Autoradiographic characterization of binding sites for [3H]milnacipran, a new antidepressant drug, and their relationship to the serotonin transporter in rat brain.
Milnacipran is a new antidepressant drug and an equipotent inhibitor of the uptake of serotonin and noradrenaline. Quantitative autoradiography and radioligand binding studies were used to characterize recognition sites of [3H]milnacipran in rat brain. [3H]Milnacipran demonstrated saturable, reversible and nanomolar affinity binding. The binding was Na(+)-dependent, potently displaced by serotonin uptake inhibitors in all structures and moderately or weakly displaced by catecholamine uptake inhibitors (order of potency: paroxetine > fluoxetine > mazindol > desipramine > nomifensine > maprotiline). High density of recognition sites were found in structures dense in serotonergic innervation (raphe, basal ganglia, colliculi, cortex). The autoradiographic pattern of [3H]milnacipran recognition sites resembled that of [3H]paroxetine, but their distribution did not correlate well in some structures. Selective lesioning of serotonergic neurons by intracerebral injection of 5,7-dihydroxytryptamine caused a large decrease of [3H]milnacipran binding in various regions (septum, caudate, hippocampus, thalamus, ventral and dorsal hypothalamus), but in other structures, the [3H]milnacipran binding was partially affected (putamen) or even unchanged (amygdala, lateral hypothalamus). In contrast, lesion of noradrenergic neurons by intraperitoneal administration of [N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine] did not affect the binding of [3H]milnacipran in any region. These results show that [3H]milnacipran mainly binds to the serotonin transporter and does not recognize the catecholamine transporters under the conditions used. In addition, [3H]milnacipran might also bind to other sites, serotonin transporter localized on non-serotonergic neurons or serotonergic neurons insensitive to 5,7-DHT neurotoxicity.
Barone
P
P
Laboratoire de pharmacologie N.I.E., Institut Pasteur, Paris, France.
Moret
C
C
Briley
M
M
Fillion
G
G
D015116:5,7-Dihydroxytryptamine; D000818:Animals; D001345:Autoradiography; D001596:Benzylamines; D001665:Binding Sites; D001667:Binding, Competitive; D001692:Biological Transport; D001921:Brain / Q000187:drug effects; D001923:Brain Chemistry; D003521:Cyclopropanes / Q000494:pharmacology*; D000078764:Milnacipran; D017374:Paroxetine; D051381:Rats; D017208:Rats, Wistar; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D014316:Tritium
D001596:Benzylamines; D003521:Cyclopropanes; D017366:Serotonin Receptor Agonists; D014316:Tritium; D015116:5,7-Dihydroxytryptamine; D017374:Paroxetine; D000078764:Milnacipran; C012102:DSP 4