction, mediated in part by the ability of nicotine to elicit dopamine release, as a result of the stimulation of nicotinic acetylcholine receptors associated with dopaminergic pathways. The smoking cessation agent bupropion is an inhibitor of the dopamine transporter, but has also been shown to inhibit nicotinic acetylcholine receptors. To assess the relative impact of its actions at these two targets, we have examined the effects of bupropion on nicotine-evoked [(3)H]dopamine release from rat striatal synaptosomes and slices, in the absence of any other transporter inhibitor. Bupropion (10 microM) significantly decreased nicotine-evoked [(3)H]dopamine release by approximately 50% in both preparations, consistent with the blockade of nicotinic receptors. In support of this interpretation, bupropion also selectively inhibited nicotine-evoked Ca(2+) increases in SH-SY5Y cells. In striatal slices (but not in synaptosomes) the concentration-response profile for bupropion has an inverted 'u' shape, with a decrease in nicotine-evoked [(3)H]dopamine release also observed in the presence of 0.1 microM bupropion. This effect of 0.1 microM bupropion (but not 10 microM bupropion) was reversed by the dopamine D(2) receptor antagonist raclopride. We propose that modest blockade of the dopamine transporter by low concentrations of bupropion results in feedback inhibition via dopamine D(2) autoreceptors. This is overcome at higher concentrations of bupropion, before inhibition of nicotinic receptors occurs. Therefore bupropion's inhibition of the dopamine transporter and nicotinic receptors appears to be separated with respect to concentration.
Sidhpura
Nimish
N
Department of Biology and Biochemistry, University of Bath, Bath BA2 7AY, UK.
Redfern
Peter
P
Wonnacott
Susan
S
D000818:Animals; D016642:Bupropion / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors*; D066298:In Vitro Techniques; D008297:Male; D009538:Nicotine / Q000494:pharmacology; D018722:Nicotinic Agonists / Q000494:pharmacology; D018733:Nicotinic Antagonists / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000187:drug effects* / Q000502:physiology; D013574:Synaptosomes / Q000187:drug effects* / Q000378:metabolism
D050483:Dopamine Plasma Membrane Transport Proteins; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic; D016642:Bupropion; D009538:Nicotine; D002118:Calcium; D004298:Dopamine